Why researchers keep coming back to peptides

A peptide is a short chain of amino acids, the same building blocks as proteins, only fewer of them. The body uses peptides as signals: insulin, GLP-1, oxytocin and vasopressin are all peptides. That is the first reason they interest drug developers. A drug that copies one of the body's own signals starts with a receptor that already exists and a biology that is already partly understood. The what are peptides page covers the basics.

A century of peptide drugs

The first was insulin. On 11 January 1922, a 14-year-old boy in Toronto received the first injection of pancreatic extract. It caused a sterile abscess and barely moved his blood sugar. Later injections of an extract purified by the biochemist J.B. Collip worked, and insulin went from crude extract to a treatment within the year.

Since then, a 2021 review in Nature Reviews Drug Discovery counts more than 80 peptide drugs that have reached the market, across diabetes, cancer, osteoporosis, multiple sclerosis, HIV and chronic pain. A 2022 review in Signal Transduction and Targeted Therapy gives the same figure, counts 33 non-insulin peptide drugs approved worldwide since 2000, and more than 170 peptides in active clinical development.

The market followed. The same 2022 review puts worldwide peptide drug sales at more than $70 billion in 2019, more than double the 2013 figure. The three best-selling non-insulin peptides that year were all GLP-1 analogues: Trulicity (dulaglutide) at $4.39 billion, Victoza (liraglutide) at $3.29 billion and Rybelsus (oral semaglutide) at $1.68 billion. That was before Wegovy and Zepbound.

Why peptides make attractive drugs

• Specificity. Peptides bind cell-surface receptors with high affinity and specificity, in a way closer to antibodies than to most small-molecule pills. A precise fit means fewer unintended targets.
• Potency. High affinity means small doses. Semaglutide is dosed in milligrams a week.
• Predictable breakdown. The body cuts peptides into amino acids. The semaglutide label describes metabolism by proteolytic cleavage of the peptide backbone and beta-oxidation of the fatty acid side chain, rather than the liver enzyme pathways that cause many small-molecule drug interactions.
• Cost and immunogenicity. Compared with large protein drugs, the 2022 review notes, peptides tend to be less immunogenic and cheaper to produce.

The weakness: they do not last

The same review lists the drawbacks. Peptide bonds are broken down quickly by enzymes, so most natural peptides have a short half-life and fast elimination. Most cannot cross cell membranes, which limits them to targets on the outside of cells. And the gut digests them, so most have to be injected.

GLP-1 is the extreme case. A 2007 review in Physiological Reviews describes native GLP-1 as "extremely rapidly" inactivated by the enzyme DPP-4, much of it before it even leaves the gut. A drug made of unmodified GLP-1 would be gone in minutes.

How the GLP-1 drugs fixed it

The first answer came from a lizard. In 1992, researchers isolated a 39-amino-acid peptide, exendin-4, from the venom of the Gila monster. It activates the GLP-1 receptor and resists DPP-4. Its synthetic version, exenatide, was approved by the FDA in 2005. Nature has supplied other peptide drugs the same way: ziconotide, a pain drug approved in 2004, comes from a cone snail.

The second answer was a fatty acid. Attaching a fatty acid chain lets the peptide ride on albumin, the most abundant protein in blood, which shields it from enzymes and the kidneys and releases it slowly.

The 2015 paper describing semaglutide's design in the Journal of Medicinal Chemistry is explicit about the goal: increase albumin affinity and secure full stability against breakdown, to reach once-weekly dosing. In mini-pigs, intravenous semaglutide had a plasma half-life of 46.1 hours. In people, the label gives about a week. The semaglutide and tirzepatide pages have the pharmacology in more depth.

The oral problem

Getting a peptide through the gut is harder. Oral semaglutide, sold as Rybelsus and as the Wegovy tablet, pairs the peptide with an absorption enhancer called SNAC and needs to be taken on an empty stomach. The other route is to stop using a peptide: orforglipron, approved as Foundayo, is a small molecule that activates the GLP-1 receptor. The oral Wegovy and Foundayo guides cover both.

What this means for unapproved peptides

The same properties that make peptides attractive make the evidence question sharper. A potent compound with a short half-life and a narrow target can do a lot in a rat and little in a person, or the reverse, and only a human trial says which. The approved peptide drugs above all went through that. Most of the peptides sold as research compounds have not. The how peptide research works page explains the steps, and the compound library shows where each one stands.

If you are on a peptide drug, the useful record is the boring one: every dose, every step, and what changed. Peptide AI logs it on one timeline, free; the download page has the app.