In 1901 Emil Fischer joined two glycine molecules in a flask. In 1922 a pancreatic extract saved a 14-year-old boy in Toronto. Today more than 80 peptide drugs are approved worldwide. This is the timeline, with the source for every date.
Toronto, August 1921Frederick Banting (right) and Charles Best, months before the first patient was treated with insulin. Photo by Henry Mahon, Thomas Fisher Rare Book Library, University of Toronto, CC BY 2.0.
Each mark is a milestone on this page, placed at its year.
Discoveries speed up.
190019251950197520002026
125 yearssince the first synthetic peptide, the glycylglycine of 1901.NobelPrize.org
23Nobel Prizes and 44 laureates linked to peptide science; six of those prizes for work on peptides themselves.See the prizes
A peptide is a short chain of amino acids joined by the bond Fischer named in 1902. They are the same language the body already uses to give orders: insulin, oxytocin, GLP-1 and ghrelin are peptides.
Natural messengers
Many hormones and neurotransmitters are peptides. A peptide drug usually mimics or modifies a signal that already exists.
High selectivity
They bind their receptor with great specificity, which generally translates into fewer off-target effects than many small molecules.
The challenge: they don't last
Enzymes break them down quickly and their half-life is short: native GLP-2 lasts about 7 minutes. Much of the recent history is about extending their life in the body, as the modern era shows.
32 milestones in four eras. Filled dots mark the moments that changed clinical practice. Each milestone links to its primary source or to an official record.
1900–1950
Discovery
Peptides were discovered before they could be made: first in a chemist's flask, then in extracts of animal glands.
Emil Fischer in his Berlin laboratory, around 1912. Unknown author, public domain.
1901
The first human-made peptide
Emil Fischer and Ernest Fourneau obtain glycylglycine, two glycines joined together. It is the first peptide synthesized in a laboratory.
At the Karlsbad congress, Franz Hofmeister proposes that proteins are chains of amino acids joined by amide bonds. At the same meeting, Fischer backs the idea and introduces the term “peptide”.
William Bayliss and Ernest Starling show that an extract of intestinal mucosa, carried by the blood, stimulates pancreatic secretion. They call that substance, a peptide, secretin. In 1905 Starling uses the word “hormone” for the first time for this kind of messenger.
William Bayliss. Maull & Fox, Wellcome Collection, CC BY 4.0.Ernest Starling, 1920. H. S. Raper, public domain.
1906
Oxytocin, before it had a name
Henry Dale observes that extract of the posterior lobe of the pituitary contracts the uterus. It is the action of the hormone that would later be called oxytocin.
Frederick Banting and Charles Best, in J. J. R. Macleod's laboratory at the University of Toronto, obtain pancreatic extracts that lower blood glucose in diabetic dogs. Biochemist James Collip joins to purify them.
On 11 January, 14-year-old Leonard Thompson receives the first extract at Toronto General Hospital. On 23 January, with the extract purified by Collip, his glucose normalizes and his condition improves. He lived thirteen more years.
Leonard Thompson (1908–1935). Unknown author, University of Toronto, public domain.
1923
Nobel Prize and the first insulin on sale
Banting and Macleod receive the Nobel Prize in Physiology or Medicine and share the prize money with Best and Collip. The team sells its patents to the University of Toronto for one dollar each. That same year Eli Lilly markets Iletin, the first commercially available insulin.
Frederick Sanger completes the structure of bovine insulin: 51 amino acids in two chains linked by disulfide bridges. It is the first protein whose complete sequence is known. Nobel Prize in Chemistry 1958.
Bruce Merrifield anchors the first amino acid to a resin and adds the next ones one at a time, washing between each step. The method makes peptide synthesis fast and automatable, and it is still the basis of their chemical production. Nobel Prize in Chemistry 1984.
The groups of Roger Guillemin and Andrew Schally identify TRH (1969) and LHRH, now GnRH (1971): hypothalamic hormones that control the pituitary. Nobel Prize in Medicine 1977, shared with Rosalyn Yalow for the radioimmunoassay of peptide hormones.
Guido Schoenenberger and Marcel Monnier characterize a nonapeptide that, infused into the cerebral ventricles of rabbits, enhances delta and spindle activity on the electroencephalogram.
On 18 October the FDA approves Genentech's Protropin for children with growth hormone deficiency. It replaces hormone extracted from the pituitaries of cadavers.
George Smith develops phage display: he displays peptides on bacteriophages to select, from millions of variants, those that bind to a target. Nobel Prize in Chemistry 2018.
Svetlana Mojsov, Gordon Weir and Joel Habener, in Boston, show in the perfused rat pancreas that GLP-1(7-37) stimulates insulin secretion. Jens Juul Holst and colleagues, in Copenhagen, independently reach the same conclusion in the perfused pig pancreas.
John Eng isolates exendin-4 from the venom of the Gila monster (Heloderma suspectum), a GLP-1-like peptide that years later would give rise to exenatide.
On 25 January the FDA approves liraglutide (Victoza): an analogue with 97% homology to human GLP-1 and an attached 16-carbon fatty acid, allowing a single daily dose.
The Lasker~DeBakey Clinical Medical Research Award honors Joel Habener, Svetlana Mojsov and Lotte Bjerre Knudsen for the discovery and development of GLP-1-based drugs.
On 19 September the FDA grants accelerated approval to elamipretide (Forzinity), the first treatment for Barth syndrome, in patients weighing at least 30 kg. It is a tetrapeptide that binds to cardiolipin in the inner mitochondrial membrane.
How a therapeutic peptide has been obtained in each era. Each method solved a limitation of the one before: quantity, purity or the ability to modify the molecule.
Extraction from animal glands
From 1922
Insulin was extracted from cattle and pig pancreases from slaughterhouses. It worked, but supply depended on the meat industry and the molecule was not identical to the human one.
Chemical synthesis in solution
1953, oxytocin
Du Vigneaud showed that a hormone could be built amino acid by amino acid. It was a slow process, with purification at every step.
Solid-phase synthesis (SPPS)
1963, Merrifield
The chain grows anchored to a resin and leftover reagents are washed away. It can be automated and allows non-natural amino acids and other modifications to be introduced.
Recombinant DNA
1978–1982, human insulin
Modified microorganisms produce the exact human sequence at industrial scale. This is how human insulin and growth hormone arrived.
Designed to last
2000–today
Amino acid changes and fatty acid chains that protect against degradation and bind to albumin: from daily to weekly doses.
Laboratory 221 at the University of Toronto, where Banting and Best worked in 1921–22. Photo from April 1929. Thomas Fisher Rare Book Library, CC BY 2.0.Front page of the Toronto Daily Star, March 1922: “Toronto doctors on track of diabetes cure”. Public domain.
Nobel Prizes linked to peptides
23 prizes and 44 laureates. First, the six prizes awarded for work on insulin, other peptides or their synthesis; then, the prizes that provided the tools and knowledge without which peptide medicines would not exist. Quoted text is the prize motivation as published by the Nobel Foundation.
for his work on biochemically important sulphur compounds, especially for the first synthesis of a polypeptide hormoneSource: NobelPrize.org
1958Chemistry
Frederick Sanger
for his work on the structure of proteins, especially that of insulinSource: NobelPrize.org
1977Physiology or Medicine
Roger Guillemin, Andrew V. Schally and Rosalyn Yalow
for their discoveries concerning the peptide hormone production of the brainYalow: for the development of radioimmunoassays of peptide hormonesSource: NobelPrize.org
1984Chemistry
RBM
R. Bruce Merrifield
for his development of methodology for chemical synthesis on a solid matrixSource: NobelPrize.org
In 1977 and 2018 the prize was divided: the other half in 1977 went to Yalow for radioimmunoassay, and in 2018 to Frances Arnold for the directed evolution of enzymes.
The science that made peptide medicines possible
Prizes whose motivation does not name peptides, but whose work underpins how they are discovered, made, analyzed and understood today.
1902Chemistry
Emil Fischer
in recognition of the extraordinary services he has rendered by his work on sugar and purine syntheses
Link to peptides: He synthesized the first dipeptide (1901) and introduced the word “peptide” (1902). His prize was for sugars and purines, but he is the father of peptide chemistry.
for his discovery of the part played by the hormone of the anterior pituitary lobe in the metabolism of sugar
Link to peptides: He showed that the anterior pituitary influences glucose metabolism, a central axis for insulin and growth hormone. (He shared the prize with Carl and Gerty Cori, awarded for glycogen metabolism.)
Link to peptides: Partition chromatography is the basis of HPLC, the method used to measure the purity of each batch of peptides. Sanger used it to sequence insulin.
Christian B. Anfinsen, Stanford Moore and William H. Stein
Anfinsen: for his work on ribonuclease, especially concerning the connection between the amino acid sequence and the biologically active conformationMoore and Stein: for their contribution to the understanding of the connection between chemical structure and catalytic activity of the active centre of the ribonuclease molecule
Link to peptides: Anfinsen showed that the amino acid sequence determines the active shape of a protein. Moore and Stein developed automated amino acid analysis.
for their discovery of G-proteins and the role of these proteins in signal transduction in cells
Link to peptides: G proteins relay the signal of many peptide hormones to the inside of the cell. Rodbell made his discovery while studying the glucagon receptor.
Fenn and Tanaka: for their development of soft desorption ionisation methods for mass spectrometric analyses of biological macromoleculesWüthrich: for his development of nuclear magnetic resonance spectroscopy for determining the three-dimensional structure of biological macromolecules in solution
Link to peptides: Mass spectrometry (ESI and MALDI) confirms the identity of each peptide, and NMR solves its structure in solution.
In 2024 the Lasker~DeBakey Clinical Medical Research Award, one of the most important medical honors in the United States, went to Habener, Mojsov and Knudsen for GLP-1-based drugs. Source: Lasker Foundation
Sources
Primary sources, official records and peer-reviewed reviews consulted for this page.
Nobel Foundation. Biography of Emil Fischer; official motivations for the prizes of 1902, 1923, 1946, 1947, 1948, 1952, 1954, 1955, 1958, 1962, 1964, 1968, 1971, 1972, 1977, 1984, 1986, 1994, 2002, 2009, 2012, 2018 and 2024 (api.nobelprize.org). nobelprize.org
Choudhary A, Raines RT. An evaluation of peptide-bond isosteres. ChemBioChem 2011;12:1801–7. PubMed 21751326
Bayliss WM, Starling EH. The mechanism of pancreatic secretion. J Physiol 1902;28:325–53. PubMed 16992627
Henderson J. Ernest Starling and 'Hormones': an historical commentary. J Endocrinol 2005;184:5–10. PubMed 15642778
Dale HH. On some physiological actions of ergot. J Physiol 1906;34:163–206. PubMed 16992821
Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA. Pancreatic extracts in the treatment of diabetes mellitus. Can Med Assoc J 1922;12:141–6. PubMed 20314060
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 1953;205:949–57. PubMed 13129273
Ryle AP, Sanger F, Smith LF, Kitai R. The disulphide bonds of insulin. Biochem J 1955;60:541–56. PubMed 13249947
Merrifield RB. Solid phase peptide synthesis. I. The synthesis of a tetrapeptide. J Am Chem Soc 1963;85:2149–54. doi:10.1021/ja00897a025
Goldstein AL, Slater FD, White A. Preparation, assay, and partial purification of a thymic lymphocytopoietic factor (thymosin). Proc Natl Acad Sci U S A 1966;56:1010–7. PubMed 5230175
Burgus R, Dunn TF, Ward DN, Vale W, Amoss M, Guillemin R. Synthetic polypeptide derivatives with thyrotropin releasing factor hypophysiotropic activity [in French]. C R Acad Hebd Seances Acad Sci D 1969;268:2116–8. PubMed 4980352
Schally AV, Arimura A, Kastin AJ, et al. Gonadotropin-releasing hormone: one polypeptide regulates secretion of luteinizing and follicle-stimulating hormones. Science 1971;173:1036–8. PubMed 4938639
Pickart L, Thaler MM. Tripeptide in human serum which prolongs survival of normal liver cells and stimulates growth in neoplastic liver. Nat New Biol 1973;243:85–7. PubMed 4349963
Schoenenberger GA, Monnier M. Characterization of a delta-electroencephalogram (-sleep)-inducing peptide. Proc Natl Acad Sci U S A 1977;74:1282–6. PubMed 265572
Goeddel DV, et al. Expression in Escherichia coli of chemically synthesized genes for human insulin. Proc Natl Acad Sci U S A 1979;76:106–10. PubMed 85300
Science History Institute. Herbert W. Boyer and Stanley N. Cohen (recombinant insulin, 1978). sciencehistory.org
Johnson IS. Human insulin from recombinant DNA technology. Science 1983;219:632–7. PubMed 6337396
Bowers CY, Momany FA, Reynolds GA, Hong A. On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology 1984;114:1537–45. PubMed 6714155
Genentech. 25th anniversary of first product approval (Protropin, 1985). gene.com
Mojsov S, Weir GC, Habener JF. Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J Clin Invest 1987;79:616–9. PubMed 3543057
Holst JJ, Orskov C, Nielsen OV, Schwartz TW. Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut. FEBS Lett 1987;211:169–74. PubMed 3542566
Eng J, et al. Isolation and characterization of exendin-4… from Heloderma suspectum venom. J Biol Chem 1992;267:7402–5. PubMed 1313797
Howard AD, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 1996;273:974–7. PubMed 8688086
Kojima M, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999;402:656–60. PubMed 10604470
U.S. FDA, Drugs@FDA: 018780 (Humulin R; NDA, BLA since 2020), 021773 (Byetta), 022341 (Victoza), 022505 (Egrifta), 209637 (Ozempic), 210557 (Vyleesi), 215256 (Wegovy), 215866 (Mounjaro), 215244 (Forzinity). accessdata.fda.gov
Lasker Foundation. 2024 Lasker~DeBakey Clinical Medical Research Award: GLP-1-based therapy for obesity. laskerfoundation.org
Wang L, et al. Therapeutic peptides: current applications and future directions. Signal Transduct Target Ther 2022;7:48. PMC8844085
Images. All photographs are historical and come from Wikimedia Commons, in the public domain or under a Creative Commons attribution licence, as indicated in each caption. Sanger, 1960: Willy Pragher, Landesarchiv Baden-Württemberg, CC BY 4.0. Banting (crop of the 1921 photo): Henry Mahon, Thomas Fisher Rare Book Library, CC BY 2.0. Macleod, around 1928: public domain. Guillemin, around 1975: National Library of Medicine, public domain. Schally: U.S. government, public domain. Yalow, 13 October 1977: US Information Agency, public domain. A sepia tone was applied to all photographs.
Laureate portraits. Photographs from Wikimedia Commons in the public domain or under a Creative Commons licence, cropped and sepia-toned. Christian B. Anfinsen: Hubbard, Edward A.; National Institutes of Health, public domain. David Baker: Jeffreyjgray, CC BY-SA 3.0. Stanley Cohen: unknown author, public domain. John B. Fenn: unknown author, public domain. Emil Fischer: Atelier Victoria, 1895, Wellcome Collection, CC BY 4.0. Alfred G. Gilman: NIH historic image, public domain. Demis Hassabis: John Sears, CC BY-SA 4.0. Dorothy Crowfoot Hodgkin: University of Bristol, CC BY-SA 2.0. Robert W. Holley: Sol Goldberg, public domain. Bernardo Houssay: unknow (uploader Claudio Elias), public domain. Earl W. Sutherland Jr.: unknown author, public domain. John Jumper: John Sears, CC BY-SA 4.0. John C. Kendrew: unknown author, public domain. H. Gobind Khorana: unknown author, public domain. Brian K. Kobilka: Charles Parnot, CC BY-SA 2.0. Robert J. Lefkowitz: Bengt Nyman, CC BY 2.0. Rita Levi-Montalcini: Kurt Hagblom, Firma Hagblom-Foto, restored by Adam Cuerden, public domain. Archer J. P. Martin: unknown author, public domain. Marshall W. Nirenberg: Hecht, Gerald V. (National Institutes of Health)., public domain. John H. Northrop: unknown author, public domain. Linus Pauling: Nobel Foundation, public domain. Max F. Perutz: Unknown, SVENSKT PRESSFOTO, public domain. Venkatraman Ramakrishnan: Royal Society uploader, CC BY-SA 4.0. Martin Rodbell: unknown author, public domain. George P. Smith: Bengt Nyman from Vaxholm, Sweden, CC BY 2.0. Wendell M. Stanley: unknown author, public domain. Thomas A. Steitz: Prolineserver (talk), CC BY-SA 3.0. James B. Sumner: unknown author, public domain. Richard L. M. Synge: unknown author, public domain. Koichi Tanaka: 日本学士院, CC BY 4.0. Arne Tiselius: Nobel Foundation, public domain. Gregory P. Winter: Aga Machaj, CC BY-SA 4.0. Kurt Wüthrich: DerHuti, CC BY-SA 3.0. Ada E. Yonath: Hareesh N. Nampoothiri, CC BY-SA 3.0. Stanford Moore, William H. Stein and R. Bruce Merrifield are shown with initials because no portraits with a verifiable free licence are available.
