@article{galiakhmetov_shah_lane_davern_proulx_nevzorov_2024, title={Peptoid-based macrodiscs of variable lipid composition for structural studies of membrane proteins by oriented-sample solid-state NMR}, volume={9}, ISSN={["2590-1524"]}, DOI={10.1016/j.yjsbx.2023.100095}, abstractNote={Solid-state Nuclear Magnetic Resonance (NMR) in combination with magnetically aligned discoidal lipid mimics allows for studying the conformations of membrane proteins in planar, lipid-rich bilayer environments and at the physiological temperature. We have recently demonstrated the general applicability of macrodiscs composed of DMPC lipids and peptoid belts, which yield magnetic alignment and NMR spectroscopic resolution comparable or superior to detergent-containing bicelles. Here we report on a considerable improvement in the magnetic alignment and NMR resolution of peptoid-based macrodiscs consisting of a mixture of the zwitterionic and negatively charged lipids (DMPC/DMPG at the 85% to 15% molar ratio). The resulting linewidths are about 30% sharper due to the higher orientational order parameter likely arising from the stabilizing electrostatic repulsion between the discs. Moreover, highly aligned, detergent-free macrodiscs can be formed with a longer-chain lipid, DPPC. Interestingly, the spectra of Pf1 in the two lipid mimetics are almost indistinguishable, which would mean that the overall transmembrane helix tilt might be governed not only by the hydrophobic matching but also possibly by the interactions of the flanking lysine and arginine residues at the membrane interface.}, journal={JOURNAL OF STRUCTURAL BIOLOGY-X}, author={Galiakhmetov, Azamat R. and Shah, Adit A. and Lane, Addison and Davern, Carolynn M. and Proulx, Caroline and Nevzorov, Alexander A.}, year={2024}, month={Jun} }
 @article{davern_proulx_2023, title={Late-Stage Chloride Displacements Enable Access to Peptoids with cis-Inducing Alkylammonium Side Chains}, volume={8}, ISSN={["1523-7052"]}, DOI={10.1021/acs.orglett.3c02393}, abstractNote={The synthesis of peptoids possessing multiple cis-inducing monomers with alkylammonium side chains is reported, where chloropropyl side chains are diversified on a solid support by late-stage SN2 displacements with amines. The conditions were optimized for a wide variety of primary, secondary, and tertiary alkyl amine nucleophiles. We also demonstrated that multiple chloride displacements could be achieved on sequences possessing trans-inducing N-aryl- and N-imino glycine monomers.}, journal={ORGANIC LETTERS}, author={Davern, Carolynn M. and Proulx, Caroline}, year={2023}, month={Aug} }
 @article{galiakhmetov_davern_esteves_awosanya_guthrie_proulx_nevzorov_2022, title={Aligned peptoid-based macrodiscs for structural studies of membrane proteins by oriented-sample NMR}, volume={121}, ISSN={["1542-0086"]}, DOI={10.1016/j.bpj.2022.07.024}, abstractNote={Development of a robust, uniform, and magnetically orientable lipid mimetic will undoubtedly advance solid-state NMR of macroscopically aligned membrane proteins. Here, we report on a novel lipid membrane mimetic based on peptoid belts. The peptoids, composed of 15 residues, were synthesized by alternating N-(2-phenethyl)glycine with N-(2-carboxyethyl)glycine residues at a 2:1 molar ratio. The chemically synthesized peptoids possess a much lower degree of polydispersity versus styrene-maleic acid polymers, thus yielding uniform discs. Moreover, the peptoid oligomers are more flexible and do not require a specific folding, unlike lipoproteins, in order to wrap around the hydrophobic membrane core. The NMR spectra measured for the membrane-bound form of Pf1 coat protein incorporated in this new lipid mimetics demonstrate a higher order parameter and uniform linewidths compared with the conventional bicelles and peptide-based macrodiscs. Importantly, unlike bicelles, the peptoid-based macrodiscs are detergent free.}, number={17}, journal={BIOPHYSICAL JOURNAL}, author={Galiakhmetov, Azamat R. and Davern, Carolynn M. and Esteves, Richard J. A. and Awosanya, Emmanuel O. and Guthrie, Quibria A. E. and Proulx, Caroline and Nevzorov, Alexander A.}, year={2022}, month={Sep}, pages={3263–3270} }
 @article{bowles_proulx_2022, title={Late-Stage N-Alkylation of Azapeptides}, volume={24}, ISSN={["1523-7052"]}, DOI={10.1021/acs.orglett.2c00046}, abstractNote={Azapeptides undergo on-resin, late-stage N-alkylations to install side chains with high chemoselectivity for the hydrazide nitrogen atoms. The major product is the N1-alkylated "azapeptoid", with only small amounts (<10%) of alkylation occurring at the other aza-amino acid nitrogen (N2). Dialkylations are also possible and afford highly functionalized, disubstituted azapeptides with side chains installed on both aza-amino acid nitrogen atoms. The site-selectivity was determined using Edman degradation, MS/MS sequencing, and comparative LCMS and NMR analyses.}, number={9}, journal={ORGANIC LETTERS}, author={Bowles, Maxwell O. and Proulx, Caroline}, year={2022}, month={Mar}, pages={1768–1773} }
 @article{young_proulx_2022, title={On-resin C alpha-functionalization of N-arylglycinyl peptides with boronic acids}, volume={5}, ISSN={["1477-0539"]}, DOI={10.1039/d2ob00524g}, abstractNote={A late-stage α-C–H functionalization reaction of resin-bound, electron-rich N-aryl peptides with boronic acid nucleophiles under mild conditions is reported.}, journal={ORGANIC & BIOMOLECULAR CHEMISTRY}, author={Young, Hailey A. and Proulx, Caroline}, year={2022}, month={May} }
 @article{bowles_proulx_2021, title={Solid phase submonomer azapeptide synthesis}, volume={656}, ISSN={["0076-6879"]}, DOI={10.1016/bs.mie.2021.04.020}, abstractNote={Azapeptides contain at least one aza-amino acid, where the α-carbon has been replaced by a nitrogen atom, and have found broad applicability in fields ranging from medicinal chemistry to biomaterials. In this chapter, we provide a step-by-step protocol for the solid phase submonomer synthesis of azapeptides, which includes three steps: (1) hydrazone activation and coupling onto a resin-bound peptide, (2) chemoselective semicarbazone functionalization for installation of the aza-amino acid side chain, and (3) orthogonal deprotection of the semicarbazone to complete the monomer addition cycle. We focus on semicarbazone functionalization by N-alkylation with primary alkyl halides, and describe conditions for coupling onto aza-amino acids. Such divergent methods accelerate the synthesis of peptidomimetics and allow the rapid introduction of a wide variety of natural and unnatural side chains directly on solid support using easily accessible submonomers.}, journal={SYNTHETIC AND ENZYMATIC MODIFICATIONS OF THE PEPTIDE BACKBONE}, author={Bowles, Maxwell and Proulx, Caroline}, year={2021}, pages={169–190} }
 @article{davern_lowe_rosfi_ison_proulx_2021, title={Submonomer synthesis of peptoids containing trans-inducing N-imino- and N-alkylamino-glycines}, volume={5}, ISSN={["2041-6539"]}, DOI={10.1039/d1sc00717c}, abstractNote={The use of hydrazones as a new type of submonomer in peptoid synthesis is described, giving access to peptoid monomers that are structure-inducing.}, journal={CHEMICAL SCIENCE}, author={Davern, Carolynn M. and Lowe, Brandon D. and Rosfi, Adam and Ison, Elon A. and Proulx, Caroline}, year={2021}, month={May} }
 @article{fregeau_sarduy_elimam_esposito_mellal_menard_graca_proulx_zhang_febbraio_et al._2020, title={Atheroprotective and atheroregressive potential of azapeptide derivatives of GHRP-6 as selective CD36 ligands in apolipoprotein E-deficient mice}, volume={307}, ISSN={["1879-1484"]}, DOI={10.1016/j.atherosclerosis.2020.06.010}, abstractNote={Background and aimsScavenger receptor class B member 3, also known as cluster of differentiation-36 (CD36) receptor, is involved in the uptake and accumulation of modified lipoprotein in macrophages, driving atherosclerosis progression. Azapeptide analogs of growth hormone-releasing peptide-6 (GHRP-6) have been developed as selective CD36 ligands and evaluated for their anti-atherosclerotic properties in apoe−/− mice.MethodsFrom 4 to 19 weeks of age, male apoe−/− mice were fed a high fat high cholesterol (HFHC) diet, then switched to normal chow and treated daily with 300 nmol/kg of MPE-001 ([aza-Tyr4]-GHRP-6) or MPE-003 ([aza-(N,N-diallylaminobut-2-ynyl)Gly4]-GHRP-6) for 9 weeks. In another protocol, mice were fed a HFHC diet throughout the study.ResultsAzapeptides decreased lesion progression in the aortic arch and reduced aortic sinus lesion areas below pre-existing lesions levels in apoe−/− mice which were switched to chow diet. In mice fed a HFHC throughout the study, azapeptides reduced lesion progression in the aortic vessel and sinus. The anti-atherosclerotic effect of azapeptides was associated with a reduced ratio of iNOS+/CD206+ macrophages within lesions, and lowered plasma inflammatory cytokine levels. Monocytes from azapeptide-treated mice showed altered mitochondrial oxygen consumption rates, consistent with an M2-like phenotype. These effects were dependent on CD36, and not observed in apoe−/−cd36−/− mice.ConclusionsAzapeptides MPE-001 and MPE-003 diminished aortic lesion progression and reduced, below pre-existing levels, lesions in the aortic sinus of atherosclerotic mice. A relative increase of M2-like macrophages was observed in lesions, associated with reduced systemic inflammation. Development of CD36-selective azapeptide ligands merits consideration for treating atherosclerotic disease.}, journal={ATHEROSCLEROSIS}, author={Fregeau, Genevieve and Sarduy, Roger and Elimam, Hanan and Esposito, Cloe L. and Mellal, Katia and Menard, Liliane and Graca, Silas D. Leitao da and Proulx, Caroline and Zhang, Jinqiang and Febbraio, Maria and et al.}, year={2020}, month={Aug}, pages={52–62} }
 @article{proulx_2020, title={Catching up to nature's ribosomes}, volume={368}, ISSN={["1095-9203"]}, DOI={10.1126/science.abb9711}, abstractNote={Flow chemistry enables total chemical synthesis of proteins without solution-phase ligation}, number={6494}, journal={SCIENCE}, author={Proulx, Caroline}, year={2020}, month={May}, pages={941–941} }
 @article{young_guthrie_proulx_2020, title={N-Arylation of Amino Acid Esters to Expand Side Chain Diversity in Ketoxime Peptide Ligations}, volume={85}, ISSN={["1520-6904"]}, DOI={10.1021/acs.joc.9b02810}, abstractNote={Palladium-catalyzed N-arylations of amino acid tert-butyl esters using 4-bromo-N,N-dimethylaniline as a coupling partner are reported. The resulting N-aryl amino acid esters are suitable building blocks for the synthesis of electron-rich N-aryl peptides, which undergo oxidative couplings to aminooxy groups to afford ketoxime peptides under mild conditions. N-aryl amino acid tert-butyl esters possessing unnatural side chains were also accessed via glycine Schiff base alkylation, further increasing the scope of Cα-substitution in ketoxime peptides.}, number={3}, journal={JOURNAL OF ORGANIC CHEMISTRY}, author={Young, Hailey A. and Guthrie, Quibria A. E. and Proulx, Caroline}, year={2020}, month={Feb}, pages={1748–1755} }
 @misc{reese_shanahan_proulx_menegatti_2020, title={Peptide science: A "rule model" for new generations of peptidomimetics}, volume={102}, ISSN={["1878-7568"]}, DOI={10.1016/j.actbio.2019.10.045}, abstractNote={Peptides have been heavily investigated for their biocompatible and bioactive properties. Though a wide array of functionalities can be introduced by varying the amino acid sequence or by structural constraints, properties such as proteolytic stability, catalytic activity, and phase behavior in solution are difficult or impossible to impart upon naturally occurring α-L-peptides. To this end, sequence-controlled peptidomimetics exhibit new folds, morphologies, and chemical modifications that create new structures and functions. The study of these new classes of polymers, especially α-peptoids, has been highly influenced by the analysis, computational, and design techniques developed for peptides. This review examines techniques to determine primary, secondary, and tertiary structure of peptides, and how they have been adapted to investigate peptoid structure. Computational models developed for peptides have been modified to predict the morphologies of peptoids and have increased in accuracy in recent years. The combination of in vitro and in silico techniques have led to secondary and tertiary structure design principles that mirror those for peptides. We then examine several important developments in peptoid applications inspired by peptides such as pharmaceuticals, catalysis, and protein-binding. A brief survey of alternative backbone structures and research investigating these peptidomimetics shows how the advancement of peptide and peptoid science has influenced the growth of numerous fields of study. As peptide, peptoid, and other peptidomimetic studies continue to advance, we will expect to see higher throughput structural analyses, greater computational accuracy and functionality, and wider application space that can improve human health, solve environmental challenges, and meet industrial needs. Many historical, chemical, and functional relations draw a thread connecting peptides to their recent cognates, the “peptidomimetics”. This review presents a comprehensive survey of this field by highlighting the width and relevance of these familial connections. In the first section, we examine the experimental and computational techniques originally developed for peptides and their morphing into a broader analytical and predictive toolbox. The second section presents an excursus of the structures and properties of prominent peptidomimetics, and how the expansion of the chemical and structural diversity has returned new exciting properties. The third section presents an overview of technological applications and new families of peptidomimetics. As the field grows, new compounds emerge with clear potential in medicine and advanced manufacturing.}, journal={ACTA BIOMATERIALIA}, author={Reese, Hannah R. and Shanahan, Calvin C. and Proulx, Caroline and Menegatti, Stefano}, year={2020}, month={Jan}, pages={35–74} }
 @misc{proulx_zhang_sabatino_chemtob_ong_lubell_2020, title={Synthesis and Biomedical Potential of Azapeptide Modulators of the Cluster of Differentiation 36 Receptor (CD36)}, volume={8}, ISSN={["2227-9059"]}, DOI={10.3390/biomedicines8080241}, abstractNote={The innovative development of azapeptide analogues of growth hormone releasing peptide-6 (GHRP-6) has produced selective modulators of the cluster of differentiation 36 receptor (CD36). The azapeptide CD36 modulators curb macrophage-driven inflammation and mitigate atherosclerotic and angiogenic pathology. In macrophages activated with Toll-like receptor-2 heterodimer agonist, they reduced nitric oxide production and proinflammatory cytokine release. In a mouse choroidal explant microvascular sprouting model, they inhibited neovascularization. In murine models of cardiovascular injury, CD36-selective azapeptide modulators exhibited cardioprotective and anti-atherosclerotic effects. In subretinal inflammation models, they altered activated mononuclear phagocyte metabolism and decreased immune responses to alleviate subsequent inflammation-dependent neuronal injury associated with retinitis pigmentosa, diabetic retinopathy and age-related macular degeneration. The translation of GHRP-6 to potent and selective linear and cyclic azapeptide modulators of CD36 is outlined in this review which highlights the relevance of turn geometry for activity and the biomedical potential of prototypes for the beneficial treatment of a wide range of cardiovascular, metabolic and immunological disorders.}, number={8}, journal={BIOMEDICINES}, author={Proulx, Caroline and Zhang, Jinqiang and Sabatino, David and Chemtob, Sylvain and Ong, Huy and Lubell, William D.}, year={2020}, month={Aug} }
 @misc{proulx_2019, title={Aerobic oxidation of N-aryl peptides for catalyst-free oxime ligations}, author={Proulx, C.}, year={2019}, month={Nov} }
 @inproceedings{guthrie_proulx_2019, title={Aerobic oxidation of N-phenylglycinyl peptides for catalyst-free oxime ligations}, booktitle={American Chemical Society (ACS) meeting}, author={Guthrie, Q.A.E. and Proulx, C.}, year={2019}, month={Mar} }
 @article{mcmechen_willis_gourville_proulx_2019, title={Aza-Amino Acids Disrupt -Sheet Secondary Structures}, volume={24}, ISSN={["1420-3049"]}, url={https://www.mdpi.com/1420-3049/24/10/1919}, DOI={10.3390/molecules24101919}, abstractNote={Cα to N substitution in aza-amino acids imposes local conformational constraints, changes in hydrogen bonding properties, and leads to adaptive chirality at the nitrogen atom. These properties can be exploited in mimicry and stabilization of peptide secondary structures and self-assembly. Here, the effect of a single aza-amino acid incorporation located in the upper β-strand at a hydrogen-bonded (HB) site of a β-hairpin model peptide (H-Arg-Tyr-Val-Glu-Val-d-Pro-Gly-Orn-Lys-Ile-Leu-Gln-NH2) is reported. Specifically, analogs in which valine3 was substituted for aza-valine3 or aza-glycine3 were synthesized, and their β-hairpin stabilities were examined using Nuclear Magnetic Resonance (NMR) spectroscopy. The azapeptide analogs were found to destabilize β-hairpin formation compared to the parent peptide. The aza-valine3 residue was more disruptive of β-hairpin geometry than its aza-glycine3 counterpart.}, number={10}, journal={MOLECULES}, author={McMechen, Michael A. and Willis, Evan L. and Gourville, Preston C. and Proulx, Caroline}, year={2019}, month={May} }
 @inproceedings{proulx_2019, place={Monterey, CA}, title={In situ oxidation of N-phenylglycinyl peptides for oxime bond formation at neutral pH}, booktitle={American Peptide Symposium 2019}, author={Proulx, C.}, year={2019} }
 @article{guthrie_young_proulx_2019, title={Ketoxime peptide ligations: oxidative couplings of alkoxyamines to N-aryl peptides}, volume={10}, ISSN={["2041-6539"]}, DOI={10.1039/c9sc04028e}, abstractNote={Ketoxime peptides are readily accessible from oxidative couplings between N-aryl peptides and alkoxyamines under catalyst-free conditions.}, number={41}, journal={CHEMICAL SCIENCE}, author={Guthrie, Quibria A. E. and Young, Hailey A. and Proulx, Caroline}, year={2019}, month={Nov}, pages={9506–9512} }
 @inproceedings{proulx_2019, title={New strategies for Ketoxime peptide ligations}, booktitle={Boulder Peptide Symposium 2019}, author={Proulx, C.}, year={2019}, month={Sep} }
 @misc{proulx_2019, title={Oxime ligation via in situ oxidation of N-phenylglycinyl peptides}, author={Proulx, C.}, year={2019}, month={Apr} }
 @article{huynh_bessi_menard_piquereau_proulx_febbraio_lubell_carpentier_burelle_ong_et al._2018, title={Adiponectin has a pivotal role in the cardioprotective effect of CP-3(iv), a selective CD36 azapeptide ligand, after transient coronary artery occlusion in mice}, volume={32}, ISSN={["1530-6860"]}, DOI={10.1096/fj.201700505r}, abstractNote={CD36 is a multiligand receptor involved in lipid metabolism. We investigated the mechanisms underlying the cardioprotective effect of CP‐3(iv), an azapeptide belonging to a new class of selective CD36 ligands. The role of CP‐3(iv) in mediating cardioprotection was investigated because CD36 signaling leads to activation of peroxisome proliferator–activated receptor‐γ, a transcriptional regulator of adiponectin. CP‐3(iv) pretreatment reduced infarct size by 54% and preserved hemodynamics in C57BL/6 mice subjected to 30 min coronary ligation and reperfusion but had no effect in CD36‐deficient mice. The effects of CP‐3(iv) were associated with an increase in circulating adiponectin levels, epididymal fat adiponectin gene expression, and adiponectin transcriptional regulators (Pparg, Cebpb, Sirt1) after 6 h of reperfusion. Reduced myocardial oxidative stress and apoptosis were observed along with an increase in expression of myocardial adiponectin target proteins, including cyclooxygenase‐2, phospho‐AMPK, and phospho‐Akt. Moreover, CP‐3(iv) increased myocardial performance in isolated hearts, whereas blockade of adiponectin with an anti‐adiponectin antibody abrogated it. CP‐3(iv) exerts cardioprotection against myocardial ischemia and reperfusion (MI/R) injury and dysfunction, at least in part, by increasing circulating and myocardial adiponectin levels. Hence, both paracrine and endocrine effects of adiponectin may contribute to reduced reactive oxygen species generation and apoptosis after MI/R, in a CD36‐dependent manner.—Huynh, D. N., Bessi, V. L., Ménard, L., Piquereau, J., Proulx, C., Febbraio, M., Lubell, W. D., Carpentier, A. C., Burelle, Y., Ong, H., Marleau, S. Adiponectin has a pivotal role in the cardioprotective effect of CP‐3(iv), a selective CD36 azapeptide ligand, after transient coronary artery occlusion in mice. FASEB J. 32, 807–818 (2018). www.fasebj.org}, number={2}, journal={FASEB JOURNAL}, author={Huynh, David N. and Bessi, Valerie L. and Menard, Liliane and Piquereau, Jerome and Proulx, Caroline and Febbraio, Maria and Lubell, William D. and Carpentier, Andre C. and Burelle, Yan and Ong, Huy and et al.}, year={2018}, month={Feb}, pages={807–818} }
 @article{battigelli_kim_dehigaspitiya_proulx_robertson_murray_rad_kirshenbaum_zuckermann_2018, title={Glycosylated Peptoid Nanosheets as a Multivalent Scaffold for Protein Recognition}, volume={12}, ISSN={1936-0851 1936-086X}, url={http://dx.doi.org/10.1021/ACSNANO.7B08018}, DOI={10.1021/ACSNANO.7B08018}, abstractNote={Glycoproteins adhered on the cellular membrane play a pivotal role in a wide range of cellular functions. Their importance is particularly relevant in the recognition process between infectious pathogens (such as viruses, bacteria, toxins) and their host cells. Multivalent interactions at the pathogen-cell interfaces govern binding events and can result in a strong and specific interaction. Here we report an approach to mimic the cell surface presentation of carbohydrate ligands by the multivalent display of sugars on the surface of peptoid nanosheets. The constructs provide a highly organized 2D platform for recognition of carbohydrate-binding proteins. The sugars were displayed using different linker lengths or within loops containing 2-6 hydrophilic peptoid monomers. Both the linkers and the loops contained one alkyne-bearing monomer, to which different saccharides were attached by copper-catalyzed azide-alkyne cycloaddition reactions. Peptoid nanosheets functionalized with different saccharide groups were able to selectively bind multivalent lectins, Concanavalin A and Wheat Germ Agglutinin, as observed by fluorescence microscopy and a homogeneous Förster resonance energy transfer (FRET)-based binding assay. To evaluate the potential of this system as sensor for threat agents, the ability of functionalized peptoid nanosheets to bind Shiga toxin was also studied. Peptoid nanosheets were functionalized with globotriose, the natural ligand of Shiga toxin, and the effective binding of the nanomaterial was verified by the FRET-based binding assay. In all cases, evidence for multivalent binding was observed by systematic variation of the ligand display density on the nanosheet surface. These cell surface mimetic nanomaterials may find utility in the inactivation of pathogens or as selective molecular recognition elements.}, number={3}, journal={ACS Nano}, publisher={American Chemical Society (ACS)}, author={Battigelli, Alessia and Kim, Jae Hong and Dehigaspitiya, Dilani C. and Proulx, Caroline and Robertson, Ellen J. and Murray, Daniel J. and Rad, Behzad and Kirshenbaum, Kent and Zuckermann, Ronald N.}, year={2018}, month={Mar}, pages={2455–2465} }
 @article{guthrie_proulx_2018, title={Oxime Ligation via in situ Oxidation of N-Phenylglycinyl Peptides}, volume={20}, ISSN={["1523-7052"]}, DOI={10.1021/acs.orglett.8b00713}, abstractNote={Mild conditions for oxime ligations via in situ generation of α-imino amide intermediates are reported. The evaluation of a variety of N-terminal N-phenylglycine residues revealed that a metal-free, chemoselective oxidation was possible using oxygen as the only oxidant in buffer at pH 7.0. Moreover, selective unmasking of an inert residue by addition of potassium ferricyanide is demonstrated. These simple and mild conditions, which can be fine-tuned by the electronic properties of the N-phenylglycine residue, offer unique advantages over conventional approaches for oxime ligations.}, number={9}, journal={ORGANIC LETTERS}, author={Guthrie, Quibria A. E. and Proulx, Caroline}, year={2018}, month={May}, pages={2564–2567} }
 @inproceedings{guthrie_proulx_2018, title={Oxime ligation via in situ oxidation of N-phenylglycinyl peptides}, author={Guthrie, Q.A. and Proulx, C.}, year={2018}, month={Feb} }
 @misc{chingle_proulx_lubell_2017, title={Azapeptide Synthesis Methods for Expanding Side-Chain Diversity for Biomedical Applications}, volume={50}, ISSN={["1520-4898"]}, DOI={10.1021/acs.accounts.7b00114}, abstractNote={Mimicry of bioactive conformations is critical for peptide-based medicinal chemistry because such peptidomimetics may augment stability, enhance affinity, and increase specificity. Azapeptides are peptidomimetics in which the α-carbon(s) of one or more amino acid residues are substituted by nitrogen. The resulting semicarbazide analogues have been shown to reinforce β-turn conformation through the combination of lone pair-lone pair repulsion of the adjacent hydrazine nitrogen and urea planarity. Substitution of a semicarbazide for an amino amide residue in a peptide may retain biological activity and add benefits such as improved metabolic stability. The applications of azapeptides include receptor ligands, enzyme inhibitors, prodrugs, probes, and imaging agents. Moreover, azapeptides have proven therapeutic utility. For example, the aza-glycinamide analogue of the luteinizing hormone-releasing hormone analogue Zoladex is a potent long-acting agonist currently used in the clinic for the treatment of prostate and breast cancer. However, the use of azapeptides was hampered by tedious solution-phase synthetic routes for selective hydrazine functionalization. A remarkable stride to overcome this bottleneck was made in 2009 through the introduction of the submonomer procedure for azapeptide synthesis, which enabled addition of diverse side chains onto a common semicarbazone intermediate, providing a means to construct azapeptide libraries by solution- and solid-phase chemistry. In brief, aza residues are introduced into the peptide chain using the submonomer strategy by semicarbazone incorporation, deprotonation, N-alkylation, and orthogonal deprotection. Amino acylation of the resulting semicarbazide and elongation gives the desired azapeptide. Since the initial report, a number of chemical transformations have taken advantage of the orthogonal chemistry of semicarbazone residues (e.g., Michael additions and N-arylations). In addition, libraries have been synthesized from libraries by diversification of aza-propargylglycine (e.g., A3 coupling reactions, [1,3]-dipolar cycloadditions, and 5-exo-dig cyclizations) and aza-chloroalkylglycine residues. In addition, oxidation of aza-glycine residues has afforded azopeptides that react in pericyclic reactions (e.g., Diels-Alder and Alder-ene chemistry). The bulk of these transformations of aza-glycine residues have been developed by the Lubell laboratory, which has applied such chemistry in the synthesis of ligands with promising biological activity for treating diseases such as cancer and age-related macular degeneration. Azapeptide analogues of growth hormone-releasing peptide-6 (His-d-Trp-Ala-Trp-d-Phe-Lys-NH2, GHRP-6) have for example been pursued as ligands of the cluster of differentiation 36 receptor (CD36) and show promising activity for the development of treatments for angiogenesis-related diseases, such as age-related macular degeneration, as well as for atherosclerosis. Azapeptides have also been employed to make a series of conformationally constrained second mitochondria-derived activator of caspase (Smac) mimetics that exhibit promising apoptosis-inducing activity in cancer cells. The synthesis of cyclic azapeptide derivatives was used to make an aza scan to study the conformation-activity relationships of the anticancer agent cilengitide, cyclo(RGDf-N(Me)V), and its parent counterpart cyclo(RGDfV), which exhibit potency against human tumor metastasis and tumor-induced angiogenesis. Innovations in the synthesis and application of azapeptides will be presented in this Account, focusing on the creation and use of side-chain diversity in medicinal chemistry.}, number={7}, journal={ACCOUNTS OF CHEMICAL RESEARCH}, author={Chingle, Ramesh and Proulx, Caroline and Lubell, William D.}, year={2017}, month={Jul}, pages={1541–1556} }
 @article{robertson_battigelli_proulx_mannige_haxton_yun_whitelam_zuckermann_2016, title={Design, Synthesis, Assembly, and Engineering of Peptoid Nanosheets}, volume={49}, ISSN={0001-4842 1520-4898}, url={http://dx.doi.org/10.1021/ACS.ACCOUNTS.5B00439}, DOI={10.1021/ACS.ACCOUNTS.5B00439}, abstractNote={Two-dimensional (2D) atomically defined organic nanomaterials are an important material class with broad applications. However, few general synthetic methods exist to produce such materials in high yields and to precisely functionalize them. One strategy to form ordered 2D organic nanomaterials is through the supramolecular assembly of sequence-defined synthetic polymers. Peptoids, one such class of polymer, are designable bioinspired heteropolymers whose main-chain length and monomer sequence can be precisely controlled. We have recently discovered that individual peptoid polymers with a simple sequence of alternating hydrophobic and ionic monomers can self-assemble into highly ordered, free-floating nanosheets. A detailed understanding of their molecular structure and supramolecular assembly dynamics provides a robust platform for the discovery of new classes of nanosheets with tunable properties and novel applications. In this Account, we discuss the discovery, characterization, assembly, molecular modeling, and functionalization of peptoid nanosheets. The fundamental properties of peptoid nanosheets, their mechanism of formation, and their application as robust scaffolds for molecular recognition and as templates for the growth of inorganic minerals have been probed by an arsenal of experimental characterization techniques (e.g., scanning probe, electron, and optical microscopy, X-ray diffraction, surface-selective vibrational spectroscopy, and surface tensiometry) and computational techniques (coarse-grained and atomistic modeling). Peptoid nanosheets are supramolecular assemblies of 16-42-mer chains that form molecular bilayers. They span tens of microns in lateral dimensions and freely float in water. Their component chains are highly ordered, with chains nearly fully extended and packed parallel to one another as a result of hydrophobic and electrostatic interactions. Nanosheets form via a novel interface-catalyzed monolayer collapse mechanism. Peptoid chains first assemble into a monolayer at either an air-water or oil-water interface, on which peptoid chains extend, order, and pack into a brick-like pattern. Upon mechanical compression of the interface, the monolayer buckles into stable bilayer structures. Recent work has focused on the design of nanosheets with tunable properties and functionality. They are readily engineerable, as functional monomers can be readily incorporated onto the nanosheet surface or into the interior. For example, functional hydrophilic "loops" have been displayed on the surfaces of nanosheets. These loops can interact with specific protein targets, serving as a potentially general platform for molecular recognition. Nanosheets can also bind metal ions and serve as 2D templates for mineral growth. Through our understanding of the formation mechanism, along with predicted features ascertained from molecular modeling, we aim to further design and synthesize nanosheets as robust protein mimetics with the potential for unprecedented functionality and stability.}, number={3}, journal={Accounts of Chemical Research}, publisher={American Chemical Society (ACS)}, author={Robertson, Ellen J. and Battigelli, Alessia and Proulx, Caroline and Mannige, Ranjan V. and Haxton, Thomas K. and Yun, Lisa and Whitelam, Stephen and Zuckermann, Ronald N.}, year={2016}, month={Jan}, pages={379–389} }
 @article{flood_proulx_robertson_battigelli_wang_schwartzberg_zuckermann_2016, title={Improved chemical and mechanical stability of peptoid nanosheets by photo-crosslinking the hydrophobic core}, volume={52}, ISSN={1359-7345 1364-548X}, url={http://dx.doi.org/10.1039/C6CC00588H}, DOI={10.1039/C6CC00588H}, abstractNote={Photo-crosslinking produced more robust nanosheets that can survive sonication, lyophilization, and other biochemical manipulations.}, number={26}, journal={Chemical Communications}, publisher={Royal Society of Chemistry (RSC)}, author={Flood, Dillon and Proulx, Caroline and Robertson, Ellen J. and Battigelli, Alessia and Wang, Shuo and Schwartzberg, Adam M. and Zuckermann, Ronald N.}, year={2016}, pages={4753–4756} }
 @article{robertson_proulx_su_garcia_yoo_nehls_connolly_taravati_zuckermann_2016, title={Molecular Engineering of the Peptoid Nanosheet Hydrophobic Core}, volume={32}, ISSN={0743-7463 1520-5827}, url={http://dx.doi.org/10.1021/ACS.LANGMUIR.6B02735}, DOI={10.1021/ACS.LANGMUIR.6B02735}, abstractNote={The relationship between the structure of sequence-defined peptoid polymers and their ability to assemble into well-defined nanostructures is important to the creation of new bioinspired platforms with sophisticated functionality. Here, the hydrophobic N-(2-phenylethyl)glycine (Npe) monomers of the standard nanosheet-forming peptoid sequence were modified in an effort to (1) produce nanosheets from relatively short peptoids, (2) inhibit the aggregation of peptoids in bulk solution, (3) increase nanosheet stability by promoting packing interactions within the hydrophobic core, and (4) produce nanosheets with a nonaromatic hydrophobic core. Fluorescence and optical microscopy of individual nanosheets reveal that certain modifications to the hydrophobic core were well tolerated, whereas others resulted in instability or aggregation or prevented assembly. Importantly, we demonstrate that substitution at the meta and para positions of the Npe aromatic ring are well tolerated, enabling significant opportunities to tune the functional properties of peptoid nanosheets. We also found that N-aryl glycine monomers inhibit nanosheet formation, whereas branched aliphatic monomers have the ability to form nanosheets. An analysis of the crystal structures of several N,N'-disubstituted diketopiperazines (DKPs), a simple model system, revealed that the preferred solid-state packing arrangement of the hydrophobic groups can directly inform the assembly of stable peptoid nanosheets.}, number={45}, journal={Langmuir}, publisher={American Chemical Society (ACS)}, author={Robertson, Ellen J. and Proulx, Caroline and Su, Jessica K. and Garcia, Rita L. and Yoo, Stan and Nehls, Eric M. and Connolly, Michael D. and Taravati, Laudann and Zuckermann, Ronald N.}, year={2016}, month={Oct}, pages={11946–11957} }
 @article{proulx_noë_yoo_connolly_zuckermann_2016, title={On-resin N
-terminal peptoid degradation: Toward mild sequencing conditions}, volume={106}, ISSN={0006-3525}, url={http://dx.doi.org/10.1002/BIP.22884}, DOI={10.1002/BIP.22884}, abstractNote={Abstract}, number={5}, journal={Biopolymers}, publisher={Wiley}, author={Proulx, Caroline and Noë, Falko and Yoo, Stan and Connolly, Michael D. and Zuckermann, Ronald N.}, year={2016}, month={Sep}, pages={726–736} }
 @article{proulx_yoo_connolly_zuckermann_2015, title={Accelerated Submonomer Solid-Phase Synthesis of Peptoids Incorporating Multiple Substituted N-Aryl Glycine Monomers}, volume={80}, ISSN={0022-3263 1520-6904}, url={http://dx.doi.org/10.1021/ACS.JOC.5B01449}, DOI={10.1021/ACS.JOC.5B01449}, abstractNote={N-Aryl glycines are a chemically diverse class of peptoid monomers that have strong structure-inducing propensities. Yet their use has been limited due to the sluggish reactivity of the weakly nucleophilic aniline submonomers. Here, we report up to a 76-fold rate acceleration of the displacement reaction using aniline submonomers in solid-phase peptoid synthesis. This is achieved by adding halophilic silver salts to the displacement reaction, facilitating bromide abstraction and AgBr precipitation. Mechanistic insight derived from analysis of a series of 15 substituted anilines reveals that the silver-mediated reaction proceeds through a transition state that has considerably less positive charge buildup on the incoming nucleophile and an enhanced leaving group. This straightforward enhancement to the submonomer method enables the rapid room temperature synthesis of a wide variety of N-aryl glycine-rich peptoid oligomers, possessing both electron-withdrawing and -donating substituents, in good yields.}, number={21}, journal={The Journal of Organic Chemistry}, publisher={American Chemical Society (ACS)}, author={Proulx, Caroline and Yoo, Stan and Connolly, Michael D. and Zuckermann, Ronald N.}, year={2015}, month={Aug}, pages={10490–10497} }
 @inproceedings{proulx_yoo_connolly_zuckermann_2015, title={Molecular Engineering of the Peptoid Nanosheet Hydrophobic Core}, author={Proulx, C. and Yoo, S. and Connolly, M.D. and Zuckermann, R.N.}, year={2015}, month={Jun} }
 @article{mannige_haxton_proulx_robertson_battigelli_butterfoss_zuckermann_whitelam_2015, title={Peptoid nanosheets exhibit a new secondary-structure motif}, volume={526}, ISSN={0028-0836 1476-4687}, url={http://dx.doi.org/10.1038/NATURE15363}, DOI={10.1038/NATURE15363}, abstractNote={Some peptoids—synthetic structural relatives of polypeptides—can assemble into two-dimensional nanometre-scale sheets; simulations and experimental measurements show that these nanosheets contain a motif unique to peptoids, namely zigzag Σ-strands, which interlock and enable the nanosheets to extend in two dimensions only. Peptoids are biomimetic peptide-like oligomers, some of which can assemble into two-dimensional bilayer nanosheets. Now Stephen Whitelam and colleagues present simulations and structural analyses of this recently discovered form. They find that the sheets contain a motif unique to peptoids, zigzag 'Σ-strands', that interlock and enable the assemblies to extend in two dimensions only. The resulting Σ-sheets are analogous to the α-helices and β-sheets found in proteins but are comprised of two distinct rotational states that allow the polymer chains to resist twist so that the nanosheets remain planar over a macroscopic extent. This work could pave the way to rationally designed nanosheets and extended nanomaterials incorporating protein-like functions. A promising route to the synthesis of protein-mimetic materials that are capable of complex functions, such as molecular recognition and catalysis, is provided by sequence-defined peptoid polymers1,2—structural relatives of biologically occurring polypeptides. Peptoids, which are relatively non-toxic and resistant to degradation3, can fold into defined structures through a combination of sequence-dependent interactions3,4,5,6,7,8. However, the range of possible structures that are accessible to peptoids and other biological mimetics is unknown, and our ability to design protein-like architectures from these polymer classes is limited9. Here we use molecular-dynamics simulations, together with scattering and microscopy data, to determine the atomic-resolution structure of the recently discovered peptoid nanosheet, an ordered supramolecular assembly that extends macroscopically in only two dimensions. Our simulations show that nanosheets are structurally and dynamically heterogeneous, can be formed only from peptoids of certain lengths, and are potentially porous to water and ions. Moreover, their formation is enabled by the peptoids’ adoption of a secondary structure that is not seen in the natural world. This structure, a zigzag pattern that we call a Σ(‘sigma’)-strand, results from the ability of adjacent backbone monomers to adopt opposed rotational states, thereby allowing the backbone to remain linear and untwisted. Linear backbones tiled in a brick-like way form an extended two-dimensional nanostructure, the Σ-sheet. The binary rotational-state motif of the Σ-strand is not seen in regular protein structures, which are usually built from one type of rotational state. We also show that the concept of building regular structures from multiple rotational states can be generalized beyond the peptoid nanosheet system.}, number={7573}, journal={Nature}, publisher={Springer Science and Business Media LLC}, author={Mannige, Ranjan V. and Haxton, Thomas K. and Proulx, Caroline and Robertson, Ellen J. and Battigelli, Alessia and Butterfoss, Glenn L. and Zuckermann, Ronald N. and Whitelam, Stephen}, year={2015}, month={Oct}, pages={415–420} }
 @article{proulx_lubell_2014, title={Analysis of N-amino-imidazolin-2-one peptide turn mimic 4-position substituent effects on conformation by X-ray crystallography}, volume={102}, ISSN={0006-3525}, url={http://dx.doi.org/10.1002/BIP.22327}, DOI={10.1002/BIP.22327}, abstractNote={ABSTRACT}, number={1}, journal={Biopolymers}, publisher={Wiley}, author={Proulx, Caroline and Lubell, William D.}, year={2014}, month={Jan}, pages={7–15} }
 @article{robertson_olivier_qian_proulx_zuckermann_richmond_2014, title={Assembly and molecular order of two-dimensional peptoid nanosheets through the oil–water interface}, volume={111}, ISSN={0027-8424 1091-6490}, url={http://dx.doi.org/10.1073/PNAS.1414843111}, DOI={10.1073/PNAS.1414843111}, abstractNote={Significance}, number={37}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Robertson, Ellen J. and Olivier, Gloria K. and Qian, Menglu and Proulx, Caroline and Zuckermann, Ronald N. and Richmond, Geraldine L.}, year={2014}, month={Sep}, pages={13284–13289} }
 @inproceedings{proulx_yoo_zuckermann_2014, title={Improvements in the Solid-Phase Synthesis of Peptoids Incorporating Weak Nucleophile Submonomers}, author={Proulx, C. and Yoo, S. and Zuckermann, R.N.}, year={2014}, month={Jun} }
 @inproceedings{proulx_yoo_connolly_zuckermann_2014, title={Influence of Backbone Flexibility on the Two-dimensional Assembly of Peptoid Nanosheets}, author={Proulx, C. and Yoo, S. and Connolly, M.D. and Zuckermann, R.N.}, year={2014}, month={Aug} }
 @inproceedings{proulx_su_yoo_olivier_garcia_connolly_mannige_haxton_whitelam_zuckermann_2014, title={Molecular Engineering of the Peptoid Nanosheet Hydrophobic Core}, author={Proulx, C. and Su, J.K. and Yoo, S. and Olivier, G.K. and Garcia, R.L. and Connolly, M.D. and Mannige, R.V. and Haxton, T.K. and Whitelam, S. and Zuckermann, R.N.}, year={2014}, month={Aug} }
 @inproceedings{zhang_proulx_lubell_2014, title={Multi-component Diversity-Oriented Synthesis of Aza-lysine-peptide Mimics}, author={Zhang, J. and Proulx, C. and Lubell, W.D.}, year={2014}, month={Jun} }
 @article{zhang_proulx_tomberg_lubell_2014, title={Multicomponent Diversity-Oriented Synthesis of Aza-Lysine-Peptide Mimics}, volume={16}, ISSN={1523-7060 1523-7052}, url={http://dx.doi.org/10.1021/OL403297V}, DOI={10.1021/OL403297V}, abstractNote={Copper catalyzed coupling of Mannich reagents to aza-propargylglycine residues has been employed to synthesize constrained aza-lysine peptides. Employing growth hormone releasing peptide-6 (GHRP-6) as a model peptide and a variety of secondary amines, 18 aza-Lys analogs were synthesized by this so-called A(3)-coupling reaction. This effective method for making constrained aza-Lys-peptides offers strong potential for exploring various recognition events implicating lysine residues including post-translational peptide modification.}, number={1}, journal={Organic Letters}, publisher={American Chemical Society (ACS)}, author={Zhang, Jinqiang and Proulx, Caroline and Tomberg, Anna and Lubell, William D.}, year={2014}, month={Dec}, pages={298–301} }
 @inbook{sun_proulx_zuckermann_2014, title={Precision Sequence Control in Bioinspired Peptoid Polymers}, ISBN={9780841230019 9780841230026}, ISSN={0097-6156 1947-5918}, url={http://dx.doi.org/10.1021/bk-2014-1170.ch003}, DOI={10.1021/bk-2014-1170.ch003}, abstractNote={’Recent advances in solid-phase organic synthesis are shrinking the gap between biopolymers and traditional polymers. It is now possible to synthesize synthetic polymers with exact control over main chain length and monomer sequence, which is leading to a new class of information-rich materials. Peptoids are a particularly promising bio-inspired polymer platform because of their highly efficient synthesis and ready availability of starting materials. Hundreds of chemically diverse side chains can be introduced from simple building blocks, allowing their properties to be finely tuned. The peptoid platform allows the systematic investigation of new materials that are intermediate between proteins and bulk polymers, in both their structure and their properties. Here we review recent examples of peptoid polymers where the polymer properties are the direct result of the specific monomer sequence.}, booktitle={ACS Symposium Series}, publisher={American Chemical Society}, author={Sun, Jing and Proulx, Caroline and Zuckermann, Ronald N.}, year={2014}, month={Jan}, pages={35–53} }
 @article{sanii_haxton_olivier_cho_barton_proulx_whitelam_zuckermann_2014, title={Structure-Determining Step in the Hierarchical Assembly of Peptoid Nanosheets}, volume={8}, ISSN={1936-0851 1936-086X}, url={http://dx.doi.org/10.1021/NN505007U}, DOI={10.1021/NN505007U}, abstractNote={Organic two-dimensional nanomaterials are of growing importance, yet few general synthetic methods exist to produce them in high yields and to precisely functionalize them. We previously developed an efficient hierarchical supramolecular assembly route to peptoid bilayer nanosheets, where the organization of biomimetic polymer sequences is catalyzed by an air-water interface. Here we determine at which stages of assembly the nanoscale and atomic-scale order appear. We used X-ray scattering, grazing incidence X-ray scattering at the air-water interface, electron diffraction, and a recently developed computational coarse-grained peptoid model to probe the molecular ordering at various stages of assembly. We found that lateral packing and organization of the chains occurs during the formation of a peptoid monolayer, prior to its collapse into a bilayer. Identifying the structure-determining step enables strategies to influence nanosheet order, to predict and optimize production yields, and to further engineer this class of material. More generally, our results provide a guide for using fluid interfaces to catalytically assemble 2D nanomaterials.}, number={11}, journal={ACS Nano}, publisher={American Chemical Society (ACS)}, author={Sanii, Babak and Haxton, Thomas K. and Olivier, Gloria K. and Cho, Andrew and Barton, Bastian and Proulx, Caroline and Whitelam, Stephen and Zuckermann, Ronald N.}, year={2014}, month={Oct}, pages={11674–11684} }
 @article{proulx_picard_boeglin_pohankova_chemtob_ong_lubell_2012, title={Azapeptide Analogues of the Growth Hormone Releasing Peptide 6 as Cluster of Differentiation 36 Receptor Ligands with Reduced Affinity for the Growth Hormone Secretagogue Receptor 1a}, volume={55}, ISSN={0022-2623 1520-4804}, url={http://dx.doi.org/10.1021/jm300557t}, DOI={10.1021/jm300557t}, abstractNote={The synthetic hexapeptide growth hormone releasing peptide-6 (GHRP-6) exhibits dual affinity for the growth hormone secretagogue receptor 1a (GHS-R1a) and the cluster of differentiation 36 (CD36) receptor. Azapeptide GHRP-6 analogues have been synthesized, exhibiting micromolar affinity to the CD36 receptor with reduced affinity toward the GHS-R1a. A combinatorial split-and-mix approach furnished aza-GHRP-6 leads, which were further examined by alanine scanning. Incorporation of an aza-amino acid residue respectively at the D-Trp(2), Ala(3), or Trp(4) position gave aza-GHRP-6 analogues with reduced affinity toward the GHS-R1a by at least a factor of 100 and in certain cases retained affinity for the CD36 receptor. In the latter cases, the D-Trp(2) residue proved important for CD36 receptor affinity; however, His(1) could be replaced by Ala(1) without considerable loss of binding. In a microvascular sprouting assay using a choroid explant, [azaTyr(4)]-GHRP-6 (15), [Ala(1), azaPhe(2)]-GHRP-6 (16), and [azaLeu(3), Ala(6)]-GHRP-6 (33) all exhibited antiangiogenic activity.}, number={14}, journal={Journal of Medicinal Chemistry}, publisher={American Chemical Society (ACS)}, author={Proulx, Caroline and Picard, Émilie and Boeglin, Damien and Pohankova, Petra and Chemtob, Sylvain and Ong, Huy and Lubell, William D.}, year={2012}, month={Jul}, pages={6502–6511} }
 @article{proulx_lubell_2012, title={N-Amino-imidazolin-2-one Peptide Mimic Synthesis and Conformational Analysis}, volume={14}, ISSN={1523-7060 1523-7052}, url={http://dx.doi.org/10.1021/ol302021n}, DOI={10.1021/ol302021n}, abstractNote={Base-promoted 5-exo-dig cyclizations of aza-propargylglycinamides provided N-amino-imidazolin-2-one peptide mimics, which exhibited turn geometry in X-ray crystallographic and NMR spectroscopic analyses. Sonogashira coupling prior to cyclization afforded N-amino-imidazolin-2-ones with diverse 4-position aromatic substituents with potential to serve as Phe and Trp mimics.}, number={17}, journal={Organic Letters}, publisher={American Chemical Society (ACS)}, author={Proulx, Caroline and Lubell, William D.}, year={2012}, month={Aug}, pages={4552–4555} }
 @book{lubell_ong_proulx_hopewell_beauregard_garcia-ramos_2012, title={Peptidomimetics Comprising N-Amino Cyclic Urea Residues and Uses Thereof}, number={US 61/655,682}, author={Lubell, William D. and Ong, Huy and Proulx, Caroline and Hopewell, Robert and Beauregard, Kim and Garcia-Ramos, Yésica}, year={2012}, month={Jun} }
 @article{garcia-ramos_proulx_lubell_2012, title={Synthesis of hydrazine and azapeptide derivatives by alkylation of carbazates and semicarbazones}, volume={90}, ISSN={0008-4042 1480-3291}, url={http://dx.doi.org/10.1139/v2012-070}, DOI={10.1139/v2012-070}, abstractNote={ Hydrazine and azapeptide analogs were synthesized effectively by alkylation of alkylidene carbazates and semicarbazones. In comparisons of benzylidene, benzhydrylidene, and fluorenylidene tert-butyl carbazates in alkylations using bases of different pKb character, superior conversion was obtained using the fluorenone derivative. Mild alkylation conditions were found employing Et4NOH as base and used to convert fluorenylidene tert-butyl carbazate into 13 different protected hydrazines. Moreover, racemization was avoided during alkylation of fluorenylidene semicarbazide in the synthesis of aza-propargylglycinylphenylalanine tert-butyl ester, the protecting groups from which could be selectively removed. }, number={11}, journal={Canadian Journal of Chemistry}, publisher={Canadian Science Publishing}, author={Garcia-Ramos, Yesica and Proulx, Caroline and Lubell, William D.}, year={2012}, month={Nov}, pages={985–993} }
 @article{proulx_sabatino_hopewell_spiegel_garcía ramos_lubell_2011, title={Azapeptides and their therapeutic potential}, volume={3}, ISSN={1756-8919 1756-8927}, url={http://dx.doi.org/10.4155/fmc.11.74}, DOI={10.4155/fmc.11.74}, abstractNote={Azapeptides are peptide analogs in which one or more of the amino residues is replaced by a semicarbazide. This substitution of a nitrogen for the α-carbon center results in conformational restrictions, which bend the peptide about the aza-amino acid residue away from a linear geometry. The resulting azapeptide turn conformations have been observed by x-ray crystallography and spectroscopy, as well as predicted based on computational models. In biologically active peptide analogs, the aza-substitution has led to enhanced activity and selectivity as well as improved properties, such as prolonged duration of action and metabolic stability. In light of these characteristics, azapeptides have found important uses as receptor ligands, enzyme inhibitors, drugs, pro-drugs, probes and imaging agents. Recent improvements in synthetic methods for their procurement have ushered in a new era of azapeptide chemistry. This review aims to provide a historical look at the development of azapeptide science along with a focus on recent developments and perspectives on the future of this useful tool for medicinal chemistry.}, number={9}, journal={Future Medicinal Chemistry}, publisher={Future Science Ltd}, author={Proulx, Caroline and Sabatino, David and Hopewell, Robert and Spiegel, Jochen and García Ramos, Yésica and Lubell, William D.}, year={2011}, month={Jul}, pages={1139–1164} }
 @inproceedings{proulx_lubell_2011, title={In search of azapeptide analogs of GHRP-6 with selective affinity for the CD36 vs GHS-R1a receptor: exploiting the reactivity of semicarbazones and aza-propargyl glycine in combinatorial azapeptide synthesis}, author={Proulx, C. and Lubell, W. D.}, year={2011}, month={Jun} }
 @article{bolduc_lambert-lanteigne_colin_zhao_proulx_boeglin_lubell_pelletier_féthière_ong_et al._2011, title={Modified peptide monolayer binding His-tagged biomolecules for small ligand screening with SPR biosensors}, volume={136}, ISSN={0003-2654 1364-5528}, url={http://dx.doi.org/10.1039/c1an15235a}, DOI={10.1039/c1an15235a}, abstractNote={A peptide self-assembled monolayer (SAM) was designed to bind His-tagged biomolecules for surface plasmon resonance (SPR) bioanalysis, which was applied for the determination of K(d) for small ligand screening against CD36. Nonspecific adsorption could be minimized using penta- and hexa-peptide monolayers. In particular, monolayers consisting of 3-mercaptopropionyl-leucinyl-histidinyl-aspartyl-leucinyl-histidinyl-aspartic acid (3-Mpa-LHDLHD) exhibited little (12 ng cm(-2)) nonspecific adsorption in crude serum. Modification of this peptide monolayer with Nα,Nα-bis(carboxymethyl)-L-lysine gave a surface competent for binding His-tagged proteins, as demonstrated using enzyme (human dihydrofolate reductase), protein/antibody and receptor (CD36) examples. Immobilization featured chelation of copper and the His-tagged protein by the peptide monolayer, which could be recycled by removing the copper using imidazole washes prior to reuse.}, number={15}, journal={The Analyst}, publisher={Royal Society of Chemistry (RSC)}, author={Bolduc, Olivier R. and Lambert-Lanteigne, Patrick and Colin, Damien Y. and Zhao, Sandy Shuo and Proulx, Caroline and Boeglin, Damien and Lubell, William D. and Pelletier, Joelle N. and Féthière, James and Ong, Huy and et al.}, year={2011}, pages={3142} }
 @article{sabatino_proulx_pohankova_ong_lubell_2011, title={Structure–Activity Relationships of GHRP-6 Azapeptide Ligands of the CD36 Scavenger Receptor by Solid-Phase Submonomer Azapeptide Synthesis}, volume={133}, ISSN={0002-7863 1520-5126}, url={http://dx.doi.org/10.1021/ja203007u}, DOI={10.1021/ja203007u}, abstractNote={The cluster of differentiation 36 (CD36) class B scavenger receptor binds a variety of biologically endogenous ligands in addition to synthetic peptides (i.e., growth hormone-releasing peptides, GHRPs), which modulate biological function related to anti-angiogenic and anti-atherosclerotic activities. Affinity labeling had previously shown that GHRP-6 analogues such as hexarelin, [2-Me-W(2)]GHRP-6 (1), bind to the lysine-rich domain of the CD36 receptor. Moreover, the azapeptide analogue [aza-F(4)]GHRP-6, 2, exhibited a characteristic β-turn conformation as described by CD and NMR spectroscopy and a slightly higher CD36 binding affinity relative to hexarelin (1.34 and 2.37 μM, respectively), suggesting receptor binding was mediated by the conformation and the aromatic residues of these peptide sequences. Ligand-receptor binding interactions were thus explored using azapeptides to examine influences of side-chain diversity and backbone conformation. In particular, considering that aromatic cation interactions may contribute to binding affinity, we have explored the potential of introducing salt bridges to furnish GHRP-6 azapeptide ligands of the CD36 receptor. Fifteen aza-glutamic acid analogues related to 2 were prepared by submonomer solid-phase synthesis. The azapeptide side chains were installed by novel approaches featuring alkylation of resin-bound semicarbazone with Michael acceptors and activated allylic acetates in the presence of phosphazene base (BTPP). Moreover, certain Michael adducts underwent intramolecular cyclization during semicarbazone deprotection, leading to novel pyrrazoline and aza-pyroglutamate N-terminal residues. Structural studies indicated that contingent on sequence the [aza-Glu]GHRP-6 analogues exhibited CD spectra characteristic of random coil, polyproline type II and β-turn secondary structures in aqueous media. In covalent competition binding studies with the GHRP-6 prototype hexarelin bearing a radiotracer, certain [aza-Glu]GHRP-6 azapeptides retained relatively high (2-27 μM) affinity for the CD36 scavenger receptor.}, number={32}, journal={Journal of the American Chemical Society}, publisher={American Chemical Society (ACS)}, author={Sabatino, David and Proulx, Caroline and Pohankova, Petra and Ong, Huy and Lubell, William D.}, year={2011}, month={Aug}, pages={12493–12506} }
 @inproceedings{proulx_lubell_2011, place={San Diego, CA}, title={Synthesis of [Azaphenylglycine4]- and [Aza-1-phenyl-2,3-triazole-3-alanine4] Growth Hormone Releasing Peptide-6 and Comparison of their Conformations with [AzaPhe4]GHRP-6}, booktitle={Peptides: Building Bridges. Proceedings of the 22nd American Peptide Symposium}, publisher={Prompt Scientific Publishing}, author={Proulx, C. and Lubell, W.D.}, editor={Lebl, M.Editor}, year={2011}, pages={80–81} }
 @inproceedings{proulx_lubell_2011, title={Synthesis of substituted imidazolinones via a cationic gold(I)-mediated intramolecular cyclization}, author={Proulx, C. and Lubell, W.D.}, year={2011}, month={Jun} }
 @inproceedings{proulx_lubell_2011, title={Teaching haemoglobin to third graders}, author={Proulx, C. and Lubell, W.D.}, year={2011}, month={Jun} }
 @inproceedings{proulx_lubell_2011, title={Tuning the selectivity of GHRP-6 towards the CD36 vs GHS-R1a receptor by exploiting the reactivity of semicarbazones and aza-propargyl glycine in combinatorial azapeptide synthesis}, author={Proulx, C. and Lubell, W. D.}, year={2011}, month={Jun} }
 @article{proulx_lubell_2010, title={Aza-1,2,3-triazole-3-alanine Synthesis via Copper-Catalyzed 1,3-Dipolar Cycloaddition on Aza-progargylglycine}, volume={75}, ISSN={0022-3263 1520-6904}, url={http://dx.doi.org/10.1021/jo100957z}, DOI={10.1021/jo100957z}, abstractNote={The parallel synthesis of seven aza-1,2,3-triazole-3-alanine azapeptides of the Growth Hormone Releasing Peptide-6 (GHRP-6) was accomplished via a Cu-catalyzed azide-alkyne [3+2] cycloaddition on an aza-propargylglycine residue anchored on Rink amide resin. Circular dichroism spectroscopy in water demonstrated that azapeptides which possess an aza-1,2,3-triazole-3-alanine residue at the Trp(4) position of the GHRP-6 sequence adopt beta-turn conformations.}, number={15}, journal={The Journal of Organic Chemistry}, publisher={American Chemical Society (ACS)}, author={Proulx, Caroline and Lubell, William D.}, year={2010}, month={Aug}, pages={5385–5387} }
 @article{proulx_lubell_2010, title={Copper-Catalyzed N-Arylation of Semicarbazones for the Synthesis of Aza-Arylglycine-Containing Aza-Peptides}, volume={12}, ISSN={1523-7060 1523-7052}, url={http://dx.doi.org/10.1021/ol100932m}, DOI={10.1021/ol100932m}, abstractNote={Parallel synthesis of 13 aza-arylglycine peptides, based on the hexapeptide sequence of Growth Hormone Releasing Peptide-6 (GHRP-6), was accomplished via selective N-arylation of a semicarbazone peptide building block anchored on Rink amide resin. Aza-peptides possessing aza-indolylglycine and aza-imidazoylglycine residues were obtained through use of the corresponding heteroaryl iodides, yielding, respectively, aza-Trp and aza-His peptidomimics. CD spectroscopy indicated the propensity for aza-peptides, containing aza-arylglycines at the Trp(4) position of the GHRP-6 sequence, to adopt beta-turns.}, number={13}, journal={Organic Letters}, publisher={American Chemical Society (ACS)}, author={Proulx, Caroline and Lubell, William D.}, year={2010}, month={Jul}, pages={2916–2919} }
 @inproceedings{proulx_lubell_2010, title={Copper-catalyzed N-arylation of a semicarbazone building block for the parallel synthesis of aryl-azaglycine containing azapeptides}, author={Proulx, C. and Lubell, W.D.}, year={2010}, month={May} }
 @inproceedings{proulx_lubell_2010, title={Copper-catalyzed N-arylation of semicarbazones for the synthesis of aza-arylglycine containing aza-peptides}, author={Proulx, C. and Lubell, W.D.}, year={2010}, month={Mar} }
 @article{bourguet_proulx_klocek_sabatino_lubell_2010, title={Solution-phase submonomer diversification of aza-dipeptide building blocks and their application in aza-peptide and aza-DKP synthesis}, volume={16}, ISSN={1075-2617 1099-1387}, url={http://dx.doi.org/10.1002/psc.1235}, DOI={10.1002/psc.1235}, abstractNote={Abstract}, number={6}, journal={Journal of Peptide Science}, publisher={Wiley}, author={Bourguet, Carine B. and Proulx, Caroline and Klocek, Sophie and Sabatino, David and Lubell, William D.}, year={2010}, month={Jun}, pages={284–296} }
 @inproceedings{proulx_boeglin_chemtob_ong_lubell_2009, title={Aza-peptide analogs of GHRP-6 with selective receptor affinity for CD36 versus GHS-R1a”}, author={Proulx, C. and Boeglin, D. and Chemtob, S. and Ong, H. and Lubell, W.D.}, year={2009}, month={Jun} }
 @inproceedings{proulx_lubell_2009, title={Cu(I)-catalyzed N-arylation of semicarbazones for the synthesis of aryl-aza glycine containing azapeptides}, author={Proulx, C. and Lubell, W.D.}, year={2009}, month={Oct} }
 @article{sabatino_proulx_klocek_bourguet_boeglin_ong_lubell_2009, title={Exploring Side-Chain Diversity by Submonomer Solid-Phase Aza-Peptide Synthesis}, volume={11}, ISSN={1523-7060 1523-7052}, url={http://dx.doi.org/10.1021/ol901423c}, DOI={10.1021/ol901423c}, abstractNote={Submonomer synthesis of aza-peptides featuring regioselective alkylation of peptide-bound aza-Gly residues provided ten aza-analogues of the Growth Hormone Releasing Peptide-6 (GHRP-6) in 15-42% yield and purity generally >or=90%. Circular dichroism demonstrated that azaPhe-peptide 7a induced a beta-turn conformation which may be responsible for its 1000-fold improvement in GHRP-6 selectivity for the CD36 receptor. This versatile method for making aza-peptides avoids solution-phase hydrazine synthesis and is well suited for studying side-chain-activity relationships of biologically active peptides.}, number={16}, journal={Organic Letters}, publisher={American Chemical Society (ACS)}, author={Sabatino, David and Proulx, Caroline and Klocek, Sophie and Bourguet, Carine B. and Boeglin, Damien and Ong, Huy and Lubell, William D.}, year={2009}, month={Aug}, pages={3650–3653} }
 @inbook{proulx_lubell_2009, place={Hoboken, N.J.}, edition={2nd}, title={O-(3,4-Dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate}, ISBN={9780470017548}, booktitle={Encyclopedia of Reagents for Organic Synthesis}, publisher={John Wiley & Sons Ltd}, author={Proulx, C. and Lubell, W.D.}, editor={Paquette, Leo A.Editor}, year={2009} }
 @inbook{proulx_lubell_2009, place={Chichester}, edition={2nd}, title={O-(6-Chloro-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate}, booktitle={Encyclopedia of Reagents for Organic Synthesis}, publisher={John Wiley & Sons Ltd}, author={Proulx, C. and Lubell, W. D.}, editor={Paquette, Leo A.Editor}, year={2009} }
 @inbook{proulx_lubell_2009, place={San Diego, CA}, title={Solid-Phase Synthesis of Aza-Proline Analogs of GHRP-6}, booktitle={Peptides: Breaking Away. Proceedings of the 21st American Peptide Symposium}, publisher={Prompt Scientific Publishing}, author={Proulx, C. and Lubell, W.D.}, editor={Lebl, M.Editor}, year={2009}, pages={56–57} }
 @inproceedings{proulx_boeglin_chemtob_ong_lubell_2008, title={Aza-peptide analogs of GHRP-6 with selective receptor affinity for CD36 versus GHS-R1a”}, author={Proulx, C. and Boeglin, D. and Chemtob, S. and Ong, H. and Lubell, W.D.}, year={2008}, month={Aug} }
 @book{ong_chemtob_lubell_boeglin_proulx_sabatino_sajjadi_2008, title={Azapeptides as CD36 Binding Compounds}, number={PCT/CA2008/001162}, author={Ong, Huy and Chemtob, Sylvain and Lubell, William D. and Boeglin, Damien and Proulx, Caroline and Sabatino, David and Sajjadi, Zohreh}, year={2008}, month={Jun} }
 @inproceedings{proulx_boeglin_chemtob_ong_lubell_2008, title={Elucidation of structural and conformational requirements for GHRP-6 binding to the GHSR-1a and CD36 receptors using aza-peptides}, author={Proulx, C. and Boeglin, D. and Chemtob, S. and Ong, H. and Lubell, W.D.}, year={2008}, month={Nov} }