PeptideJournal
Reference15 min read

Timeline of Peptide Discovery: From Insulin to GLP-1

The history of peptide therapeutics is a 100-year story of scientific breakthroughs, Nobel Prizes, and paradigm shifts in medicine.

The history of peptide therapeutics is a 100-year story of scientific breakthroughs, Nobel Prizes, and paradigm shifts in medicine. It begins in a Toronto laboratory in 1921, when two researchers extracted a substance from dog pancreases that could lower blood sugar — and it extends to today, when weekly injections of engineered peptides are reshaping the treatment of obesity, diabetes, cardiovascular disease, and potentially Alzheimer's.

This timeline traces the key milestones: the discoveries that proved peptides could be medicines, the technologies that made them manufacturable, and the clinical breakthroughs that turned them into a $49 billion market.

Table of Contents

The Pre-Insulin Era: 1901-1920

1901 — The First Synthetic Peptide

German chemist Emil Fischer and French chemist Ernest Fourneau synthesized glycyl-glycine (Gly-Gly), a dipeptide made of two glycine amino acids joined by a peptide bond. It was a modest molecule — just two amino acids — but it proved that peptide bonds could be created in the laboratory. Fischer went on to coin the term "peptide" and won the Nobel Prize in Chemistry in 1902 for his work on sugar and purine synthesis.

1902 — Discovery of Secretin

British physiologists William Bayliss and Ernest Starling discovered secretin, a peptide produced in the small intestine that stimulates pancreatic secretion. This was the first hormone ever identified — and it was a peptide. The discovery established that chemical messengers, not just nerves, could coordinate organ function. Starling introduced the word "hormone" in 1905.

1905 — Gastrin Identified

Edkins reported the existence of gastrin, a peptide hormone that stimulates gastric acid secretion. Together with secretin, gastrin established that the gut is an endocrine organ — a concept that would eventually lead to the discovery of GLP-1 eight decades later.

1913 — Fischer's Legacy

By the time of his death in 1919, Emil Fischer had synthesized peptides containing up to 18 amino acids. His methods were painstaking: each coupling reaction had to be carried out in solution, purified, and verified. Synthesizing a peptide of even modest length could take months or years. This bottleneck would persist for half a century.

The Insulin Revolution: 1921-1958

1921 — Banting and Best Isolate Insulin

In the summer of 1921, at the University of Toronto, surgeon Frederick Banting and medical student Charles Best ligated the pancreatic ducts of dogs, waited for the exocrine tissue to degenerate, then extracted a substance from the remaining islet cells. They called it "isletin." When injected into diabetic dogs, it lowered blood sugar dramatically.

By January 1922, a 14-year-old boy named Leonard Thompson became the first human to receive an insulin injection. The initial extract was crude and caused abscesses, but biochemist James Collip purified it, and subsequent injections brought Thompson's blood sugar under control. The boy lived another 13 years.

1923 — Nobel Prize for Insulin

Banting and J.J.R. Macleod received the Nobel Prize in Physiology or Medicine for the discovery of insulin — just two years after the initial experiments. Banting, angry that Best was excluded, shared his prize money with Best. Macleod shared his with Collip. The award reflected how immediately transformative insulin was: before 1922, a Type 1 diabetes diagnosis was a death sentence.

1923-1930s — Industrial Insulin Production

Eli Lilly began mass-producing animal-derived insulin (from pig and cattle pancreases). The peptide hormone became the first commercially available protein drug. Production required enormous quantities of animal tissue — roughly 8,000 pounds of animal pancreas glands to produce one pound of insulin.

1951-1955 — Sanger Sequences Insulin

British biochemist Frederick Sanger spent a decade determining the complete amino acid sequence of insulin. He developed new methods for identifying the order of amino acids, ultimately showing that insulin consists of two chains (A-chain: 21 amino acids; B-chain: 30 amino acids) linked by disulfide bonds.

This was transformative. Before Sanger's work, it was unclear whether proteins had defined, reproducible sequences. His proof that they do opened the door to understanding protein structure, function, and eventually synthesis. Sanger received the Nobel Prize in Chemistry in 1958 — his first of two (he won again in 1980 for DNA sequencing).

The Synthesis Breakthrough: 1953-1984

1953 — du Vigneaud Synthesizes Oxytocin

Vincent du Vigneaud and his team at Cornell University Medical College achieved the first total synthesis of a biologically active peptide hormone: oxytocin, a 9-amino-acid peptide with a disulfide bridge. They then synthesized vasopressin (ADH), a related 9-amino-acid peptide.

du Vigneaud received the 1955 Nobel Prize in Chemistry for this work. The significance wasn't just making the molecules — it was proving that synthetic peptides could be biologically identical to their natural counterparts. If you could make it, you could potentially use it as medicine.

1963 — Merrifield Invents Solid-Phase Peptide Synthesis

Robert Bruce Merrifield, a biochemist at Rockefeller University, published a paper in the Journal of the American Chemical Society describing a radically new approach to peptide synthesis. Instead of laborious solution-phase chemistry — where each intermediate had to be isolated and purified — Merrifield anchored the first amino acid to an insoluble polystyrene resin bead. Subsequent amino acids were coupled one at a time while the growing chain remained attached to the bead. Excess reagents and byproducts were simply washed away.

The result: what had taken months could now be done in days. SPPS (solid-phase peptide synthesis) reduced the synthesis of a 10-amino-acid peptide from weeks of work to a matter of hours.

Merrifield quickly demonstrated the power of his method by synthesizing bradykinin (9 amino acids), angiotensin (8 amino acids), and desamino-oxytocin. In 1969, he and colleague Bernd Gutte synthesized ribonuclease A — a 124-amino-acid enzyme. It was the first enzyme ever made by chemical synthesis, proving that enzymes are purely chemical entities.

The 1963 JACS paper became the fifth most cited paper in the journal's history. Merrifield received the 1984 Nobel Prize in Chemistry — as the sole author, one of few in that prize's history.

1965 — First Automated Peptide Synthesizer

Merrifield built the first automated peptide synthesizer, mechanizing the repetitive coupling/washing/deprotection cycles of SPPS. This machine made peptide synthesis accessible to laboratories without specialized organic chemistry expertise and set the stage for commercial peptide production.

1978 — Recombinant Insulin

Scientists at Genentech and City of Hope National Medical Center used recombinant DNA technology to produce human insulin in E. coli bacteria. This was the first recombinant pharmaceutical protein. The FDA approved recombinant human insulin (Humulin) in 1982, eliminating dependence on animal-derived insulin and marking the birth of the biotechnology industry.

The First Peptide Drugs: 1970s-1990s

1970s — ACE Inhibitors and Captopril

In the 1970s, researchers discovered that peptides in the venom of the Brazilian pit viper (Bothrops jararaca) could inhibit angiotensin-converting enzyme (ACE). This led to the development of captopril, approved in 1981 — the first ACE inhibitor and one of the most important cardiovascular drugs ever developed. While captopril itself is a small molecule (not a peptide), its discovery came directly from studying peptide-enzyme interactions.

1984 — Somatostatin Analogs: Octreotide

Native somatostatin, a 14-amino-acid peptide that inhibits growth hormone and other hormones, has a half-life of just 1-3 minutes — too short for clinical use. Sandoz (now Novartis) developed octreotide, an 8-amino-acid analog incorporating D-amino acids, which extended the half-life to about 1.5 hours. FDA-approved in 1988 as Sandostatin, octreotide became the first somatostatin analog used clinically and demonstrated a principle that would become central to peptide drug development: structural modifications can transform a biologically active but pharmacologically impractical peptide into a viable drug.

1985 — LHRH Analogs: Leuprolide

Leuprolide (Lupron), a synthetic analog of gonadotropin-releasing hormone (GnRH/LHRH), was FDA-approved. Unlike the natural 10-amino-acid GnRH peptide (which stimulates sex hormone production), continuous administration of leuprolide paradoxically suppresses the reproductive axis. Combined with depot formulations that release the drug over 1-6 months from a single injection, leuprolide became a mainstay treatment for prostate cancer, endometriosis, and precocious puberty.

1985 — Calcitonin for Osteoporosis

Salmon calcitonin (Miacalcin) received FDA approval for osteoporosis. The choice of salmon calcitonin over human calcitonin was deliberate — the salmon version is more potent and has a longer half-life than the human peptide, demonstrating that cross-species peptide engineering could yield better drugs.

1990 — Desmopressin for Diabetes Insipidus

Desmopressin (DDAVP), a synthetic analog of vasopressin with selective V2 receptor activity (antidiuretic effect) and negligible V1 activity (no blood pressure effects), was in wide clinical use by the late 1980s. Its modifications — deamination of the N-terminal cysteine and replacement of L-arginine with D-arginine — extended its half-life from vasopressin's 10-20 minutes to 1.5-2.5 hours and enabled intranasal administration.

1997 — Sermorelin Approved

Sermorelin, a 29-amino-acid fragment of growth hormone-releasing hormone (GHRH), was FDA-approved for the diagnosis and treatment of growth hormone deficiency in children. It was the first GHRH analog approved for clinical use, establishing the principle that stimulating the body's own GH production (rather than injecting exogenous GH) was a viable therapeutic approach. Sermorelin was later discontinued in 2008 due to manufacturing difficulties, not safety concerns.

The GLP-1 Era: 1983-Present

The GLP-1 story is perhaps the most remarkable chapter in peptide drug history — a journey from basic gut hormone research to the development of the highest-revenue drugs in pharmaceutical history.

1983 — Exendin-4 Discovered in Gila Monster Venom

John Eng, an endocrinologist at the VA Medical Center in the Bronx, was studying peptides in the venom of the Gila monster (Heloderma suspectum) when he identified exendin-4, a 39-amino-acid peptide that shared 53% sequence homology with human GLP-1 but resisted degradation by DPP-4. Where native GLP-1 lasted 2 minutes, exendin-4 persisted for hours.

1984-1986 — GLP-1 Characterized

Svetlana Mojsov, Daniel Drucker, and Joel Habener independently characterized glucagon-like peptide-1 and demonstrated its ability to stimulate insulin secretion in a glucose-dependent manner. This meant GLP-1 only triggered insulin release when blood sugar was elevated — a built-in safety mechanism against hypoglycemia.

1993 — Eng Patents Exendin-4

Eng filed a patent for exendin-4 as a potential diabetes treatment. He then spent three years searching for a pharmaceutical company willing to develop it. In 1996, Amylin Pharmaceuticals licensed the patent.

2005 — Exenatide (Byetta) Approved

Exenatide, a synthetic version of exendin-4, became the first GLP-1 receptor agonist approved by the FDA. Marketed as Byetta, it required twice-daily subcutaneous injections. The approval proved that targeting the GLP-1 receptor was a viable strategy for treating Type 2 diabetes and inspired a wave of follow-on development.

2010 — Liraglutide (Victoza) Approved

Novo Nordisk took a different engineering approach. Instead of using a lizard peptide, they modified human GLP-1 itself — adding a fatty acid chain (C-16 palmitic acid) at position 26 that enabled albumin binding, extending the half-life to 13 hours. Liraglutide (Victoza) became the first once-daily GLP-1 agonist, a meaningful improvement in patient convenience over Byetta's twice-daily dosing.

2012 — Exenatide Extended-Release (Bydureon) Approved

By encapsulating exenatide in PLGA (poly-lactic-co-glycolic acid) biodegradable microspheres, the extended-release formulation achieved once-weekly dosing — the first weekly GLP-1 agonist.

2014 — Liraglutide Approved for Obesity (Saxenda)

The FDA approved a higher dose of liraglutide (3.0 mg vs. 1.8 mg for diabetes) for chronic weight management. This was a watershed moment: the first GLP-1 approved specifically for obesity, signaling that these peptides could treat metabolic disease beyond blood sugar control.

2017 — Semaglutide (Ozempic) Approved

Novo Nordisk refined the liraglutide formula further. Semaglutide incorporated two modifications: an amino acid substitution at position 8 (Aib replacing Ala) that blocked DPP-4, and a longer C-18 fatty diacid chain that strengthened albumin binding. The result: a half-life of approximately 7 days, enabling once-weekly injection. The SUSTAIN trials showed semaglutide reduced HbA1c by over 1% and cut the risk of major cardiovascular events.

2019 — Oral Semaglutide (Rybelsus) Approved

In what many considered impossible, Novo Nordisk developed an oral peptide tablet. Semaglutide was co-formulated with SNAC (sodium N-[8-(2-hydroxybenzoyl) amino] caprylate), a permeation enhancer that protects the peptide from gastric degradation and promotes absorption across the stomach lining. Rybelsus became the first oral GLP-1 agonist — a milestone in peptide delivery technology.

2021 — Semaglutide for Obesity (Wegovy) Approved

The STEP trials showed that semaglutide 2.4 mg weekly produced an average of 14.9% body weight loss over 68 weeks (vs. 2.4% for placebo). Wegovy's approval reshaped obesity treatment and triggered unprecedented public demand. By 2023, semaglutide-based products were generating over $20 billion in annual revenue.

2022 — Tirzepatide (Mounjaro) Approved

Eli Lilly's tirzepatide broke new ground as a dual GIP/GLP-1 receptor agonist — a single molecule that activates two incretin receptors simultaneously. The SURPASS trials showed tirzepatide produced HbA1c reductions of up to 2.3% and weight loss exceeding 20% in some trial arms, outperforming semaglutide head-to-head.

2023 — Tirzepatide for Obesity (Zepbound) Approved

The SURMOUNT-1 trial reported that tirzepatide 15 mg achieved 22.5% weight loss at 72 weeks — approaching the results of bariatric surgery without an operation. The FDA approved Zepbound for chronic weight management in November 2023.

2024-2025 — Expanding Indications

Semaglutide received FDA approval for cardiovascular risk reduction (based on the SELECT trial showing a 20% reduction in major adverse cardiovascular events) and for reducing kidney disease progression in Type 2 diabetes patients. The peptide's therapeutic reach now extends well beyond diabetes and obesity.

2025 — First Generic GLP-1 Agonists

The FDA approved generic exenatide (Amneal, late 2024) and generic liraglutide for weight loss (Teva, August 2025), signaling the beginning of the GLP-1 patent cliff. An oral semaglutide pill was approved in December 2025 with mass production starting in January 2026.

The Modern Peptide Renaissance: 2010-Present

The GLP-1 success story has catalyzed a broader renaissance in peptide therapeutics across multiple fields.

Antimicrobial Peptides

With antibiotic resistance rising globally, researchers have turned to antimicrobial peptides (AMPs) as potential alternatives. LL-37, the only human cathelicidin, has been studied in clinical trials for wound healing. Dozens of other AMPs are in preclinical and early clinical development.

Peptide-Drug Conjugates

Building on the success of antibody-drug conjugates (ADCs), peptide-drug conjugates (PDCs) use tumor-targeting peptides to deliver cytotoxic payloads directly to cancer cells. The smaller size of peptides compared to antibodies offers advantages in tissue penetration.

Growth Hormone Secretagogues

Tesamorelin received FDA approval in 2010 for HIV-associated lipodystrophy, and research peptides like CJC-1295 and ipamorelin gained popularity in anti-aging and wellness medicine — though most lack formal FDA approval.

Cosmetic Peptides

The skincare industry embraced peptides including GHK-Cu (copper tripeptide), Matrixyl, Argireline, and Syn-Ake, creating a multi-billion-dollar market for topical anti-aging products backed by varying levels of clinical evidence.

The Regenerative Peptide Movement

BPC-157, TB-500, and related healing peptides gained significant attention in the biohacking and sports medicine communities, driven by preclinical data showing remarkable tissue repair properties. The FDA's 2023-2024 crackdown on compounded peptides — categorizing several as "Category 2" substances with safety concerns — brought regulatory scrutiny to this rapidly growing space.

Future Directions

Triple Agonists

Retatrutide, a triple GLP-1/GIP/glucagon receptor agonist, showed 24% weight loss in Phase 2 trials — the highest ever reported for a drug. Phase 3 results are expected in 2026.

Oral Peptide Delivery

The success of oral semaglutide has opened the floodgates. Oral GLP-1 agonists from multiple companies (including Eli Lilly's orforglipron, a non-peptide GLP-1 agonist) are in late-stage development. The technology that enabled oral semaglutide (SNAC permeation enhancer) is being applied to other peptides.

AI-Designed Peptides

Machine learning and artificial intelligence are accelerating peptide discovery. AI can predict peptide-receptor interactions, optimize sequences for stability and bioavailability, and design entirely novel peptides that don't exist in nature. This could compress the traditional decades-long drug development timeline.

Peptide Vaccines

Peptide-based vaccines use short peptide sequences from pathogen proteins to trigger immune responses. Multiple peptide vaccine candidates are in clinical trials for cancer immunotherapy, infectious diseases, and autoimmune conditions.

Beyond Injection

Advanced delivery systems — including nanoparticles, microneedle patches, implantable devices, and engineered gut bacteria that produce therapeutic peptides — aim to make peptide therapy as simple as taking a daily vitamin.

FAQ

Why is insulin considered the starting point for peptide therapeutics?

Insulin was the first peptide isolated from tissue, the first used therapeutically in humans (1922), the first to have its amino acid sequence determined (Sanger, 1955), and the first produced using recombinant DNA technology (1978). Every major milestone in peptide science — from sequencing to synthesis to genetic engineering — was first achieved with insulin. It remains the most widely used peptide drug in the world.

What was the significance of Merrifield's invention?

Before SPPS, synthesizing a 10-amino-acid peptide was a months-long project requiring specialized organic chemistry expertise. After SPPS, the same synthesis could be done in days by following a standardized protocol. Merrifield's method democratized peptide chemistry and made the commercial peptide industry possible. Today, virtually every research and therapeutic peptide is made using SPPS or its derivatives. For more on peptide terminology, see our Peptide Glossary.

How did GLP-1 go from a gut hormone to the biggest drug class in the world?

Three insights converged. First, the discovery that GLP-1 stimulates insulin only when blood sugar is elevated (glucose-dependent mechanism), which avoids the hypoglycemia risk of insulin or sulfonylureas. Second, the realization that GLP-1 also suppresses appetite, slows gastric emptying, and protects the cardiovascular system — effects that go far beyond blood sugar control. Third, engineering breakthroughs (DPP-4-resistant analogs, fatty acid conjugation, oral formulation) that transformed a 2-minute peptide into a once-weekly or even oral medication. The full pharmacology story is covered in our semaglutide guide.

How many peptide drugs are currently approved?

Approximately 80 peptide drugs are approved for clinical use worldwide, with over 150 in clinical development and an additional 400-600 in preclinical research. The peptide therapeutics market is projected to reach $49.68 billion in 2026. For a complete list of FDA-approved peptides, see our FDA-Approved Peptide Drug List.

What's the relationship between the Gila monster and modern GLP-1 drugs?

John Eng discovered exendin-4 in Gila monster saliva in 1983. This peptide activates the human GLP-1 receptor but resists DPP-4 degradation, giving it a much longer half-life than native GLP-1. Exendin-4 became exenatide (Byetta), the first approved GLP-1 agonist. While semaglutide and tirzepatide are based on modified human peptide sequences (not exendin), exenatide proved the concept that GLP-1 receptor activation was a viable drug strategy. Without the Gila monster, the GLP-1 drug revolution might have been delayed by years.

Why were some peptides recently banned from compounding pharmacies?

In 2023-2024, the FDA categorized several peptides (BPC-157, thymosin beta-4, CJC-1295, ipamorelin, epitalon, and others) as "Category 2" substances under Section 503A of the FD&C Act, meaning they raise significant safety concerns. The FDA cited risks of immunogenicity from impurities, lack of adequate human clinical data, and the absence of FDA-approved indications. This effectively prohibited 503A compounding pharmacies from preparing these peptides for individual patients.

The Bottom Line

From Fischer's first dipeptide in 1901 to AI-designed peptide drugs in 2026, the field has undergone a transformation that few branches of medicine can match. The throughline is an engineering problem: natural peptides are potent biological signals, but they're fragile, short-lived, and hard to deliver orally. Each generation of scientists has found new ways to overcome these limitations — D-amino acid substitution, albumin-binding fatty acids, depot formulations, permeation enhancers, and now machine learning-driven design.

The GLP-1 story is the clearest proof of concept. A gut hormone that lasts 2 minutes has been engineered into weekly injections and daily pills that treat diabetes, obesity, cardiovascular disease, and kidney disease — with trials ongoing for Alzheimer's, addiction, PCOS, and liver disease. If the next 100 years of peptide science are anything like the first, we're just getting started.

References

  1. Fischer E, Fourneau E. "Ueber einige Derivate des Glykocolls." Berichte der deutschen chemischen Gesellschaft. 1901;34(2):2868-2877.
  2. Banting FG, Best CH. "The Internal Secretion of the Pancreas." Journal of Laboratory and Clinical Medicine. 1922;7:251-266.
  3. Sanger F. "The free amino groups of insulin." Biochemical Journal. 1945;39(5):507.
  4. du Vigneaud V, et al. "The synthesis of an octapeptide amide with the hormonal activity of oxytocin." JACS. 1953;75(19):4879-4880.
  5. Merrifield RB. "Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide." JACS. 1963;85(14):2149-2154.
  6. Eng J, et al. "Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom." Journal of Biological Chemistry. 1992;267(11):7402-7405.
  7. Mojsov S, et al. "Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release." JCI. 1987;79(2):616-619.
  8. Teichman SL, et al. "Prolonged stimulation of growth hormone and insulin-like growth factor I secretion by CJC-1295." JCEM. 2006;91(3):799-805. PubMed
  9. Wilding JPH, et al. "Once-Weekly Semaglutide in Adults with Overweight or Obesity." NEJM. 2021;384:989-1002.
  10. Jastreboff AM, et al. "Tirzepatide Once Weekly for the Treatment of Obesity." NEJM. 2022;387:205-216.
  11. "Peptide Hormones in Medicine: A 100-Year History." Russian Journal of Bioorganic Chemistry. 2022. Springer
  12. "Development Trends of Peptide Pharmaceuticals." PatSnap Synapse. synapse.patsnap.com
  13. American Peptide Society. "Early Discoveries and Key Figures." americanpeptidesociety.org
  14. "History of GLP-1 Approvals in the U.S." Alliance Clinical Network. allianceclinicalnetwork.com
  15. FDA. "FDA-Approved Peptide Drug List." FDA.gov