SYMPOSIUM: Peptide Drug Hunting—From Emerging Technologies to Clinical Impact

Peptides are increasingly delivering differentiated medicines across extracellular, intracellular, and targeted-delivery applications. Their success depends on more than binding affinity: translation requires early, integrated decisions across target biology, modality selection, chemical design, pharmacology, exposure, delivery, developability, and clinical strategy. Using the “Life of a Peptide” as a framework, this talk will examine how multidisciplinary teams can engineer peptide medicines from discovery through translational impact, including emerging design technologies, AI-enabled workflows, structure–pharmacology relationships, and modality-specific strategies. It will also highlight PDHC’s role in sharing lessons and accelerating peptide drug discovery and development.

Cyclotides are excellent scaffolds for the incorporation of bioactive peptide epitopes to stablize them. This presentation describes our work on the discovery, structural characterization and applications of cyclotides in medicine, with recent examples using mRNA display to combinatorially vary backbone loops in the cyclotide scaffold. The approach will be illustrated by the development of a potent inhibitor of factor XII to minimize clotting in extracorporeal membrane oxygenation procedures without bleeding complications.

Peptides occupy the therapeutic space between small molecules and antibodies, yet most remain injectable and confined to nature's twenty amino acids. Aizen's DaX is an interaction-centric foundation model that learns the physics of molecular binding rather than sequence patterns—enabling de novo design of non-canonical peptides beyond the reach of conventional discovery. This talk presents the approach and its application to oral biologics against previously intractable receptor classes.

Poor cell permeability and bioavailability greatly limits the utility macrocyclic peptides (MPs) in drug development. Most approaches to improving cytosolic penetration focus on either making the MP as hydrophobic as possible (following lessons learned from Cyclosporin A) or incorporating multiple Arg moieties to promote uptake via some form of endocytosis. We took a very different approach and searched for chemical moieties that can be included in an MP that intrinsically accelerate their passive diffusion through a membrane. In this lecture, we will describe two such moieties and show that they enable even large, polar peptides to readily enter cells passively.

The ability of cyclic peptides to cross biological barriers makes them promising compounds for the potential development of treatments for neurological diseases, but how to optimize these peptides for activity in the CNS is unclear. Dr. Aldrich will discuss her laboratory's efforts to optimize cyclic peptides for activity at CNS targets and their potential development as treatments for neurological diseases, focusing on substance abuse and neurodegeneration.

Recent advances have begun to blur the lines between the arenas of peptide and small-molecule drug discovery; a better understanding of fundamental biology and molecular design has enabled new modalities to enter the clinic and previously undruggable targets to be modulated with molecules that would have once not been considered “drug-like." This talk will focus on several recent success stories in peptide drug discovery and highlight how researchers generated remarkably potent molecules with pharmacokinetic profiles amenable to targeting intracellular proteins and, in some cases, to be dosed orally.