Abstract
Since the introduction of insulin almost a century ago, more than 80 peptide drugs have reached the market for a wide range of diseases, including diabetes, cancer, osteoporosis, multiple sclerosis, HIV infection and chronic pain. In this Perspective, we summarize key trends in peptide drug discovery and development, covering the early efforts focused on human hormones, elegant medicinal chemistry and rational design strategies, peptide drugs derived from nature, and major breakthroughs in molecular biology and peptide chemistry that continue to advance the field. We emphasize lessons from earlier approaches that are still relevant today as well as emerging strategies such as integrated venomics and peptide-display libraries that create new avenues for peptide drug discovery. We also discuss the pharmaceutical landscape in which peptide drugs could be particularly valuable and analyse the challenges that need to be addressed for them to reach their full potential.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Merrifield, R. B. Solid phase peptide synthesis. I. The synthesis of a tetrapeptide. J. Am. Chem. Soc. 85, 2149–2154 (1963).
Reichert, J. Development trends for peptide therapeutics (Peptide Therapeutics Foundation, 2010).
Fosgerau, K. & Hoffmann, T. Peptide therapeutics: current status and future directions. Drug Discov. Today 20, 122–128 (2014).
Lau, J. L. & Dunn, M. K. Therapeutic peptides: historical perspectives, current development trends, and future directions. Bioorg. Med. Chem. 26, 2700–2707 (2018).
Matchar, D. B. et al. Systematic review: comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for treating essential hypertension. Ann. Intern. Med. 148, 16–29 (2008).
Izzo, J. L. Jr. & Weir, M. R. Angiotensin-converting enzyme inhibitors. J. Clin. Hypertens. 13, 667–675 (2011).
Regulska, K., Stanisz, B., Regulski, M. & Murias, M. How to design a potent, specific, and stable angiotensin-converting enzyme inhibitor. Drug Discov. Today 19, 1731–1743 (2014).
Acharya, K. R., Sturrock, E. D., Rirodan, J. F. & Ehlers, M. R. W. ACE revisited: a new target for structure-based drug design. Nat. Rev. Drug Discov. 2, 891–902 (2003).
Regulski, M. et al. Chemistry and pharmacology of angiotensin-converting enzyme inhibitors. Curr. Pharm. Des. 21, 1764–1775 (2015).
Luther, A., Bisang, C. & Obrecht, D. Advances in macrocyclic peptide-based antibiotics. Bioorg. Med. Chem. 26, 2850–2858 (2018).
Brown, E. D. & Wright, G. D. Antibacterial drug discovery in the resistance era. Nature 529, 336–343 (2016).
Infoholic Research LLP. Global Human Insulin Market 2018–2024. Research and Markets, ID: 4470733 (2018).
Nestor, J. J. The medicinal chemistry of peptides. Curr. Med. Chem. 16, 4399–4418 (2009).
Adessi, C. & Soto, C. Converting a peptide into a drug: strategies to improve stability and bioavailability. Curr. Med. Chem. 9, 963–978 (2002).
Gentilucci, L., De Marco, R. & Cerisoli, L. Chemical modifications designed to improve peptide stability: incorporation of non-natural amino acids, pseudo-peptide bonds, and cyclization. Curr. Pharm. Des. 16, 3185–3203 (2010).
Jost, K., Lebl, M. & Brtnik, F. CRC Handbook of Neurohypophyseal Hormone Analogs. Volumes I & II (eds Jost, K., Lebl, M. & Brtnik, F.). (CRC Press, 1987).
Zaoral, M., Kolc, J. & Sorm, F. Amino acids and peptides. LXXI. Synthesis of 1-deamino-8-D-gamma-aminobutyrine vasopressin, 1-deamino-8-D-lysine vasopressin, and 1-deamino-8-D-arginine vasopressin. Collect. Czech. Chem. Commun. 32, 1250–1257 (1967).
Dimson, S. B. Desmopressin as a treatment for enuresis. Lancet 1, 1260 (1977).
Melin, P., Trojnar, J., Johansson, B., Vilhardt, H. & Aakerlund, M. Synthetic antagonists of the myometrial response to vasopressin and oxytocin. J. Endocrinol. 111, 125–131 (1986).
Du Vigneaud, V., Winestock, G., Murti, V. V., Hope, D. B. & Kimbrough, R. D. Jr. Synthesis of 1-beta-mercantopropionic acid oxytocin (desamino-oxytocin), a highly potent analogue of oxytocin. J. Biol. Chem. 235, PC64–PC66 (1960).
Hope, D. B., Murti, V. V. S. & du Vigneaud, V. A highly potent analog of oxytocin, deaminooxytocin. J. Biol. Chem. 237, 1563–1566 (1962).
Manning, M., Balaspiri, L., Acosta, M. & Sawyer, W. H. Solid phase synthesis of [1-deamino,4-valine]-8-D-arginine-vasopressin (DVDAVP), a highly potent and specific antidiuretic agent possessing protracted effects. J. Med. Chem. 16, 975–978 (1973).
Kyncl, J. & Rudinger, J. Excretion of antidiuretic activity in the urine of cats and rats after administration of the synthetic hormonogen, Nα-glycyl-glycyl-glycyl-[8-lysine]-vasopressin (triglycylvasopressin). J. Endocrinol. 48, 157–165 (1970).
Kruszynski, M. et al. [1-(β-mercapto-β,β-cyclopentamethylenepropionic acid),2-(O-methyl)tyrosine]arginine-vasopressin and [1-(β-mercapto-β,β-cyclopentamethylenepropionic acid)]arginine-vasopressin, two highly potent antagonists of the vasopressor response to arginine-vasopressin. J. Med. Chem. 23, 364–368 (1980).
Meraldi, J. P., Hruby, V. J. & Brewster, A. I. R. Relative conformational rigidity in oxytocin and [1-penicillamine]oxytocin: a proposal for the relation of conformational flexibility to peptide hormone agonism and antagonism. Proc. Natl Acad. Sci. USA 74, 1373–1377 (1977).
Walter, R. & du Vigneaud, V. 1-Deamino-1,6-L-selenocystineoxytocin; a highly potent isolog of 1-deaminooxytocin. J. Am. Chem. Soc. 88, 1331–1332 (1966).
Walter, R. & du Vigneaud, V. 6-Hemi-L-selenocystine-oxytocin and 1-deamino-6-hemi-L-selenocystine-oxytocin, highly potent isologs of oxytocin and 1-deamino-oxytocin. J. Am. Chem. Soc. 87, 4192–4193 (1965).
Yamanaka, T. et al. Crystalline deamino-dicarba-oxytocin. Preparation and some pharmacological properties. Mol. Pharmacol. 6, 474–480 (1970).
Sweeney, G. et al. Pharmacokinetics of carbetocin, a long-acting oxytocin analog, in nonpregnant women. Curr. Ther. Res. 47, 528–540 (1990).
Manning, M. et al. Oxytocin and vasopressin agonists and antagonists as research tools and potential therapeutics. J. Neuroendocrinol. 24, 609–628 (2012).
Manning, M. et al. Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V1a, V1b, V2 and OT receptors: research tools and potential therapeutic agents. Prog. Brain Res. 170, 473–512 (2008).
Ling, N., Burgus, R., Rivier, J., Vale, W. & Brazeau, P. Use of mass spectrometry in deducing the sequence of somatostatin, a hypothalamic polypeptide that inhibits the secretion of growth hormone. Biochem. Biophys. Res. Commun. 50, 127–133 (1973).
Theodoropoulou, M. & Stalla, G. K. Somatostatin receptors: from signaling to clinical practice. Front. Neuroendocrinol. 34, 228–252 (2013).
Biron, E. et al. Improving oral bioavailability of peptides by multiple N-methylation: somatostatin analogues. Angew. Chem. Int. Ed. 47, 2595–2599 (2008).
Janecka, A., Zubrzycka, M. & Janecki, T. Somatostatin analogs. J. Pept. Res. 58, 91–107 (2001).
Vale, W., Brown, M., Rivier, C., Perrin, M. & Rivier, J. Development and applications of analogs of LRF and somatostatin. in Brain Peptides: A New Endocrinology, 71–88 (Elsevier/North-Holland Biomedical Press, 1979).
Susini, C. & Buscail, L. Rationale for the use of somatostatin analogs as antitumor agents. Ann. Oncol. 17, 1733–1742 (2006).
De Jong, M., Breeman, W. A. P., Kwekkeboom, D. J., Valkema, R. & Krenning, E. P. Tumor imaging and therapy using radiolabeled somatostatin analogues. Acc. Chem. Res. 42, 873–880 (2009).
Kwekkeboom, D. J. et al. [177Lu-DOTA0Tyr3]octreotate: comparison with [111In-DTPA0]octreotide in patients. Eur. J. Nucl. Med. 28, 1319–1325 (2001).
Brabander, T. et al. Long-term efficacy, survival, and safety of [177Lu-DOTA0,Tyr3]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clin. Cancer Res. 23, 4617–4624 (2017).
Strosberg, J. et al. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N. Engl. J. Med. 376, 125–135 (2017).
Millar, R. P. & Newton, C. L. Current and future applications of GnRH, kisspeptin and neurokinin B analogues. Nat. Rev. Endocrinol. 9, 451–466 (2013).
Tan, O. & Bukulmez, O. Biochemistry, molecular biology and cell biology of gonadotropin-releasing hormone antagonists. Curr. Opin. Obstet. Gynecol. 23, 238–244 (2011).
Mitragotri, S., Burke, P. A. & Langer, R. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat. Rev. Drug Discov. 13, 655–672 (2014).
Zhang, J., Desale, S. S. & Bronich, T. K. Polymer-based vehicles for therapeutic peptide delivery. Ther. Deliv. 6, 1279–1296 (2015).
Wang, Y., Qu, W. & Choi, S. H. FDA’s regulatory science program for generic PLA/PLGA-based drug products. Am. Pharm. Rev. 20, 52–55 (2017).
Itakura, K. et al. Expression in Escherichia coli of a chemically synthesized gene for the hormone somatostatin. Science 198, 1056–1063 (1977).
Johnson, I. S. Human insulin from recombinant DNA technology. Science 219, 632–637 (1983).
Zaykov, A. N., Mayer, J. P. & DiMarchi, R. D. Pursuit of a perfect insulin. Nat. Rev. Drug Discov. 15, 425–439 (2016).
Goeddel, D. V. et al. Expression in Escherichia coli of chemically synthesized genes for human insulin. Proc. Natl Acad. Sci. USA 76, 106–110 (1979).
Hirsch, I. B. Insulin analogues. N. Engl. J. Med. 352, 174–183 (2005).
Inzerillo, A. M., Zaidi, M. & Huang, C. L. H. Calcitonin: physiological actions and clinical applications. J. Pediatr. Endocrinol. Metab. 17, 931–940 (2004).
Copp, D. H. & Cheney, B. Calcitonin-a hormone from the parathyroid which lowers the calcium level of the blood. Nature 193, 381–382 (1962).
Copp, D. H. & Cameron, E. C. Demonstration of a hypocalcemic factor (calcitonin) in commercial parathyroid extract. Science 134, 2038 (1961).
Collip, J. B. The extraction of a parathyroid hormone which will prevent or control parathyroid tetany and which regulates the level of blood calcium. J. Biol. Chem. 63, 395–438 (1925).
Kim, E. S. & Keating, G. M. Recombinant human parathyroid hormone (1–84): a review in hypoparathyroidism. Drugs 75, 1293–1303 2015).
Haas, A. V. & LeBoff, M. S. Osteoanabolic agents for osteoporosis. J. Endocr. Soc. 2, 922–932 (2018).
Huang, Y. & Liu, T. Therapeutic applications of genetic code expansion. Synth. Syst. Biotechnol. 3, 150–158 (2018).
Young, D. D. & Schultz, P. G. Playing with the molecules of life. ACS Chem. Biol. 13, 854–870 (2018).
Arranz-Gibert, P., Vanderschuren, K. & Isaacs, F. J. Next-generation genetic code expansion. Curr. Opin. Chem. Biol. 46, 203–211 (2018).
Subtelny, A. O., Hartman, M. C. T. & Szostak, J. W. Ribosomal synthesis of N-methyl peptides. J. Am. Chem. Soc. 130, 6131–6136 (2008).
Kawakami, T., Murakami, H. & Suga, H. Messenger RNA-programmed incorporation of multiple N-methyl-amino acids into linear and cyclic peptides. Chem. Biol. 15, 32–42 (2008).
Goto, Y., Murakami, H. & Suga, H. Initiating translation with D-amino acids. RNA 14, 1390–1398 (2008).
Fujino, T., Goto, Y., Suga, H. & Murakami, H. Reevaluation of the D-amino acid compatibility with the elongation event in translation. J. Am. Chem. Soc. 135, 1830–1837 (2013).
Achenbach, J. et al. Outwitting EF-Tu and the ribosome: translation with D-amino acids. Nucleic Acids Res. 43, 5687–5698 (2015).
Fujino, T., Goto, Y., Suga, H. & Murakami, H. Ribosomal synthesis of peptides with multiple β-amino acids. J. Am. Chem. Soc. 138, 1962–1969 (2016).
Katoh, T. & Suga, H. Ribosomal incorporation of consecutive β-amino acids. J. Am. Chem. Soc. 140, 12159–12167 (2018).
Maini, R. et al. Ribosomal formation of thioamide bonds in polypeptide synthesis. J. Am. Chem. Soc. 141, 20004–20008 (2019).
Kawakami, T., Murakami, H. & Suga, H. Ribosomal synthesis of polypeptoids and peptoid-peptide hybrids. J. Am. Chem. Soc. 130, 16861–16863 (2008).
Huang, Y., Wiedmann, M. M. & Suga, H. RNA display methods for the discovery of bioactive macrocycles. Chem. Rev. 119, 10360–10391 (2018).
Taylor, R. D., Rey-Carrizo, M., Passioura, T. & Suga, H. Identification of nonstandard macrocyclic peptide ligands through display screening. Drug Discov. Today Technol. 26, 17–23 (2017).
Passioura, T. & Suga, H. A RaPID way to discover nonstandard macrocyclic peptide modulators of drug targets. Chem. Commun. 53, 1931–1940 (2017).
Borel, J. F., Feurer, C., Gubler, H. U. & Staehelin, H. Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions 6, 468–475 (1976).
Saehelin, H. F. The history of cyclosporin A (Sandimmune) revisited: another point of view. Experientia 52, 5–13 (1996).
Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 46, 3–26 (2001).
Rydel, T. J. et al. The structure of a complex of recombinant hirudin and human α-thrombin. Science 249, 277–280 (1990).
Warkentin, T. E. & Koster, A. Bivalirudin: a review. Expert Opin. Pharmacother. 6, 1349–1371 (2005).
Behrendt, R., White, P. & Offer, J. Advances in Fmoc solid-phase peptide synthesis. J. Pept. Sci. 22, 4–27 (2016).
Coin, I., Beyermann, M. & Bienert, M. Solid-phase peptide synthesis: from standard procedures to the synthesis of difficult sequences. Nat. Protoc. 2, 3247–3256 (2007).
Paradis-Bas, M., Tulla-Puche, J. & Albericio, F. The road to the synthesis of “difficult peptides”. Chem. Soc. Rev. 45, 631–654 (2016).
Schnölzer, M., Alewood, P. F., Jones, A., Alewood, D. & Kent, S. B. H. In situ neutralization in Boc-chemistry solid phase peptide synthesis. Rapid, high yield assembly of difficult sequences. Int. J. Pept. Protein Res. 40, 180–193 (1992).
Dawson, P. E., Muir, T. W., Clark-Lewis, I. & Kent, S. B. Synthesis of proteins by native chemical ligation. Science 266, 776–779 (1994).
Miranda, L. P. & Alewood, P. F. Accelerated chemical synthesis of peptides and small proteins. Proc. Natl Acad. Sci. USA 96, 1181–1186 (1999).
Kent, S. B. H. Total chemical synthesis of proteins. Chem. Soc. Rev. 38, 338–351 (2009).
Kent, S. Chemical protein synthesis: inventing synthetic methods to decipher how proteins work. Bioorg. Med. Chem. 25, 4926–4937 (2017).
King, G. F. Venoms as a platform for human drugs: translating toxins into therapeutics. Expert Opin. Biol. Ther. 11, 1469–1484 (2011).
Robinson, S. D., Undheim, E. A. B., Ueberheide, B. & King, G. F. Venom peptides as therapeutics: advances, challenges and the future of venom-peptide discovery. Expert Rev. Proteom. 14, 931–939 (2017).
Holford, M., Daly, M., King, G. F. & Norton, R. S. Venoms to the rescue: insights into the evolutionary biology of venoms are leading to therapeutic advances. Science 361, 842–844 (2018).
Jin, A.-H. et al. Conotoxins: chemistry and biology. Chem. Rev. 119, 11510–11549 (2019).
Akondi, K. B. et al. Discovery, synthesis, and structure-activity relationships of conotoxins. Chem. Rev. 114, 5815–5847 (2014).
Drucker, D. J. & Nauck, M. A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368, 1696–1705 (2006).
Elahi, D. et al. The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7–37) in normal and diabetic subjects. Regul. Pept. 51, 63–75 (1994).
Nielsen, L. L., Young, A. A. & Parkes, D. G. Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes. Regul. Pept. 117, 77–88 (2004).
Eng, J., Kleinman, W. A., Singh, L., Singh, G. & Raufman, J. P. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J. Biol. Chem. 267, 7402–7405 (1992).
Ruiz-Gomez, G., Tyndall, J. D., Pfeiffer, B., Abbenante, G. & Fairlie, D. P. Update 1 of: over one hundred peptide-activated G protein-coupled receptors recognize ligands with turn structure. Chem. Rev. 110, PR1–PR41 (2010).
DeYoung, M. B., MacConell, L., Sarin, V., Trautmann, M. & Herbert, P. Encapsulation of exenatide in poly-(D,L-lactide-Co-glycolide) microspheres produced an investigational long-acting once-weekly formulation for type 2 diabetes. Diabetes Technol. Ther. 13, 1145–1154 (2011).
Miljanich, G. P. Ziconotide: neuronal calcium channel blocker for treating severe chronic pain. Curr. Med. Chem. 11, 3029–3040 (2004).
Vetter, I. et al. Venomics: a new paradigm for natural products-based drug discovery. Amino Acids 40, 15–28 (2011).
Dutertre, S. et al. in Venoms to Drugs: Venom as a Source for the Development of Human Therapeutics (ed. King, G. F.) 80–96 (Royal Society of Chemistry, 2015).
Klint, J. K. et al. Production of recombinant disulfide-rich venom peptides for structural and functional analysis via expression in the periplasm of E. coli. PLoS ONE 8, e63865 (2013).
Muttenthaler, M. et al. Solving the α-conotoxin folding problem: efficient selenium-directed on-resin generation of more potent and stable nicotinic acetylcholine receptor antagonists. J. Am. Chem. Soc. 132, 3514–3522 (2010).
Muttenthaler, M. & Alewood, P. F. Selenopeptide chemistry. J. Pept. Sci. 14, 1223–1239 (2008).
Vetter, I., Hodgson, W. C., Adams, D. J. & McIntyre, P. in Venoms to drugs: venom as a source for the development of human therapeutics (ed. King, G. F.) 97–128 (Royal Society of Chemistry, 2015).
Ziemert, N., Alanjary, M. & Weber, T. The evolution of genome mining in microbes - a review. Nat. Prod. Rep. 33, 988–1005 (2016).
Makarewich, C. A. & Olson, E. N. Mining for micropeptides. Trends Cell Biol. 27, 685–696 (2017).
Hetrick, K. J. & van der Donk, W. A. Ribosomally synthesized and post-translationally modified peptide natural product discovery in the genomic era. Curr. Opin. Chem. Biol. 38, 36–44 (2017).
Tietz, J. I. et al. A new genome-mining tool redefines the lasso peptide biosynthetic landscape. Nat. Chem. Biol. 13, 470–478 (2017).
Mendel, H. C., Kaas, Q. & Muttenthaler, M. Neuropeptide signalling systems - an underexplored target for venom drug discovery. Biochem. Pharmacol. 181, 114129 (2020).
Gruber, C. W. & Muttenthaler, M. Discovery of defense- and neuropeptides in social ants by genome-mining. PLoS ONE 7, e32559 (2012).
Ling, L. L. et al. A new antibiotic kills pathogens without detectable resistance. Nature 517, 455–459 (2015).
Karas, J. A. et al. Synthesis and structure-activity relationships of teixobactin. Ann. N. Y. Acad. Sci. 1459, 86–105 (2020).
Gunjal, V. B., Thakare, R., Chopra, S. & Reddy, D. S. Teixobactin: a paving stone toward a new class of antibiotics? J. Med. Chem. 63, 12171–12195 (2020).
Mookherjee, N., Anderson, M. A., Haagsman, H. P. & Davidson, D. J. Antimicrobial host defence peptides: functions and clinical potential. Nat. Rev. Drug Discov. 19, 311–332 (2020).
Johnson, V. & Maack, T. Renal extraction, filtration, absorption, and catabolism of growth hormone. Am. J. Physiol. 233, F185–F196 (1977).
Maack, T., Johnson, V., Kau, S. T., Figueiredo, J. & Sigulem, D. Renal filtration, transport, and metabolism of low-molecular-weight proteins: a review. Kidney Int. 16, 251–270 (1979).
Katz, A. I. & Emmanouel, D. S. Metabolism of polypeptide hormones by the normal kidney and in uremia. Nephron 22, 61–72 (1978).
Pollaro, L. & Heinis, C. Strategies to prolong the plasma residence time of peptide drugs. Med. Chem. Commun. 1, 319–324 (2010).
Kolate, A. et al. PEG - a versatile conjugating ligand for drugs and drug delivery systems. J. Control. Release 192, 67–81 (2014).
Kurtzhals, P. et al. Albumin binding of insulins acylated with fatty acids: characterization of the ligand-protein interaction and correlation between binding affinity and timing of the insulin effect in vivo. Biochem. J. 312, 725–731 (1995).
Elbrond, B. et al. Pharmacokinetics, pharmacodynamics, safety, and tolerability of a single-dose of NN2211, a long-acting glucagon-like peptide 1 derivative, in healthy male subjects. Diabetes Care 25, 1398–1404 (2002).
Falutz, J. et al. Metabolic effects of a growth hormone-releasing factor in patients with HIV. N. Engl. J. Med. 357, 2359–2370 (2007).
Ferdinandi, E. S. et al. Non-clinical pharmacology and safety evaluation of TH9507, a human growth hormone-releasing factor analogue. Basic Clin. Pharmacol. Toxicol. 100, 49–58 (2007).
Baggio, L. L., Huang, Q., Brown, T. J. & Drucker, D. J. A recombinant human glucagon-like peptide (GLP)-1-albumin protein (Albugon) mimics peptidergic activation of GLP-1 receptor-dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis. Diabetes 53, 2492–2500 (2004).
Matthews, J. E. et al. Pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 93, 4810–4817 (2008).
Glaesner, W. et al. Engineering and characterization of the long-acting glucagon-like peptide-1 analogue LY2189265, an Fc fusion protein. Diabetes Metab. Res. Rev. 26, 287–296 (2010).
D’Souza, A. A. & Shegokar, R. Polyethylene glycol (PEG): a versatile polymer for pharmaceutical applications. Expert Opin. Drug Deliv. 13, 1257–1275 (2016).
Park, E. J., Choi, J., Lee, K. C. & Na, D. H. Emerging PEGylated non-biologic drugs. Expert Opin. Emerg. Drugs 24, 107–119 (2019).
Sahu, A., Kay, B. K. & Lambris, J. D. Inhibition of human complement by a C3-binding peptide isolated from a phage-displayed random peptide library. J. Immunol. 157, 884–891 (1996).
Liao, D. S. et al. Complement C3 inhibitor pegcetacoplan for geographic atrophy secondary to age-related macular degeneration: a randomized phase 2 trial. Ophthalmology 127, 186–195 (2020).
Bianchi, E. et al. A PEGylated analog of the gut hormone oxyntomodulin with long-lasting antihyperglycemic, insulinotropic and anorexigenic activity. Bioorg. Med. Chem. 21, 7064–7073 (2013).
Smith, G. P. Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science 228, 1315–1317 (1985).
Davis, A. M., Plowright, A. T. & Valeur, E. Directing evolution: the next revolution in drug discovery? Nat. Rev. Drug Discov. 16, 681–698 (2017).
Schmid, H. Peginesatide for the treatment of renal disease-induced anemia. Expert Opin. Pharmacother. 14, 937–948 (2013).
MacDougall, I. C. et al. Peginesatide for anemia in patients with chronic kidney disease not receiving dialysis. N. Engl. J. Med. 368, 320–332 (2013).
Hermanson, T., Bennett, C. L. & MacDougall, I. C. Peginesatide for the treatment of anemia due to chronic kidney disease – an unfulfilled promise. Expert Opin. Drug Saf. 15, 1421–1426 (2016).
Wrighton, N. C. et al. Small peptides as potent mimetics of the protein hormone erythropoietin. Science 273, 458–463 (1996).
Wrighton, N. et al. Increased potency of an erythropoietin peptide mimetic through covalent dimerization. Nat. Biotechnol. 15, 1261–1265 (1997).
Fan, Q. et al. Preclinical evaluation of Hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia. Exp. Hematol. 34, 1303–1311 (2006).
Molineux, G. & Newland, A. Development of romiplostim for the treatment of patients with chronic immune thrombocytopenia: from bench to bedside. Br. J. Haematol. 150, 9–20 (2010).
Lehmann, A. Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery. Expert Opin. Biol. Ther. 8, 1187–1199 (2008).
Nixon, A. E., Sexton, D. J. & Ladner, R. C. Drugs derived from phage display: from candidate identification to clinical practice. MAbs 6, 73–85 (2014).
Tavassoli, A. SICLOPPS cyclic peptide libraries in drug discovery. Curr. Opin. Chem. Biol. 38, 30–35 (2017).
Rentero Rebollo, I. & Heinis, C. Phage selection of bicyclic peptides. Methods 60, 46–54 (2013).
Deyle, K., Kong, X.-D. & Heinis, C. Phage selection of cyclic peptides for application in research and drug development. Acc. Chem. Res. 50, 1866–1874 (2017).
Kong, X.-D. et al. De novo development of proteolytically resistant therapeutic peptides for oral administration. Nat. Biomed. Eng. 4, 560–571 (2020).
Baeriswyl, V. et al. A synthetic factor XIIa inhibitor blocks selectively intrinsic coagulation initiation. ACS Chem. Biol. 10, 1861–1870 (2015).
Middendorp, S. J. et al. Peptide macrocycle inhibitor of coagulation factor XII with subnanomolar affinity and high target selectivity. J. Med. Chem. 60, 1151–1158 (2017).
Zhao, L. & Lu, W. Mirror image proteins. Curr. Opin. Chem. Biol. 22, 56–61 (2014).
Zhou, X. et al. A novel D-peptide identified by mirror-image phage display blocks TIGIT/PVR for cancer immunotherapy. Angew. Chem. Int. Ed. 59, 15114–15118 (2020).
Diaz-Perlas, C. et al. Protein chemical synthesis combined with mirror-image phage display yields D-peptide EGF ligands that block the EGF-EGFR interaction. ChemBioChem 20, 2079–2084 (2019).
Rudolph, S. et al. Competitive mirror image phage display derived peptide modulates amyloid beta aggregation and toxicity. PLoS ONE 11, e0147470 (2016).
Tsiamantas, C., Otero-Ramirez Manuel, E. & Suga, H. Discovery of functional macrocyclic peptides by means of the RaPID system. Methods Mol. Biol. 2001, 299–315 (2019).
Guillen Schlippe, Y. V., Hartman, M. C. T., Josephson, K. & Szostak, J. W. In vitro selection of highly modified cyclic peptides that act as tight binding inhibitors. J. Am. Chem. Soc. 134, 10469–10477 (2012).
Howard, J. F. et al. Clinical effects of the self-administered subcutaneous complement inhibitor zilucoplan in patients with moderate to severe generalized myasthenia gravis: results of a phase 2 randomized, double-blind, placebo-controlled, multicenter clinical trial. JAMA Neurol. 77, 582–592 (2020).
Craik, D. J., Fairlie, D. P., Liras, S. & Price, D. The future of peptide-based drugs. Chem. Biol. Drug Des. 81, 136–147 (2013).
Nielsen, D. S. et al. Orally absorbed cyclic peptides. Chem. Rev. 117, 8094–8128 (2017).
Muttenthaler, M. et al. Modulating oxytocin activity and plasma stability by disulfide bond engineering. J. Med. Chem. 53, 8585–8596 (2010).
Erak, M., Bellmann-Sickert, K., Els-Heindl, S. & Beck-Sickinger, A. G. Peptide chemistry toolbox - Transforming natural peptides into peptide therapeutics. Bioorg. Med. Chem. 26, 2759–2765 (2018).
Northfield, S. E. et al. Disulfide-rich macrocyclic peptides as templates in drug design. Eur. J. Med. Chem. 77, 248–257 (2014).
Liu, R., Li, X. & Lam, K. S. Combinatorial chemistry in drug discovery. Curr. Opin. Chem. Biol. 38, 117–126 (2017).
Huo, L. et al. Heterologous expression of bacterial natural product biosynthetic pathways. Nat. Prod. Rep. 36, 1412–1436 (2019).
Walensky, L. D. & Bird, G. H. Hydrocarbon-stapled peptides: principles, practice, and progress. J. Med. Chem. 57, 6275–6288 (2014).
Verdine, G. L. & Hilinski, G. J. Stapled peptides for intracellular drug targets. Methods Enzymol. 503, 3–33 (2012).
Cromm, P. M., Spiegel, J. & Grossmann, T. N. Hydrocarbon stapled peptides as modulators of biological function. ACS Chem. Biol. 10, 1362–1375 (2015).
Chang, Y. S. et al. Stapled α-helical peptide drug development: A potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Proc. Natl Acad. Sci. USA 1-10, 10 (2013).
Carvajal, L. A. et al. Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia. Sci. Transl. Med. 10, eaao3003 (2018).
Schmidt, M., Toplak, A., Quaedflieg, P. J. L. M. & Nuijens, T. Enzyme-mediated ligation technologies for peptides and proteins. Curr. Opin. Chem. Biol. 38, 1–7 (2017).
Nuijens, T. et al. Engineering a diverse ligase toolbox for peptide segment condensation. Adv. Synth. Catal. 358, 4041–4048 (2016).
Mijalis, A. J. et al. A fully automated flow-based approach for accelerated peptide synthesis. Nat. Chem. Biol. 13, 464–466 (2017).
Farra, R. et al. First-in-human testing of a wirelessly controlled drug delivery microchip. Sci. Transl. Med. 4, 122ra21 (2012).
Hogan, N. C., Taberner, A. J., Jones, L. A. & Hunter, I. W. Needle-free delivery of macromolecules through the skin using controllable jet injectors. Expert Opin. Drug Deliv. 12, 1637–1648 (2015).
Kumar, S. et al. Peptides as skin penetration enhancers: mechanisms of action. J. Control. Release 199, 168–178 (2015).
Zhang, Y. et al. Advances in transdermal insulin delivery. Adv. Drug Deliv. Rev. 139, 51–70 (2019).
Kochba, E., Levin, Y., Raz, I. & Cahn, A. Improved insulin pharmacokinetics using a novel microneedle device for intradermal delivery in patients with type 2 diabetes. Diabetes Technol. Ther. 18, 525–531 (2016).
Daddona, P. E., Matriano, J. A., Mandema, J. & Maa, Y.-F. Parathyroid hormone (1-34)-coated microneedle patch system: clinical pharmacokinetics and pharmacodynamics for treatment of osteoporosis. Pharm. Res. 28, 159–165 (2011).
Kim, E. S. & Plosker, G. L. AFREZZA® (insulin human) inhalation powder: a review in diabetes mellitus. Drugs 75, 1679–1686 (2015).
Sherr, J. L. et al. Glucagon nasal powder: a promising alternative to intramuscular glucagon in youth with type 1 diabetes. Diabetes Care 39, 555–562 (2016).
Drucker, D. J. Advances in oral peptide therapeutics. Nat. Rev. Drug Discov. 19, 277–289 (2020).
Brayden, D. J., Hill, T. A., Fairlie, D. P., Maher, S. & Mrsny, R. J. Systemic delivery of peptides by the oral route: formulation and medicinal chemistry approaches. Adv. Drug Deliv. Rev. 157, 2–36 (2020).
Granhall, C., Soendergaard, F. L., Thomsen, M. & Anderson, T. W. Pharmacokinetics, safety and tolerability of oral semaglutide in subjects with renal impairment. Clin. Pharmacokinet. 57, 1571–1580 (2018).
Ahnfelt-Roenne, J. et al. Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist. Sci. Transl. Med. 10, eaar7047 (2018).
Biermasz, N. R. New medical therapies on the horizon: oral octreotide. Pituitary 20, 149–153 (2017).
Eldor, R., Arbit, E., Corcos, A. & Kidron, M. Glucose-reducing effect of the ORMD-0801 oral insulin preparation in patients with uncontrolled type 1 diabetes: a pilot study. PLoS ONE 8, e59524 (2013).
Abramson, A. et al. A luminal unfolding microneedle injector for oral delivery of macromolecules. Nat. Med. 25, 1512–1518 (2019).
Abramson, A. et al. An ingestible self-orienting system for oral delivery of macromolecules. Science 363, 611–615 (2019).
Moroz, E., Matoori, S. & Leroux, J.-C. Oral delivery of macromolecular drugs: where we are after almost 100 years of attempts. Adv. Drug Deliv. Rev. 101, 108–121 (2016).
Copolovici, D. M., Langel, K., Eriste, E. & Langel, U. Cell-penetrating peptides: design, synthesis, and applications. ACS Nano 8, 1972–1994 (2014).
Shi, N.-Q., Qi, X.-R., Xiang, B. & Zhang, Y. A survey on “Trojan Horse” peptides: opportunities, issues and controlled entry to “Troy”. J. Control. Rel. 194, 53–70 (2014).
Staecker, H. et al. Efficacy and safety of AM-111 in the treatment of acute unilateral sudden deafness - a double-blind, randomized, placebo-controlled phase 3 study. Otol. Neurotol. 40, 584–594 (2019).
Hill, M. D. et al. Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial. Lancet 395, 878–887 (2020).
Guidotti, G., Brambilla, L. & Rossi, D. Cell-penetrating peptides: from basic research to clinics. Trends Pharmacol. Sci. 38, 406–424 (2017).
Cohen-Inbar, O. & Zaaroor, M. Glioblastoma multiforme targeted therapy: the chlorotoxin story. J. Clin. Neurosci. 33, 52–58 (2016).
Williams, J. A., Day, M. & Heavner, J. E. Ziconotide: an update and review. Expert. Opin. Pharmacother. 9, 1575–1583 (2008).
Bray, B. L. Large-scale manufacture of peptide therapeutics by chemical synthesis. Nat. Rev. Drug Discov. 2, 587–593 (2003).
Zompra, A. A., Galanis, A. S., Werbitzky, O. & Albericio, F. Manufacturing peptides as active pharmaceutical ingredients. Future Med. Chem. 1, 361–377 (2009).
Mayer, J. P., Zhang, F. & DiMarchi, R. D. Insulin structure and function. Biopolymers 88, 687–713 (2007).
Lien, S. & Lowman, H. B. Therapeutic peptides. Trends Biotechnol. 21, 556–562 (2003).
Pangalos, M. N., Schechter, L. E. & Hurko, O. Drug development for CNS disorders: strategies for balancing risk and reducing attrition. Nat. Rev. Drug Discov. 6, 521–532 (2007).
Gruber, C. W., Muttenthaler, M. & Freissmuth, M. Ligand-based peptide design and combinatorial peptide libraries to target G protein-coupled receptors. Curr. Pharm. Des. 16, 3071–3088 (2010).
Cragg, G. M. & Newman, D. J. Natural products: a continuing source of novel drug leads. Biochim. Biophys. Acta Gen. Subj. 1830, 3670–3695 (2013).
Davenport, A. P., Scully, C. C. G., de Graaf, C., Brown, A. J. H. & Maguire, J. J. Advances in therapeutic peptides targeting G protein-coupled receptors. Nat. Rev. Drug Discov. 19, 389–413 (2020).
Tsomaia, N. Peptide therapeutics: targeting the undruggable space. Eur. J. Med. Chem. 94, 459–470 (2015).
Milroy, L.-G., Grossmann, T. N., Hennig, S., Brunsveld, L. & Ottmann, C. Modulators of protein-protein interactions. Chem. Rev. 114, 4695–4748 (2014).
Lochhead, J. J. & Thorne, R. G. Intranasal delivery of biologics to the central nervous system. Adv. Drug Deliv. Rev. 64, 614–628 (2012).
Kosfeld, M., Heinrichs, M., Zak, P. J., Fischbacher, U. & Fehr, E. Oxytocin increases trust in humans. Nature 435, 673–676 (2005).
Veening, J. G. & Olivier, B. Intranasal administration of oxytocin: behavioral and clinical effects, a review. Neurosci. Biobehav. Rev. 37, 1445–1465 (2013).
Leng, G. & Ludwig, M. Intranasal oxytocin: myths and delusions. Biol. Psychiatry 79, 243–250 (2016).
Walum, H., Waldman, I. D. & Young, L. J. Statistical and methodological considerations for the interpretation of intranasal oxytocin studies. Biol. Psychiatry 79, 251–257 (2016).
Oller-Salvia, B., Sanchez-Navarro, M., Giralt, E. & Teixido, M. Blood-brain barrier shuttle peptides: an emerging paradigm for brain delivery. Chem. Soc. Rev. 45, 4690–4707 (2016).
Chen, Y. & Liu, L. Modern methods for delivery of drugs across the blood-brain barrier. Adv. Drug Deliv. Rev. 64, 640–665 (2012).
Dockray, G. J. Gastrointestinal hormones and the dialogue between gut and brain. J. Physiol. 592, 2927–2941 (2014).
Lalatsa, A., Schatzlein, A. G. & Uchegbu, I. F. Strategies to deliver peptide drugs to the brain. Mol. Pharm. 11, 1081–1093 (2014).
Lajoie, J. M. & Shusta, E. V. Targeting receptor-mediated transport for delivery of biologics across the blood-brain barrier. Annu. Rev. Pharmacol. Toxicol. 55, 613–631 (2015).
Acar, H., Ting, J. M., Srivastava, S., La Belle, J. L. & Tirrell, M. V. Molecular engineering solutions for therapeutic peptide delivery. Chem. Soc. Rev. 46, 6553–6569 (2017).
Fani, M., Maecke, H. R. & Okarvi, S. M. Radiolabeled peptides: valuable tools for the detection and treatment of cancer. Theranostics 2, 481–501 (2012).
Hirayama, M. & Nishimura, Y. The present status and future prospects of peptide-based cancer vaccines. Int. Immunol. 28, 319–328 (2016).
Chen, X., Yang, J., Wang, L. & Liu, B. Personalized neoantigen vaccination with synthetic long peptides: recent advances and future perspectives. Theranostics 10, 6011–6023 (2020).
Skwarczynski, M. & Toth, I. Peptide-based synthetic vaccines. Chem. Sci. 7, 842–854 (2016).
Malonis, R. J., Lai, J. R. & Vergnolle, O. Peptide-based vaccines: current progress and future challenges. Chem. Rev. 120, 3210–3229 (2020).
Busby, R. W. et al. Pharmacologic properties, metabolism, and disposition of linaclotide, a novel therapeutic peptide approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. J. Pharmacol. Exp. Ther. 344, 196–206 (2013).
Hancock, R. E. W. & Sahl, H.-G. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat. Biotechnol. 24, 1551–1557 (2006).
Kang, H.-K., Kim, C., Seo, C. H. & Park, Y. The therapeutic applications of antimicrobial peptides (AMPs): a patent review. J. Microbiol. 55, 1–12 (2017).
Blanes-Mira, C. et al. A synthetic hexapeptide (Argireline) with antiwrinkle activity. Int. J. Cosmet. Sci. 24, 303–310 (2002).
Robinson, L. R. et al. Topical palmitoyl pentapeptide provides improvement in photoaged human facial skin. Int. J. Cosmet. Sci. 27, 155–160 (2005).
Pickart, L. The human tri-peptide glycine-histidine-lysine and tissue remodeling. J. Biomater. Sci. Polym. Ed. 19, 969–988 (2008).
Du Vigneaud, V., Ressler, C., Swan, J. M., Roberts, C. W. & Katsoyannis, P. G. The synthesis of oxytocin. J. Am. Chem. Soc. 76, 3115–3121 (1954).
Du Vigneaud, V., Ressler, C. & Trippett, S. The sequence of amino acids in oxytocin, with a proposal for the structure of oxytocin. J. Biol. Chem. 205, 949–957 (1953).
Global Information Inc. Global Peptide Therapeutics Sales Market Report 2018. QYResearch, 387893 (2018).
Weinstock-Guttman, B., Nair, K. V., Glajch, J. L., Ganguly, T. C. & Kantor, D. Two decades of glatiramer acetate: from initial discovery to the current development of generics. J. Neurol. Sci. 376, 255–259 (2017).
Teitelbaum, D., Meshorer, A., Hirshfeld, T., Arnon, R. & Sela, M. Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide. Eur. J. Immunol. 1, 242–248 (1971).
Johnson, K. P. et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. Neurology 45, 1268–1276 (1995).
Aharoni, R. The mechanism of action of glatiramer acetate in multiple sclerosis and beyond. Autoimmun. Rev. 12, 543–553 (2013).
Lalive, P. H. et al. Glatiramer acetate in the treatment of multiple sclerosis: emerging concepts regarding its mechanism of action. CNS Drugs 25, 401–414 (2011).
Matthews, T. et al. Enfuvirtide: the first therapy to inhibit the entry of HIV-1 into host CD4 lymphocytes. Nat. Rev. Drug Discov. 3, 215–225 (2004).
Wild, C., Greenwell, T. & Matthews, T. A synthetic peptide from HIV-1 gp41 is a potent inhibitor of virus-mediated cell-cell fusion. AIDS Res. Hum. Retroviruses 9, 1051–1053 (1993).
Bruckdorfer, T., Marder, O. & Albericio, F. From production of peptides in milligram amounts for research to multi-tons quantities for drugs of the future. Curr. Pharm. Biotechnol. 5, 29–43 (2004).
Kintzing, J. R. & Cochran, J. R. Engineered knottin peptides as diagnostics, therapeutics, and drug delivery vehicles. Curr. Opin. Chem. Biol. 34, 143–150 (2016).
Pallaghy, P. K., Nielsen, K. J., Craik, D. J. & Norton, R. A common structural motif incorporating a cystine knot and a triple-stranded β-sheet in toxic and inhibitory polypeptides. Protein Sci. 3, 1833–1836 (1994).
Undheim, E. A. B., Mobli, M. & King, G. F. Toxin structures as evolutionary tools: using conserved 3D folds to study the evolution of rapidly evolving peptides. Bioessays 38, 539–548 (2016).
Murray, J. K. et al. Engineering potent and selective analogues of GpTx-1, a tarantula venom peptide antagonist of the Nav1.7 sodium channel. J. Med. Chem. 58, 2299–2314 (2015).
Flinspach, M. et al. Insensitivity to pain induced by a potent selective closed-state Nav1.7 inhibitor. Sci. Rep. 7, 39662 (2017).
Revell, J. D. et al. Potency optimization of Huwentoxin-IV on hNav1.7: a neurotoxin TTX-S sodium-channel antagonist from the venom of the Chinese bird-eating spider Selenocosmia huwena. Peptides 44, 40–46 (2013).
Schmalhofer, W. A. et al. ProTx-II, a selective inhibitor of Nav1.7 sodium channels, blocks action potential propagation in nociceptors. Mol. Pharmacol. 74, 1476–1484 (2008).
Santos, R. et al. A comprehensive map of molecular drug targets. Nat. Rev. Drug Discov. 16, 19–34 (2017).
Yu, F. H., Yarov-Yarovoy, V., Gutman, G. A. & Catterall, W. A. Overview of molecular relationships in the voltage-gated ion channel superfamily. Pharmacol. Rev. 57, 387–395 (2005).
Catterall, W. A. Voltage-gated sodium channels at 60: structure, function and pathophysiology. J. Physiol. 590, 2577–2589 (2012).
Ahern, C. A., Payandeh, J., Bosmans, F. & Chanda, B. The hitchhiker’s guide to the voltage-gated sodium channel galaxy. J. Gen. Physiol. 147, 1–24 (2016).
Pan, X. et al. Molecular basis for pore blockade of human Na+ channel Nav1.2 by the μ-conotoxin KIIIA. Science 363, 1309–1313 (2019).
Shen, H. et al. Structural basis for the modulation of voltage-gated sodium channels by animal toxins. Science 362, eaau2596 (2018).
Acknowledgements
The authors thank K. Woolcock for help with editing the manuscript. M.M. is supported by the European Research Council under the European Union’s Horizon 2020 research and innovation programme (714366), by the Australian Research Council (DE150100784 and DP190101667) and by the Vienna Science and Technology Fund (WWTF; LS18-053). P.F.A., G.F.K. and D.J.A. were supported by Program Grant APP1072113 from the Australian National Health & Medical Research Council (NHMRC) and NHMRC Principal Research Fellowships to G.F.K. (APP1136889) and P.F.A. (APP1080593).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Peer review information
Nature Reviews Drug Discovery thanks J. Mayer and the other, anonymous, reviewers for their contribution to the peer review of this work.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Muttenthaler, M., King, G.F., Adams, D.J. et al. Trends in peptide drug discovery. Nat Rev Drug Discov 20, 309–325 (2021). https://doi.org/10.1038/s41573-020-00135-8
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41573-020-00135-8
This article is cited by
-
Design of target specific peptide inhibitors using generative deep learning and molecular dynamics simulations
Nature Communications (2024)
-
A practical guide for the preparation of C1-labeled α-amino acids using aldehyde catalysis with isotopically labeled CO2
Nature Protocols (2024)
-
Cyclic peptides discriminate BCL-2 and its clinical mutants from BCL-XL by engaging a single-residue discrepancy
Nature Communications (2024)
-
A lncRNA Dleu2-encoded peptide relieves autoimmunity by facilitating Smad3-mediated Treg induction
EMBO Reports (2024)
-
Multiparametric in vitro and in vivo analysis of the safety profile of self-assembling peptides
Scientific Reports (2024)
