With the advances in peptide formulation and delivery for GLP-1 agonists such as Mounjaro®, Wegovy®, and Ozembic®, there is a renewed interest in peptides as a modality for drug discovery. Historically, peptides have struggled with low stability, poor oral bioavailability, rapid clearance, and the requirement for an injectable form, making them less attractive than their small molecule counterparts. The Boulder Peptide Symposium (BPS), held September 15-18, 2025, showcased new advancements, supporting that we are witnessing a renaissance of peptides as therapeutics for several diseases, where this modality can play a critical role in the advancement of treatment. This article summarizes four key trends to consider when developing peptide therapeutics.
- Discovery – Peptide drug candidates are primarily discovered through two strategies. 1) Researchers build off known protein interacting partners or natural peptide ligands to develop optimized peptides through medicinal chemistry approaches. The goal is to enhance affinity, selectivity, and gut transport. 2) For de novo peptide discovery, the first trend is that researchers are utilizing peptide screening tools such as phage and mRNA display to offer researchers access to libraries of billions of peptides. The libraries can be tailored to adopt distinct structures, including linear and cyclic, and secondary libraries provide a path forward to enhance their affinity, selectivity, and physical-chemical properties.
- Affinity – Several presentations at BPS highlighted the high affinities that can be achieved using peptides. In one example, a large pharma presentation discussed rapid progress from discovery to a novel IL-23 receptor inhibitor in the clinic in less than 6 years. Their drug exhibits picomolar affinities with high selectivity over similar targets. The second trend is the goal to achieve sub-nanomolar affinities, which aims to overcome challenges with bioavailability, resulting in only a small amount of peptide required to be efficacious.
- Permeability and Metabolism – Peptides are meant to be broken down in the gut into amino acids for absorption by the body. To overcome this challenge and enhance stability, the third trend noted is the strategy to modify peptides using fatty acids and non-natural amino acids. Advanced medicinal chemistry campaigns have successfully converted early peptide hits into leads with highly desirable pharmacokinetic profiles for several programs utilizing these modifications.
- Half-life – A short half-life is typically a disadvantage in the drug discovery world. However, the final trend highlights how the radiopharmaceuticals and theranostics communities benefit from the short half-lives of both radiopharmaceuticals and theranostics for both therapeutic and diagnostic applications. Incorporating a radionuclide into a peptide is a powerful tool for diagnostic imaging and localizing a radionuclide payload to a target, thereby destroying tumor cells. The short half-life and rapid kidney clearance ensure that these otherwise toxic molecules are eliminated from the body after their desired activity, in order to prevent potentially harmful side effects.
Radiopharma and Theranostics
There are now over 20 companies in the radiopharma and theranostics space working on new therapies, with four of these companies participating in a panel discussion at the BPS conference. This panel presented data on the most advanced targeted therapies for prostate-specific membrane antigen (PSMA), where there are currently 60 drugs being developed to this target. Outside of PSMA’s popularity and its leading example of effective radiotherapy, this panel presented 17 additional targets in discovery and development. These targets represent the next generation of radiopharma’s breakthrough therapies for cancer and beyond.
This is only the beginning of the peptide renaissance! The pathway to effective peptide drugs is clearer now than ever before. Regardless of the target of interest, the process starts with discovery of novel peptide hits with high affinity and on-target activity. Tango Biosciences is at the cutting edge of peptide discovery with over 20 phage display peptide libraries, representing over 200 billion different peptides in linear, cyclic, and macrocyclic formats. We look forward to continuing to contribute to this promising modality for therapeutic and diagnostic tools.
