Peptides 101: what peptides are and how they work

What is a peptide?

A peptide is a short chain of amino acids joined end-to-end by peptide bonds (amide bonds formed between the carboxyl group of one amino acid and the amino group of the next, releasing a molecule of water). There is no single official cutoff, but in drug-development usage a peptide is usually a chain of roughly 2 to 50 amino acids; longer chains that fold into stable three-dimensional structures are generally called proteins ¹².

Amino acids are the building blocks. Twenty are encoded by the human genetic code; chemists can also use non-natural ones.
Peptides sit between small-molecule drugs and large biologics in size, which gives them high target selectivity but also some of the fragility of proteins.
Proteins (for example, antibodies) are much larger and are usually made in living cells.

Many of the body's own signaling molecules are peptides, including insulin, glucagon, oxytocin, vasopressin, and GLP-1. That is one reason peptides are attractive as medicines: they often mimic or block a natural hormone at its own receptor ¹.

How peptides are made

Solid-phase peptide synthesis (SPPS). Developed by R. Bruce Merrifield and published in 1963, SPPS anchors the first amino acid to an insoluble resin bead, then adds protected amino acids one at a time. Because the growing chain stays attached to the bead, excess reagents and by-products are simply washed away instead of being purified out after every step ³. The Nobel committee noted that this allows step yields of 99.5% or better and made automated synthesizers possible; Merrifield received the 1984 Nobel Prize in Chemistry for the method ⁴. After assembly, the peptide is cleaved from the resin (often using trifluoroacetic acid, which is why many synthetic peptides are supplied as TFA salts), then purified, typically by reversed-phase HPLC.

Liquid-phase (solution) synthesis is the older approach and is still used for some short peptides or large-scale manufacturing.

Recombinant production. Longer peptides and proteins can be produced by inserting the gene for the sequence into bacteria or yeast. Human insulin made this way (Humulin) was licensed by the FDA in October 1982, the first recombinant pharmaceutical approved in the U.S. ⁷

Modern peptide drugs often combine approaches, for example a recombinantly expressed backbone that is then chemically modified ².

Routes of administration: why most peptides are injected

Most peptide medicines are given by subcutaneous (under the skin) or intravenous injection. The main reasons ¹²:

Digestion. The stomach and intestine are built to break peptide bonds; proteases such as pepsin, trypsin and chymotrypsin rapidly degrade most peptides.
Poor absorption. Peptides are relatively large and polar, so they cross the intestinal lining poorly. Oral bioavailability for unmodified peptides is typically well under 1-2%.
First-pass metabolism in the liver removes a further share of what is absorbed.

Exceptions exist. Oral semaglutide is co-formulated with an absorption enhancer, and some cyclic peptides (such as cyclosporine) are orally active. Nasal sprays, inhaled forms, topical products and implants are used for selected peptides. Even so, these routes usually deliver a small and variable fraction of the dose, which is why claims that a peptide works well as a pill, drink, or skin cream deserve scrutiny unless backed by human pharmacokinetic data.

Half-life and chemical modifications

Natural peptide hormones often last only minutes in the blood: native GLP-1, for instance, is cleaved by the enzyme DPP-4 and cleared by the kidneys within a few minutes. Drug developers use several strategies to extend half-life and improve stability ¹²:

Amino-acid substitution, including swapping in D-amino acids or other non-natural residues at cleavage sites so proteases no longer recognize them.
Cyclization (head-to-tail or side-chain bridges, including disulfide bonds) to make the peptide rigid and protease-resistant.
Lipidation: attaching a fatty-acid chain so the peptide binds reversibly to albumin in the blood. Liraglutide and semaglutide use this approach; semaglutide's half-life is about a week.
PEGylation: attaching polyethylene glycol to increase size and reduce kidney clearance.
Drug Affinity Complex (DAC): a reactive linker that bonds the peptide to circulating albumin (used in the experimental compound CJC-1295 with DAC).
Fusion to larger proteins such as an antibody Fc fragment or albumin (dulaglutide is an example).

Each modification changes the molecule's behavior, so data on one version of a peptide do not automatically apply to another.

A short history of peptide medicines

1921-1922: Banting and Best, working under Macleod at the University of Toronto, isolate insulin; 14-year-old Leonard Thompson receives the first purified extract on January 23, 1922 ⁶.
1953: Vincent du Vigneaud's group synthesizes oxytocin, the first peptide hormone made in the lab; he receives the 1955 Nobel Prize in Chemistry ⁵.
1963: Merrifield publishes solid-phase peptide synthesis ³; Nobel Prize 1984 ⁴.
1982: FDA licenses Humulin, recombinant human insulin ⁷.
1980s-2000s: Peptide analogs such as leuprolide (GnRH agonist), octreotide (somatostatin analog) and the first GLP-1 receptor agonist, exenatide (2005), reach the market ¹.
2010s: Long-acting lipidated GLP-1 drugs (liraglutide, then semaglutide) transform diabetes and obesity care ².
2022: FDA approves tirzepatide (Mounjaro), the first dual GIP/GLP-1 receptor agonist, on May 13, 2022 ⁸.

How big is the peptide drug field?

More than 80 peptide drugs had reached the market worldwide by 2021, and hundreds more were in clinical development ¹². Since then, GLP-1-based medicines have become some of the best-selling drugs in the world, making peptides one of the fastest-growing segments of the pharmaceutical industry.

Published dollar estimates of the "peptide therapeutics market" vary widely depending on whether insulin and GLP-1 drugs are counted and which commercial research firm produced them; treat any single figure with caution and check what it includes.

Peptide Basics: What Peptides Are and How Peptide Drugs Work