SYMPOSIUM: Peptide Drug Hunting 101: The Life of a Peptide

The amazing story of peptide science and breakthrough peptide medicines is still being written. Great advancements in peptide chemistry, biology, structural biology, computational chemistry, pharmacokinetics, and drug delivery have been achieved. Leveraging such knowledge, a new generation of multidisciplinary peptide-drug hunters is now contributing to diverse peptide modalities, lead optimization, screening tools, design rules, and translation into the clinic campaigns. This talk will highlight this inspiring, yet unfinished story.

Proteins have long been at the center of biological design, yet peptides offer unique features that proteins often lack—for example, their ability to interact with and cross membranes, as well as their ease of synthesis. At the same time, many fundamental questions about peptides remain open: Can deep learning approaches be applied effectively to them? How exactly do they traverse cellular membranes? And how can we best harness their properties for therapeutic or technological applications? In this talk, I will briefly highlight some of the recent successes in peptide research and outline the challenges and opportunities that lie ahead.

This talk reviews computational approaches to peptide design and concludes with our integrated computational–experimental platform for Helicons. Helicons are helically constrained peptides that represent a next-generation strategy for modulating intracellular targets often inaccessible to small molecules. Early computational efforts rooted in traditional structure-based drug design showed promise but were limited by sampling inefficiencies and poor transferability across peptide modalities, challenges further amplified by the expanding chemical space of non-natural amino acids. Today, emerging frameworks that couple modern predictive and/or generative machine learning with physics-based modeling offer new opportunities to explore this vast peptide landscape with greater predictive accuracy and efficiency.

AI tools can generate vast therapeutic libraries, but biological evaluation remains a major bottleneck. Orbit Discovery’s Functional Screening platform combines microfluidics with DNA-encoded peptide libraries to rapidly assess millions of peptides. In collaboration with ProteinQure, we screened an AI-designed library to identify novel Delta and Mu Opioid Receptor agonists. We present our screening workflow and validation data, demonstrating efficient translation of AI designs into therapeutic hits.

Advances in high-throughput screening methods have been critical for enabling peptide-based drug discovery. In this talk, we present an overview of the screening approaches commonly used today, including ribosomal-based methods such as phage display and mRNA display, and synthetic methods such as DNA-encoded libraries and one-bead-one-compound screening. We will share examples where parallelized phage screening was used to discover novel helical peptides (Helicons) and molecular glues to challenging intracellular targets.

Peptide-based therapeutics hold a unique and advantageous space in the pharmacological landscape of therapeutic modalities. They bridge the gap between conventional small molecules and biologics, allowing them to combine their best attributes while overcoming their limitations. Drug-target selection strategies are fundamental in providing therapeutic modality advantage while creating opportunities to address unmet medical needs. Target-selection strategies and experimental approaches for target identification will be discussed.

Despite decades of research, peptide therapeutics are still largely limited to needle administration due to insufficient oral bioavailability. This presentation will go over current limitations in the field of peptide drug delivery and most recent advancements to overcome them. Specifically, the identification of suitable permeation enhancers and challenges associated converting these from liquid formulation concepts into clinically and commercially viable solid dosage formulations.

Oral peptide antagonists targeting IL-23/IL-17 are an emerging class for chronic immune-mediated diseases. Icotrokinra (JNJ-2113), the first oral IL-23 receptor antagonist, showed strong efficacy and safety, achieving durable skin clearance in Phase 3 psoriasis trials and clinical response and remission in Phase 2 ulcerative colitis, advancing to Phase 3 for UC and Crohn’s. PN-881, a next-generation oral IL-17 antagonist, offers broad IL-17 inhibition, high stability, and compelling preclinical efficacy.

Wnt signaling pathway mutations leading to constitutive activation of ß-catenin occur in at least 15% of all human cancers. We have developed FOG-001, a hyperstabilized a-helical peptide (Helicon) that binds directly to ß-catenin, achieves cytosolic exposure, and inhibits Wnt pathway signaling. Multiple backbone cyclizations enforce peptide helicity, and unnatural amino acids on ß-catenin-facing residues yield picomolar binding affinity. FOG-001 demonstrates pharmacodynamic modulation and efficacy in Wnt pathway-activated tumors.