For decades peptides were considered difficult molecules: potent and selective, but quickly degraded and hard to deliver. Much of the progress since has come from chemistry that addresses those weaknesses. Here are the main directions shaping the field.
1. Half-life extension
Natural peptide hormones often last only minutes in circulation. Researchers have developed several ways to stretch that:
- Lipidation: attaching a fatty-acid chain so the peptide binds reversibly to the blood protein albumin, slowing clearance.
- Unnatural amino acids: substituting residues at cleavage sites so proteases can't recognise them.
- PEGylation and fusion: attaching polyethylene glycol chains or fusing the peptide to larger proteins such as antibody Fc fragments.
These techniques turned peptides that act for minutes into molecules that can last for days.
2. Multi-receptor (polyagonist) peptides
One of the most active areas is single peptides designed to act on more than one receptor at once. Incretin research is the best-known example. It began with molecules that act on the GLP-1 receptor and progressed to dual GIP/GLP-1 agonists. Triple agonists that add the glucagon receptor have since been studied in large clinical trial programmes. Designing these molecules means carefully balancing how strongly the peptide acts at each receptor, and that balance is an active area of structure–activity research.
3. Oral delivery
Peptides are normally digested in the gut, which is why most have historically been given by injection. Researchers are testing several ways around this: absorption enhancers co-formulated with the peptide, protective coatings, and peptides re-engineered to resist digestive enzymes. At least one oral peptide product using an absorption enhancer has already reached regulatory approval. That shows the problem can be solved, though usually only a small fraction of the dose is absorbed.
4. Macrocyclic and constrained peptides
Joining a peptide's chain into a ring, or "stapling" it with a chemical brace, locks it into a defined shape. Constrained peptides tend to be more stable, bind more tightly, and in some cases can reach targets inside cells that linear peptides can't. Display technologies such as phage and mRNA display let researchers screen billions of cyclic sequences against a target at once.
5. Peptide–drug and peptide–radionuclide conjugates
Because some peptides bind very selectively to receptors that are over-expressed on certain cells, they can act as delivery vehicles. Attaching a drug or a radioactive isotope to a targeting peptide makes it possible to direct a payload to specific tissues. Peptide-receptor radionuclide therapy and imaging are established examples of the approach.
6. Antimicrobial peptides
Many organisms produce short, positively charged peptides that disrupt bacterial membranes. With antibiotic resistance rising, these antimicrobial peptides are being studied as templates for new anti-infective agents. The main hurdles are toxicity to host cells and stability.
7. AI-assisted peptide design
Machine-learning models trained on sequence and structure data are increasingly used to predict how peptides fold, which targets they'll bind and how stable they'll be. Combined with protein-structure prediction tools, these methods can narrow huge sequence spaces down to a short list of candidates before anything is synthesised.
Following the field: peer-reviewed sources such as the Journal of Medicinal Chemistry, the Journal of Peptide Science and Nature Reviews Drug Discovery, plus trial registries such as ClinicalTrials.gov, are the most reliable ways to track new developments.
Related articles
- How laboratories validate analytical methods
- Antimicrobial peptides: an ancient defence against modern superbugs
- How clinical trials are designed
Sources and further reading
- Muttenthaler M, King GF, Adams DJ, Alewood PF. Trends in peptide drug discovery. Nat Rev Drug Discov 2021;20:309–325. doi:10.1038/s41573-020-00135-8 · PMID: 33536635
- Lau JL, Dunn MK. Therapeutic peptides: historical perspectives, current development trends, and future directions. Bioorg Med Chem 2018;26:2700–2707. doi:10.1016/j.bmc.2017.06.052 · PMID: 28720325
- Craik DJ, Fairlie DP, Liras S, Price D. The future of peptide-based drugs. Chem Biol Drug Des 2013;81:136–147. doi:10.1111/cbdd.12055 · PMID: 23253135
- Schafmeister CE, Po J, Verdine GL. An all-hydrocarbon cross-linking system for enhancing the helicity and metabolic stability of peptides. J Am Chem Soc 2000;122:5891–5892. doi:10.1021/ja000563a
- Smith GP. Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science 1985;228:1315–1317. doi:10.1126/science.4001944 · PMID: 4001944
- Jumper J et al. Highly accurate protein structure prediction with AlphaFold. Nature 2021;596:583–589. doi:10.1038/s41586-021-03819-2 · PMID: 34265844