Cyclic peptides are having a moment

Merck & Co.’s cyclic peptide enlicitide decanoate was one of the first two drug candidates the US Food and Drug Administration selected to receive the new Commissioner’s National Priority Voucher in December. The pilot program is intended to review important drug candidates in just 1–2 months, compared with 6 or more months for other FDA priority review programs.

Enlicitide is a cholesterol-lowering molecule that works by inhibiting a protein called PCSK9, which degrades receptors that help clear low-density lipoproteins from the blood. If approved, it will be the first PCSK9 inhibitor that people can take as a pill. Financial analysts forecast that enlicitide could bring in more than $2 billion in annual sales after a few years on the market.

All peptides, or short chains of amino acids, are of keen interest to the pharmaceutical industry these days. The multibillion-dollar weight-loss drugs Wegovy and Zepbound are peptides, as is retatrutide, a promising new weight-loss drug candidate from Eli Lilly and Company that activates three receptors in the body.

But there are downsides to most traditional linear peptides. They must be injected. They can also suffer from poor metabolic stability, membrane permeability, and oral bioavailability, according to an analysis by the pharmaceutical-services firm WuXi AppTec. Cyclic peptides, in contrast, have better drug-like properties, owing to their enhanced conformational rigidity, elimination of unstable terminal residues, and better metabolic stability, to name a few causes, WuXi says. These traits also allow medicines to be taken in pill form, as is the case for enlicitide.

It’s thus not a surprise that a recent analysis by CAS, a division of the American Chemical Society that specializes in scientific-knowledge management, finds that the publishing of patents and academic papers about peptides is on the rise. (C&EN is published by ACS.) Notably, an exploration of data from the CAS Content Collection, which CAS calls the largest human-curated collection of published scientific information, reveals that the oral delivery of cyclic peptides is gaining attention.

What may be surprising is that metabolic disorders like obesity are actually a relatively minor area of research for cyclic peptides. The top three areas are cancer, infection, and inflammatory diseases, CAS finds.

Patent activity by leading pharmaceutical companies bears out this finding. Recent patent filings by Bicycle Therapeutics, a biotech firm specializing in two-ringed peptides known as bicyclic peptides, show an interest in molecules that bind to and activate natural killer cells, white blood cells that destroy infected and diseased cells, including cancer cells.

Bristol Myers Squibb, the number 2 corporate patentee of cyclic-peptide technology after Bicycle, is interested in the peptides as treatments for cancer and infectious, inflammatory, and autoimmune diseases. One BMS patent from 2024 describes modifying a cancer-treating cyclic peptide with a decanoic acid salt to improve its oral bioavailability.

Novartis patents, meanwhile, show an interest in making cyclic peptides part of radioligand therapies and imaging agents. For example, a 2025 patent from Novartis describes linking a cyclic peptide that targets a receptor implicated in cancer to a cancer-killing radionuclide or cytotoxic drug.

Cyclic peptides, the WuXi analysis says, are a transformative class of therapeutics that combine the advantages of small molecules and biologics. Expect to see more intellectual property from chemists in industry and academia in the years ahead.