Cambridge Healthtech Institute’s Oral & Macrocyclic Peptides conference focuses on the design and development of peptide therapeutics that are either oral, membrane-permeable, or both! The ideal peptide therapeutic is orally bioavailable for patient convenience AND membrane-permeable so intracellular molecular complexes can be targeted. Macrocyclic peptides offer the potential for both properties in one molecule. The meeting’s expanded format (Part 1 and Part 2) not only reflects the excitement inspired by the success of GLP1-related anti-obesity peptide therapeutics but allows coverage of newer applications of macrocyclic peptides such as radioligands or drug conjugates. We also address formulation and translational considerations in appreciation of the growing impact of downstream chemistry on early-stage peptide therapeutic design. Join us to learn from and connect with leading discovery chemists in sharing insights and advances in the field of discovery peptide therapeutics.
12:00 pm Registration Open
1:00 pm Dessert Break in the Exhibit Hall
Enjoy a dessert break in the Exhibit Hall! Network with our sponsors and exhibitors.
1:30 pm Welcome Remarks
1:35 pm Chairperson's Remarks
Katerina Leftheris, PhD, formerly CSO, Vilya Therapeutics
1:40 pm Wrangling Property Space in Encoded Macrocyclic Libraries: Towards Potent and Permeable Hits
Scott Lokey, PhD, Professor, Chemistry and Biochemistry, University of California, Santa Cruz
We have been investigating the membrane permeability of large cyclic peptide scaffold model systems. In our efforts to apply the insights gained from these systems to find macrocycles that are both permeable and bioactive, we have designed mRNA-display and DNA-encoded libraries with enhanced permeability, using simple design criteria such as avoiding charged groups and hydrogen bond donors in the side chains, and limiting backbone NH groups via N-methylation. We now report lead compounds from these libraries selected against two intracellular proteins, their permeabilities, as well as their biochemical and cellular activities.
2:10 pm Discovery of a New Class of Cell-Permeable Macrocycles
Thomas Kodadek, PhD, Professor, Department of Chemistry, University of Florida, Scripps Biomedical Research
The development of macrocyclic peptides (MPs) able to access intracellular protein targets is of keen interest. Here we describe new types of MPs in which the ring is closed through formation of a moiety in which a permanent positive charged is embedded within a hydrophobic heterocyclic ring system. We show that this strategy increases the passive membrane permeability of any MP, often dramatically. We also describe the synthesis and screening of combinatorial libraries of these novel MPs.
2:40 pm Next-Generation Macrocyclic DNA-Encoded Libraries (DEL) for Protein–Protein Interaction Drug Discovery
Subbarao Yalamanchili, Senior Research Scientist, Project Chemistry, X-Chem, Inc.
Macrocyclic DELs enable rapid, systematic exploration of beyond-Ro5 chemical space that is challenging to access efficiently with peptide or mRNA display. We describe a platform that yielded low-nanomolar, highly selective inhibitors of Bcl-2 family proteins and revealed structural principles governing potency and selectivity. We also highlight lessons learned and strategies for designing next-generation macrocyclic DELs.
3:10 pm Refreshment Break in the Exhibit Hall with Poster Viewing
4:00 pm Permeation Screening of DNA-Encoded Macrocyclic Peptides
Juan Hu, PhD, Assistant Professor, Chemistry & Biochemistry, San Diego State University
Macrocyclic peptides promise access to intracellular “undruggable” targets but suffer poor permeability. We developed a microfluidic, liposome-based permeation screen using click chemistry and a 19.6K-member thioether-cyclized DNA-encoded macrocycle library. Using DOPC liposomes, we identified, resynthesized, and plate-validated permeant hits, demonstrating scalable, permeability-driven selection. Next, we’ll diversify scaffolds and deploy bacterial and mammalian-derived membranes to better mimic barriers, sharpening structure–permeability insight in the bRo5 space and enabling predictive PK modeling.
4:30 pm Advances in Peptidic Conjugates with Limited Permeability: Strategies to Enhance and Validate Cellular Uptake
Jakob Fuhrmann, PhD, Senior Principal Scientist, Peptide Therapeutics, Genentech, Inc.
Peptidic conjugates offer a promising strategy for targeting intracellular proteins, yet limited cell permeability remains a major barrier. This work introduces strategies to enhance and validate the cellular uptake of moderately permeable peptides. By integrating an innovative assay system with structure–permeability design principles beyond PAMPA, MDCK, and Caco-2 models, the study provides insights to advance peptide-based modalities for intracellular drug discovery.
5:00 pm Breakout Discussions (In-Person Only)
Breakout Discussions are informal, moderated discussions, allowing participants to exchange ideas and experiences and develop future collaborations around a focused topic. Each breakout will be led by a facilitator who keeps the discussion on track and the group engaged. Please visit the Breakout Discussions page on the conference website for a complete listing of topics and descriptions. Breakout Discussions are offered in-person only.
Sepideh Afshar, PhD, Senior Director, Head of Peptide Therapeutics, Genentech Inc.
Alison Heick Varghese, Principal Scientist, Pfizer Inc.
5:45 pm Close of Day
6:15 pm Recommended Dinner Short Course*
*Premium Pricing or separate registration required. See Short Courses page for details.
7:45 am Registration and Morning Coffee
8:15 am Plenary Welcome Remarks from Lead Content Director
Anjani Shah, PhD, Senior Conference Director, Cambridge Healthtech Institute
8:25 am Directed and Random Walks in Chemical Space
Brian K Shoichet, PhD, Professor & Chair, Pharmaceutical Chemistry, University of California San Francisco (UCSF)
In the last six years, docking libraries have expanded from three million to over a trillion molecules. In controlled experiments, we compare billion vs. million molecule library docking on the same targets, demonstrating that as the libraries grow so too do hit-rates and affinities. I consider how and if new ML methods separate true from false positives in these campaigns, and how good our subsequent ligand optimization strategies are versus what we might expect against a random background (surprisingly unimpressive).
9:10 am Coffee Break in the Exhibit Hall with Poster Viewing and Best of Show Awards Announced
10:00 am Chairperson's Remarks
Bryan C. Fuchs, PhD, Senior Director & Research Therapeutic Area Head, GI & Liver Disease, Ferring Research Institute
10:05 am Strategies to Enhance Peptide Affinity
