The History of Peptide Research: From Insulin to Modern Therapeutics

Introduction#

The history of peptide research spans over a century, from the discovery of insulin in 1921 to the modern era of engineered peptide therapeutics that are reshaping medicine. This history is not merely academic -- it provides essential context for understanding why some peptides are FDA-approved blockbusters while others remain in the early stages of investigation.

Each major advance in peptide science built on what came before: the discovery of peptide hormones led to efforts to synthesize them, which led to techniques for modifying them, which ultimately produced the engineered therapeutics like semaglutide and tirzepatide that are transforming the treatment of obesity and diabetes.

This article traces the key milestones in peptide research from the early 20th century to the present day.

The Discovery Era (1900s-1950s)#

Insulin: The First Peptide Therapeutic (1921)#

The story of peptide therapeutics begins with insulin. In 1921, Frederick Banting and Charles Best, working at the University of Toronto, isolated insulin from the pancreatic extracts of dogs. By January 1922, the first human patient -- 14-year-old Leonard Thompson -- received insulin injections, transforming type 1 diabetes from a death sentence into a manageable condition.

Key milestones in insulin history:

Insulin demonstrated three principles that would guide peptide therapeutics for the next century: peptide hormones regulate critical biological processes, they can be extracted and administered as drugs, and their therapeutic potential is immense.

Discovery of Other Peptide Hormones#

The decades following insulin's discovery saw a wave of peptide hormone identification:

Each discovery expanded the understanding of how peptides regulate physiology and opened new therapeutic targets.

The Synthesis Revolution (1950s-1980s)#

Vincent du Vigneaud and the First Peptide Synthesis (1953)#

A transformative moment came in 1953 when Vincent du Vigneaud chemically synthesized oxytocin -- a 9-amino-acid peptide hormone involved in labor and lactation. This was the first time a biologically active peptide had been made entirely in the laboratory, proving that peptides could be manufactured rather than just extracted from animal tissues.

Du Vigneaud received the Nobel Prize in Chemistry in 1955 for this achievement.

Solid-Phase Peptide Synthesis (1963)#

The single most important technical advance in peptide chemistry came from Bruce Merrifield, who developed solid-phase peptide synthesis (SPPS) in 1963. Before Merrifield, synthesizing peptides in solution was extraordinarily tedious -- each amino acid addition required purification steps, and yields were poor for longer sequences.

Merrifield's innovation was conceptually simple but revolutionary: anchor the growing peptide chain to an insoluble solid support (a resin bead). This allowed excess reagents and byproducts to be washed away at each step without losing the peptide product. The approach dramatically reduced synthesis time and enabled the production of peptides that were previously impractical to make.

Merrifield received the Nobel Prize in Chemistry in 1984. SPPS remains the foundation of peptide synthesis today, though the chemistry has been refined significantly (particularly the introduction of Fmoc chemistry in the 1970s-80s, which replaced Merrifield's original Boc strategy with milder reaction conditions).

Recombinant DNA Technology and Peptide Production (1970s-80s)#

For larger peptides and proteins that exceeded the practical limits of SPPS, recombinant DNA technology provided an alternative production route. In 1978, Genentech produced recombinant human insulin in E. coli bacteria -- the first recombinant pharmaceutical product. This approach enabled the mass production of human-sequence proteins without relying on animal extraction.

Recombinant human growth hormone (somatropin) followed in 1985, replacing the pituitary-derived GH that had been associated with Creutzfeldt-Jakob disease transmission.

The Therapeutic Development Era (1980s-2010s)#

GnRH Agonists: Early Peptide Drug Successes#

The gonadotropin-releasing hormone (GnRH) agonists were among the first peptide drugs designed based on understanding of peptide receptor pharmacology. Leuprolide (Lupron, 1985), goserelin (Zoladex, 1989), and nafarelin (Synarel, 1990) demonstrated that modified peptides could be developed into commercially successful drugs.

These peptides also introduced the concept of depot formulations -- injectable slow-release preparations that could deliver a peptide over weeks to months from a single injection.

Somatostatin Analogs#

Octreotide (Sandostatin, 1988) was a milestone in peptide engineering. Natural somatostatin has a half-life of only 2-3 minutes, making it impractical as a drug. By designing a shorter, modified analog with a half-life of approximately 90 minutes (and later a long-acting release formulation extending this to weeks), researchers demonstrated that peptide modifications could overcome the inherent pharmacokinetic limitations of natural peptides.

The GLP-1 Agonist Story#

The development of GLP-1 receptor agonists illustrates the full arc of modern peptide therapeutics:

The progression from the discovery of a 2-minute half-life hormone to the development of a once-weekly injectable (and eventually oral) drug that produces 15-17% weight loss represents decades of iterative peptide engineering.

For a detailed explanation of semaglutide's mechanism, see our how semaglutide works guide.

Key Technical Advances#

Chemical Modification Strategies#

Several modification strategies developed over the decades now form the standard toolkit for peptide drug design:

Delivery Technology Advances#

Peptide delivery has evolved significantly:

• Depot injections: Microsphere and polymer-based slow-release formulations (e.g., Lupron Depot)
• Pen injectors: Pre-filled, easy-to-use injection devices (e.g., Ozempic pen)
• Nasal sprays: Intranasal delivery for peptides like desmopressin, calcitonin, and oxytocin
• Oral formulations: SNAC absorption enhancer enabling oral semaglutide (Rybelsus)
• Implants: Subcutaneous implants for sustained peptide delivery (e.g., histrelin implant)

The Modern Era (2020s-Present)#

The GLP-1 Revolution#

The 2020s have been defined by the explosive growth of GLP-1-based therapeutics. Semaglutide and tirzepatide have become among the highest-revenue pharmaceutical products globally, driven by their effectiveness for weight management and type 2 diabetes.

This era has also seen the emergence of multi-agonist peptides:

• Dual agonists: Tirzepatide (GLP-1/GIP), survodutide (GLP-1/glucagon)
• Triple agonists: Retatrutide (GLP-1/GIP/glucagon)
• Oral GLP-1 agonists: Non-peptide small molecules (orforglipron) that activate GLP-1 receptors

Expanding Indications#

Research is actively expanding the therapeutic applications of established peptides:

• Cardiovascular protection: Semaglutide's SELECT trial demonstrated 20% reduction in major cardiovascular events
• Kidney disease: GLP-1 agonists showing renal protective effects
• MASH/NASH: Multiple peptides in trials for metabolic liver disease
• Addiction: Early research on GLP-1 agonists reducing alcohol and substance use behaviors
• Neurodegeneration: Investigation of GLP-1 agonists for Alzheimer's and Parkinson's disease

The Compounding Controversy#

The modern era has also brought regulatory tension. The popularity of peptides like BPC-157, thymosin alpha-1, and others through compounding pharmacies led to FDA enforcement actions in 2024, with numerous peptides placed in Category 2 (banned from compounding). This regulatory landscape continues to evolve.

For the current regulatory status, see our FDA regulation guide and banned peptides list.

Timeline Summary#

Key Takeaways#

1. Peptide research began with insulin in 1921 -- the discovery that transformed diabetes treatment and launched the field of peptide therapeutics.

2. Solid-phase peptide synthesis (1963) was the most transformative technical advance. Merrifield's method made peptide production practical and enabled the synthesis of increasingly complex molecules.

3. Each generation of peptide drugs built on previous advances. From extracting natural hormones to engineering modified analogs with optimized pharmacokinetics, the field progressed incrementally.

4. The GLP-1 agonist story exemplifies the full trajectory -- from hormone discovery in the 1980s to blockbuster drugs in the 2020s, spanning nearly 40 years of iterative development.

5. Multi-agonist peptides represent the current frontier. Dual and triple receptor agonists like tirzepatide and retatrutide target multiple pathways simultaneously for greater therapeutic effects.

6. Regulatory and commercial pressures now shape the field alongside scientific discovery, as the popularity of peptides has brought increased FDA scrutiny of compounding and research peptide markets.

To visualize how half-lives vary across different generations of peptide therapeutics, see the half-life comparison tool. For current FDA regulatory status, see our guide on FDA peptide regulation in 2026.

Related Peptide Profiles#

Learn more about the peptides discussed in this article:

• Insulin Overview and Research Guide
• Insulin Dosing Protocols
• Insulin Side Effects and Safety
• Semaglutide Overview and Research Guide
• Semaglutide Dosing Protocols
• Semaglutide Side Effects and Safety
• Oxytocin Overview and Research Guide
• Oxytocin Dosing Protocols
• Oxytocin Side Effects and Safety