How Peptides Are Expanding The Possibilities Of Drug Discovery

By Karsten Eastman, Ph.D., Cofounder and CEO, Sethera Therapeutics

GLP-1 therapies have brought substantial attention to peptides. Their success has changed expectations for treating obesity and metabolic disease and encouraged a broader conversation about what peptides can accomplish. These molecules can address diverse biology, and the additional attention creates an opportunity to look at many diseases where peptide medicines could make a difference.

In 2026, oral peptide approvals in psoriasis and cardiovascular medicine have strengthened the case for peptides as a broadly applicable therapeutic modality. Growing federal attention to peptide compounding adds to this momentum, while advances in molecular design are giving developers greater control over how peptides bind their targets and behave in biological systems. These developments support an ambitious next step: using peptides to reach disease mechanisms that have remained difficult to address with existing medicines. Examples include interactions that suppress p53 activity in cancer and regulate Nrf2-mediated defenses against cellular stress and oxidative damage.^1,2

Broadened Clinical Progress

The approval of icotrokinra, an oral peptide targeting the interleukin-23 receptor, for moderate-to-severe plaque psoriasis illustrates this progress. It brings an oral peptide approach to an inflammatory pathway that has already proved therapeutically valuable. Enlicitide, an oral macrocyclic peptide that inhibits PCSK9, adds another example through its approval for lowering low-density lipoprotein (LDL) cholesterol in adults with hypercholesterolemia.^3,4

These milestones show that peptide engineering can translate into medicines across distinct biological pathways. For patients, an oral route of delivery makes treatment fit more easily into daily life. A target's biology should help determine which modality is pursued. As peptide capabilities expand, there is more reason to consider them early, including for programs where the available small molecules or antibodies leave important needs unmet. For example, the MDM2–p53 and Keap1–Nrf2 interactions are intracellular targets that conventional antibodies do not readily access. Peptides that combine selective recognition of these interfaces with sufficient cellular exposure could offer another way to intervene in their disease biology.^1,2

Government Attention Is Expanding

Federal policy is adding another dimension to this momentum. In late October 2026, the U.S. Department of Health and Human Services published a draft enforcement-discretion policy covering the compounding of six peptides: BPC-157, epitalon, KPV, MOTS-c, Semax, and TB-500. It outlines conditions for expanded access while the FDA considers their inclusion on the 503A bulks list.^5,6

Further expansion is already being considered. The FDA plans an advisory committee meeting before the end of February 2027 to review five additional substances: LL-37, GHK-Cu, dihexa acetate, melanotan II, and pegylated mechano growth factor (PEG-MGF).⁷

In my view, this federal attention is a sign of how much interest peptides are attracting. Favorable decisions could broaden opportunities for compounding pharmacies and increase demand for peptide manufacturing and analytical testing. Clearer access pathways could also encourage investment in the clinical research needed to establish where these compounds provide meaningful benefit.

Greater Control Over Molecular Design

Peptides are a chemically versatile starting point. Their amino acid sequences provide multiple opportunities to tune interactions with a target. However, a molecule that binds well in an assay still needs to survive in the body and reach the location where it can act. Historically, enzymatic degradation, rapid clearance, and limited permeability have made that transition difficult for many promising peptides.¹

Advances in macrocyclization and the incorporation of unnatural amino acids are helping to address these limitations. Connecting parts of a peptide to form a ring can constrain its shape and improve resistance to degradation. Changing individual building blocks or modifying the backbone can further tune molecular recognition and the properties that influence membrane passage. This gives medicinal chemists a wider range of structures to explore than the standard amino acid alphabet alone would permit.^1,8,9

The value lies in understanding how these changes work together. A modification that improves stability may also alter binding or solubility. Increasing permeability can require a different balance of exposed polar groups and conformational flexibility. Designing a successful molecule therefore involves learning which combinations preserve biological activity while producing the behavior needed for a particular therapeutic application.⁸

Selectivity is equally important. Closely related proteins can perform different functions, and a useful therapeutic effect may depend on distinguishing among them. The ability to adjust a peptide's binding surface creates opportunities to investigate those distinctions. For discovery teams, that means evaluating the intended mechanism and unwanted interactions together as the molecule evolves.

Computational design is becoming an increasingly useful partner in that process, making it simpler to explore candidate structures, propose sequences, and prioritize candidates for synthesis and testing. Recent work adapting AlphaFold-based approaches to cyclic peptides has produced designed structures that closely match experimental measurements, alongside peptides capable of binding selected protein targets.¹

I expect the strongest discovery programs to combine these tools with repeated experimental feedback. Each cycle of design, synthesis, and testing can sharpen our understanding of why a molecule works.

The Peptide Landscape In 2027

I believe the most consequential development to watch in 2027 will be progress toward peptide therapeutics that address targets that conventional small molecules and antibodies struggle to reach.

Many important biological processes depend on interactions between proteins. Some of these interactions involve broad or relatively shallow surfaces that are difficult to engage effectively with conventional small molecules. Antibodies can recognize complex protein surfaces, but their limited access to intracellular targets leaves many disease mechanisms beyond their usual reach.²

Peptides offer opportunities to engage these surfaces through multiple points of contact. Their structures can be engineered to reproduce important features of a natural interaction or establish a new binding arrangement. If those capabilities can be combined with sufficient stability and access to the relevant tissue and cellular compartment, the range of tractable targets could expand substantially.²

There are encouraging research examples. Work published in 2026 described cyclic peptides that inhibit the intracellular interaction between Keap1 and Nrf2, with optimization producing a compound active in living cells. Findings like this help connect molecular design with the functional activity needed to pursue difficult intracellular biology.²

Making further progress requires treating delivery as a series of specific problems. Oral absorption, distribution into a tissue, and access to an intracellular target are distinct achievements. A peptide intended to act outside cells may need a different design strategy from one intended to alter an intracellular signaling complex. Defining the required destination early should guide both chemistry and experimental validation.

Finding Meaningful Medicines

For drug developers, the most reasonable opportunity is to connect these advances around a clear therapeutic objective. Potency matters, but so do the concentrations a molecule can achieve where it needs to act, how long it remains active, and whether that exposure produces the intended biological response. These questions should shape discovery from the beginning.

The same applies to manufacturing and the eventual treatment experience. A peptide candidate needs a feasible route to consistent production and dosing appropriate for patients. An oral medicine may be particularly valuable in some settings; in others, a long-acting injectable or a locally delivered treatment may better serve the clinical objective.

In 2027, I will be watching for programs that bring these requirements together convincingly. Evidence of target engagement in relevant biological systems, useful exposure, and a clear connection between mechanism and disease will tell us how far the field is advancing.

Scientific advances and sustained policy attention are strengthening the outlook for peptides. We can increasingly approach their limitations as specific chemical and biological problems to investigate, with a growing set of tools available to address them. I believe that will encourage greater ambition in the targets we choose and the diseases we pursue.

GLP-1 therapies have helped demonstrate the impact peptide medicines can have. The opportunity ahead is to extend that impact across a much broader range of biology and achieve new ways to intervene.

References

1. Rettie SA, et al. Cyclic peptide structure prediction and design using AlphaFold2. Nature Communications. 2025;16:4730.
2. Ji X, et al. Generation of membrane-permeable cyclic peptides inhibiting protein–protein interaction. Nature Chemical Biology. 2026;22:1351–1361.
3. U.S. Food and Drug Administration. Drug Trials Snapshots: ICOTYDE. Original approval March 17, 2026.
4. U.S. Food and Drug Administration. FDA Approves First Oral PCSK9 Inhibitor to Lower LDL Cholesterol in Adults with High Cholesterol. July 17, 2026. See also LIPFENDRA prescribing information, section 12.1.
5. U.S. Department of Health and Human Services. Enforcement Discretion Policy Regarding 503A Compounding Using Certain Peptide Bulk Drug Substances. Federal Register. 2026;91:68526–68527. October 30, 2026.
6. U.S. Department of Health and Human Services. HHS Enforcement Discretion Policy Regarding 503A Compounding Using Certain Peptide Bulk Drug Substances. Policy and Appendices A and B. October 2026.
7. U.S. Food and Drug Administration. Meeting of the Pharmacy Compounding Advisory Committee. Planned before the end of February 2027. Accessed November 3, 2026.
8. Bhardwaj G, et al. Accurate de novo design of membrane-traversing macrocycles. Cell. 2022;185:3520–3532.e26.
9. Kawai M, et al. RaPID discovery of cell-permeable helical peptide inhibitors containing cyclic beta-amino acids against SARS-CoV-2 main protease. RSC Chemical Biology. 2025;6:1089–1099.

About The Author

Karsten Eastman, Ph.D., is cofounder and CEO of Sethera Therapeutics, a biotechnology company developing peptide medicines through enzymatic engineering. He earned his doctorate in chemistry at the University of Utah under Professor Vahe Bandarian, where his research helped establish the scientific foundation for Sethera’s technology. His work focuses on radical SAM enzymes, peptide macrocyclization, and methods for creating structurally diverse peptides with new therapeutic possibilities. At Sethera, he leads efforts to translate these discoveries into a drug discovery platform that can address difficult biological targets