What a peptide actually is (and why more than 80 medicines are made of them)

A century-old idea

In January 1922, in Toronto, the biochemist James Collip managed to purify an extract of pancreas clean enough to give to people ^[4]. Its active ingredient was insulin, a hormone made of 51 amino acids in two linked chains. Frederick Banting and John Macleod received the Nobel Prize for the discovery the following year ^[4].

Insulin was the first of a long line. Since its introduction, more than 80 peptide drugs have reached the market, for conditions from diabetes and osteoporosis to multiple sclerosis, HIV infection and chronic pain ^[1]. Counting diagnostic agents as well, one database found more than 100 approved peptide products by 2020 ^[2]. To understand why, it helps to start with the building blocks.

Amino acids: an alphabet of twenty letters

Proteins and peptides are built from a set of about 20 standard amino acids. Each has the same backbone, an amino group at one end and a carboxylic acid group at the other, plus a side chain that gives it its personality: greasy, charged, small, bulky, or able to form bridges with its neighbours.

When the amino group of one amino acid reacts with the acid group of another, they release a molecule of water and lock together through a peptide bond. Repeat that, and you get a chain with a direction: it starts at the amino end (the N-terminus) and finishes at the acid end (the C-terminus).

The order of the residues is everything. Think of the amino acids as letters: a peptide is a word, and a protein is a paragraph that folds itself into a three-dimensional sculpture. Swap one letter and the word can mean something completely different.

Where peptides end and proteins begin

Size is the usual dividing line, but it is a convention rather than a law of nature. Biochemists commonly call chains up to about 50 amino acids peptides and longer ones proteins.

Regulators need a sharper rule. Since March 2020, the US FDA has defined a protein as any chain of amino acids with a specific sequence longer than 40 amino acids ^[3]. That is why insulin, at 51, is now regulated in the US as a biological product, while shorter chains are regulated as drugs.

In practice, size changes how a molecule is made. Short peptides are usually built chemically, one amino acid at a time; our guide on how peptides are made and tested explains how. Large proteins are usually produced by engineered cells.

Oxytocin: the first hormone built from scratch

For decades, peptide hormones could only be extracted from animal glands. In 1953, the American chemist Vincent du Vigneaud and his team reported that they had synthesised oxytocin in the laboratory and that the synthetic molecule had the hormone's biological activity ^[5]. It earned him the 1955 Nobel Prize in Chemistry, "for the first synthesis of a polypeptide hormone" ^[6].

There is a small puzzle in the paper's title, which describes an "octapeptide amide". Oxytocin has nine amino acids, but two of them are cysteines joined by a sulphur bridge, and chemists of the time counted that pair as a single unit, cystine. Our article on oxytocin covers what the hormone does.

Oxytocin, the hormone of childbirth and bonding, is just nine amino acids long. Insulin is 51. The GLP-1 drugs that changed obesity treatment sit in between.

Synthesis made it possible to change peptides as well as copy them: to swap residues, add fatty side chains so they last longer in the blood, or design sequences that nature never made. BPC-157, for example, is a synthetic 15-amino-acid chain.

Why most peptides are injected

Swallowing a peptide is a bit like posting a letter through a shredder. The stomach and gut are built to break proteins and peptides down into single amino acids for food, and their lining absorbs large molecules poorly. Oral delivery of therapeutic peptides is hindered on both counts: poor absorption across the gut barrier and extensive breakdown by digestive enzymes ^[7].

Oral semaglutide is the famous workaround. Each tablet contains an absorption enhancer called SNAC. Studies in people and dogs showed that the drug is absorbed in the stomach, right next to the dissolving tablet, where SNAC buffers the local acidity and protects the peptide from enzymes while briefly helping it cross the stomach lining ^[7]. The FDA approved the first oral semaglutide tablet in September 2019 ^[9].

Even then, the numbers are humbling. The label estimates absolute bioavailability at roughly 0.4% to 2%, depending on the tablet ^[8]. In other words, most of each dose never reaches the blood, which is why most peptide medicines are still injections.

The GLP-1 era

GLP-1 is a peptide hormone released by the gut after meals. Drugs that mimic it, starting with diabetes treatments and growing into weight-loss medicines such as semaglutide, turned peptides into some of the most talked-about drugs in the world. Science named GLP-1-based obesity drugs its Breakthrough of the Year for 2023 ^[10].

The newest candidates go further, combining activity at two or three hormone receptors in one engineered chain, an evolution traced in our article on GLP-1, GLP-2 and GLP-3 agonists. Many approved peptides began as copies of human hormones; others came from nature's own chemistry, including animal venoms ^[1].

What this means for research peptides

Research peptides are made with the same chemistry as peptide medicines, but with one crucial difference: most have never been through the trials that medicines must pass. A sequence that is short, natural-sounding or chemically elegant is not, by itself, evidence of anything.

The questions that matter are the same for every compound: what has been shown, in what kind of study, and how strongly. Our guide to levels of evidence explains how to tell a cell-culture result from an approved medicine.

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