On Sunday the 18th June, 2017, at the 25th American Peptide Symposium (APS) in Whistler, BC, Canada, the society's highest honor, the Merrifield Award for Career-Long Scientific Creativity in Peptide Science, was aptly awarded to Professors Charles M. Deber and Robert S. Hodges, who notably advanced their brilliant careers at the University of Toronto and the University of Alberta in Canada. The meeting was the fourth occasion the APS was held in Canada, and organized by Professors John Vederas and Jonathan Lai. It was preceded by the 9th, 13th and 20th symposia, which were respectively organized in Toronto by Deber and Professor Kenneth D. Kopple, in Edmonton by Hodges (who is currently at the University of Colorado, Denver, U.S.A.), and in Montréal by Professor Emanuel Escher and me. Canadian scientists including Deber and Hodges, along with Professor Peter W. Schiller (Institut de recherches cliniques de Montréal) have also served as Presidents of the American Peptide Society. This strong Canadian influence on the American Peptide Society reflects a long history of achievements in the field by peptide scientists performing research in Canada, that may be dated back to the Nobel Prize-distinguished research of Canadian physician Frederick Banting, who with medical student Charles H. Best, discovered the peptide hormone insulin in pancreatic extracts of dogs at the University of Toronto in 1921. This is the fourth Emerging Peptide Science issue of Peptide Science. Previous issues have covered recent developments in Japan, Australia and Italy. When asked to organize this issue, I accepted in part to pay homage to the Canadian pioneers in the field, as much as to bring attention to the hot bed of contemporary activity presently being performed by my colleagues in Canada. Thankful for the positive response of the latter, before leaping into the contents of this special issue, I would thus like to mention some representative Canadian discoveries since Banting and Best. Please kindly note that the following description is meant in no way to be exhaustive. Instead, I hope to provide perspective from which to discuss the outstanding accomplishments of the young lions in this issue, and to create a vista from which the future of Canadian peptide science may be viewed. Canadian achievements have touched all aspects of peptide science.1 Moreover, Canadian laboratories have been key components in fruitful international collaborations that have advanced the field of peptide science on a global scale. To cite but a few contributions, in 1960, the University of Toronto laboratory of Professor G. W. Dixon regenerated insulin from the inactive A and B peptide chains.2 The useful coupling agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was prepared by the laboratory of Professor B. Belleau (University of Ottawa) in 1968.3 In parallel, seminal studies on the various factors influencing racemization (“enantiomerization”) were performed at the University of Ottawa by the laboratory of Professor L. N. Benoiton. They delved into the heart of peptide assembly, describing various useful protocols, including methods for the synthesis and coupling of N-(methyl)amino acids and peptide fragments.4-7 At the University of Alberta in 1972,8 a Ph.D. student named Robert Hodges reported the sequence of the peptide tropomyosin, identified the first two-stranded coiled-coil protein, and launched a long-term interest in the properties of this protein folding model that led to de novo design of synthetic peptide vaccines and antimicrobial agents.9 In Quebec, the laboratory of Schiller began to identify topographical relationships between peptide and non-peptide opioid receptor ligands, leading to the synthesis of potent cyclic enkephalin analogs in 1980.10, 11 Pioneering the use of photo-affinity labeling to study peptide receptor binding at the Université de Sherbrooke, Escher introduced 4-azidophenylalanine in analogs of bradykinin and tagged kinin receptors in 1981.12 During that same time in Ontario, Deber studied cyclic octapeptides that mediated metal ion transport across phosphatidylcholine vesicles, and began a long-term fruitful interest in peptide membrane interactions.13, 14 At the Université de Montréal, Professor S. Hanessian prepared enantiomerically pure vinylglycine in 1984,15 cultivating an interest in the synthesis of unusual amino acids dating back to the preparation of cycloheptatrienylglycine in 1969,16 and leading to the conception of various peptidomimetics and medicinally relevant enzyme inhibitors, e.g., γ-peptides,17 crystalline poly-proline type II helices featuring methanoprolines,18 and macrocyclic aspartic protease inhibitors.19 Targeting antibiotics with low host toxicity, Vederas developed practical methods for the synthesis of α-hydrazino and β-substituted α-amino acids,20, 21 toward the preparation of diaminopimelic acid analogs for inhibiting bacterial synthesis of lysine and peptidoglycan in 1986 at the University of Alberta.22 In the 1990s, the intellectual contributions and flow of high-quality students from these academic laboratories combined to give birth to a cutting-edge Canadian pharmaceutical industry, which initiated a new wave of peptide-based drug design.23 Against the celebrated background of the seminal discoveries of Banting and Best in Toronto, the peptide community made its first formal foray North of the border in June 1985, as the 9th American Peptide Symposium was held in Toronto, co-organized by Charles Deber (Hospital for Sick Children; University of Toronto) and the late Ken Kopple (Illinois Institute of Technology) on the University campus. At that time, peptide science was already well-represented across Canada, as epitomized by the laboratories of V. S. Ananthanarayanan (McMaster University); Leo Benoiton (University of Ottawa); Penelope Codding (University of Calgary); Charles Deber; Richard and Rachel Epand (McMaster University); Robert Hodges (University of Alberta); Bibudendra Sarkar (University of Toronto); and Peter Schiller (Clinical Research Institute of Montreal). The Symposium was attended by over 700 scientists and contained a healthy portion of Canadian content, highlighted by the free-afternoon trip to Niagara Falls, and a gala "Canada Sea-to-Sea" closing banquet at the historic Old Mill restaurant. The restaurant was lavishly decorated with hundreds of red and white balloons, and each course was 'paraded in' by actors dressed in traditional costumes representing several Canadian provinces from East-to-West (albeit dessert was baked Alaska). Interestingly, many of the topics covered at the Toronto Symposium resonate even today. A partial list includes the design, synthesis, conformational analysis and pharmacological testing of peptide hormones, such as the enkephalins and opioid peptides, luteinizing hormone-releasing hormone, and somatostatin; the use of non-peptidic amino acids; identification of antigenic sites and schemes for producing synthetic vaccines; peptide-lipid interactions; and amphiphilic secondary structures. In addition, specific sessions were devoted to atrial natriuretic factors (organized by Ralph Hirschmann) and problems in solid phase peptide coupling (organized by Bruce Merrifield). The Pierce Award (now Merrifield Award) was won by Robert Schwyzer of the Eidgenossiche Technische Hochschule, Zurich, who spoke on "Peptide chemistry as a tool in molecular biology". Indeed, a couple of early papers on the site-directed mutagenesis of genes could also be gleaned from the Proceedings. As a historic footnote, this Symposium took place five years before the American Peptide Society was formed in 1990, and as such, was an important contributor towards unifying peptide scientists both in Canada and internationally. A set of reviews follow in which peptide analogs alter physical and physiological processes. Reporting on the field of cryopreservation science, Professor R. N. Ben, A. Ampaw, T. A. Charlton and J. G. Briard review the development of peptidomimetic and small molecule ice recrystallization inhibitors inspired by naturally occurring antifreeze proteins. Examining modern applications of amyloid peptides, Professor S. Bourgault, S. Al-Halifa, M. Babych, X. Zottig and D. Archambault discuss the advantages of using the self-assembly of multiple copies of antigenic determinants to enhance vaccination metabolic stability, improve immunogenicity and enhance immune response. The use of self-assembled amyloid nanowires in biosensors is also described. Surveying the roles of the ubiquitin proteasome system in regulating signaling networks and maintaining cell homeostasis, Professor S. S. Sidhu and G. Veggiani review modern therapeutic strategies that employ ubiquitin-binding domains to generate protein-protein interactions that may facilitate degradation and control the half-life of specific proteins in vivo. Finally, Professor D. M. Perrin and A. Blanc review tryptophan oxidation to 3a-hydroxyhexahydropyrrolo[2,3-b]indole-2-carboxamide summarizing biological activities and synthetic routes to natural products containing this residue. Current activities in Canadian laboratories are highlighted by 14 original research articles. Three articles contain conjugate and crosslinking chemistry to improve physical properties. The first, by Professor R. E. W. Hancock, E. F. Haney, K. C. Wuerth, N. Rahanjam, N. S. Nikouei, A. Ghassemi, M. A. Noghani and A. Boey, identifies modified hyper-branched polyglycerols as a promising vehicle for in vitro delivery of innate defense regulator peptides without aggregation and loss of immunomodulatory function. With the aim of enhancing intracellular antibiotic concentration by facilitating membrane penetration, Professor F. Schweizer, Y. Lyu, R. Domalaon, and X. Yang describe the attachment of amphiphilic lysine residues to the aminoglycoside tobramycin using a hydrocarbon tether. They obtain a conjugate having enhanced membrane permeability and depolarization ability, with activity against antibiotic-resistant Pseudomonas aeruginosa, as well as the capacity to synergize with other antibiotics. In a study of hydrolysate from mussel byssal fibrous protein by Professors I. Marcotte and C. Pellerin with F. Byette, infrared spectroscopy is used to demonstrate that chemical treatment with carbodiimide and glutaraldehyde crosslinks favors a hydrated collagen-like PPII structure that exhibits better resistance to enzymatic degradation and tunable mechanical properties, with increased tensile strength correlating to crosslinking density. Two studies are presented on transmembrane peptides. Highlighting the subtleties of Leu versus Ile in transmembrane helix folding, membrane penetration and lipid interaction, Professor C. M. Deber and T. A. Stone compare the physical properties of sets of compositionally identical pairs of Leu- and Ile-containing peptides. In an investigation of the influences of environment on fluorinated peptide conformation in eukaryotic biomimetic membranes and hexafluoroisopropanol, by Professors N. Voyer and M. Auger, together with M. Auger, T. Lefèvre and F. Otis, spectroscopic techniques and computational analysis are used to evaluate the assembly of α-helical peptides featuring a strip of 2-amino-4,4,4-trifluorobutyric acid residues in a poly-leucine sequence that forms tetrameric ion channels exhibiting a selectivity preference for sodium ions. Reporting a study in genetically encoded fragment-based discovery using phage-display, Professor R. Derda and H. Lin screen libraries of conjugates consisting of peptide-derived aldehydes and aminooxy glycans. They highlight the discrepancies of using surface-immobilized and soluble receptor to identify glycopeptide ligands that bind the shallow sites involved in carbohydrate recognition of the β-D-galactopyranoside binding lectin galectin-3. Three articles feature development of GPCR ligands for potential therapeutic applications. Furthering the study of cyclic-opioid receptor ligands, Professor P. W. Schiller, G. Weltrowska, T. M.-D. Nguyen, N. N. Chung and B. C. Wilkes describe the first pairs of multiple-chiral-center enantiomeric GPCR ligands having similar nanomolar receptor binding affinity; contingent on structure, the cyclic enantiomers exhibit similar or divergent activation of the mu receptor subtype. The role of the fifth position of Leu-enkephalin for mu and delta opioid receptor subtype binding is investigated by Professors R. Leduc, B. Guérin, L. Gendron and Y. L. Dory along with D. B. Ndong, V. Blais, B. J. Holleran, A. Proteau-Gagné, I. Cantin-Savoie, W. Robert, J.-F. Nadon, S. Beauchemin and G. Piñeyro. They report the synthesis of 12 C-terminal amino acid analogs and evaluate peptide capacity to activate G protein dependent-signaling and β-arrestin recruitment. Pursuing a fluorescent probe to screen for over expressed ghrelin receptor in cancer cell lines and tumor tissues, Professor L. G. Luyt, T. Lalonde, T. G. Shepherd and S. Dhanvantari employ a lactam bridge scan of ghrelin(1–20) and identify a dye-labeled i to i + 4 crosslinked peptide exhibiting increased helicity and receptor affinity. Five articles feature novel solid-phase approaches to make libraries of peptide analogs. Professor A. K. Yudin, H. S. Soor, J. Hansen, D. B. Diaz and S. Appavoo employ N-methyliminodiacetyl boryl acetaldehyde in reductive amination reactions to synthesize peptide β-aminoboronic acids on 2-chlorotrityl resin with excellent selectivity for monoalkylation without protodeboronation. In devising a novel route to macrocyclic peptides, Professor E. Biron, S. Jobin and C. Beaumont report the use of a 4-(4-formyl-3,5-dimethoxyphenoxy)butanoate linker in Ugi reactions with Fmoc-protected peptide and amino carboxylates, cumyl glycinate, and tert-butyl isocyanate to produce orthogonally protected backbone anchored peptide precursors that are cyclized prior to resin cleavage. Toward a One-Bead-One-Compound (OBOC) library of α-amanitin analogs, Professor D. M. Perrin, A. Blanc and D. J. Dietrich present a solid-phase synthesis approach to derivatives of the natural bicyclic octapeptide RNA polymerase II inhibitor. The fluorescent analogs they synthesize are observed by confocal microscopy to localize in the cell nucleus, contingent on membrane permeability. Targeting analogs of the cyclic lipodepsipeptide antibiotic daptomycin, Professor S. D. Taylor, G. Barnawi, M. Noden, R. Taylor, C. Lohani, D. Beriashvili and M. Palmer report the first entirely Fmoc-based solid-phase synthesis of a novel antibacterial daptomycin analog lead with similar membrane pore-forming ability as the parent peptide. Their strategy features a carbodiimide-esterification of a linear sequence employing a catalytic quantity of 4-dimethylaminopyridine and triton X-100 as an additive on Tentagel resin. Finally, from my own laboratory, Ahsanullah, R. Chingle, R. G. Ohm and P. S. Chauhan describe an effective means for introducing aza-propargylglycine into peptide sequences that are applied in an Ala-scan of a potent azacyclopeptide CD36 modulator. Considering the diversity and quality of the science described in this special issue, Banting, would likely feel proud to see that from the manifestation of his pioneering studies on insulin has emerged a vibrant field of research touching various subjects in laboratories throughout Canada. The glimpse provided by this snapshot of the field depicts a Canadian landscape rich with color like an Emily Carr or Alexander Young Jackson landscape. Novel peptide science is emerging each day in Canada as illustrated by the full spectrum of reviews and the innovative research articles presented herein. Enjoy the read. Dedicated to the memory of Professor Michele Auger l'Université Laval (1963-2018).