Discovery and Optimization of an mRNA Display Cyclic Peptide inhibitor of the IL1b/IL1R Interaction
Year: 2026
Type: conference-paper
Abstract: SAR EvolutionInterleukin-1β (IL-1β), a member of the IL1 family of cytokines, is a key mediator of the inflammatory response 1 .Dysregulated IL-1β signaling plays a critical role in the pathogenesis of numerous diseases, including autoimmune, autoinflammatory, infectious, and degenerativedisorders 2 .IL-1β is also involvedas target in cardiovascular(CV)diseases, since inflammationdrives the progression of atherosclerosis.Lowering inflammationthrough IL-1β pathway,provides atheroprotection , independentof lipid levels 3 .IL-1β activity can be inhibitedby blocking the protein-proteininteraction (PPI) betweenIL-1β and its cell-surface receptorIL1R.Clinically,IL-1β inhibitionhas beenachievedusing injectableanti-IL-1β monoclonalantibodies 3,4 .However,monoclonalantibody-based therapies are limited by challenges in fine-tuning cytokinemodulationandachievingan optimalrisk-benefitprofile.✓ An mRNA Display macrocyclic peptide lead inhibiting IL1 β/IL1R PPI was evolved through structure -based design and data -driven multi -parameter optimization to a proofof-concept molecule demonstrating formulation -enabled oral exposure (>2% F) in rodent ID PK study with a permeation enhancer (30% Na Caprate) and PD effect in in vivo with a profile which compares favorably with benchmark antibody Canakinumab and retains a similar MOA ✓ This work demonstrated the tractability of macrocyclic peptides as alternative chemical modality to efficiently tackle the PP I between IL1 β and IL1R, and opens the path to future development of peptide -based oral therapies for diseases involving this pathway Fig.
Source: European Peptide Symposium (EPS)
Authors: Stefania Colarusso, Francesca Pavone, Elisabetta Bianchi, Roberto Iaccarino, Emanuela Mandic, Emanuela Nizi, Willy Constantini, Martina di Geronimo, Faben Cruz, Dennis Feng, Yan Guo, Jennifer Hanisak, Charles Jayne, Ahmet Kekec, Angelea Kerekes, Victor Mak, Michael Lo, Jennifer Hickey, Christopher Plummer
Institutions: IRBM, Merck & Co., Inc., Rahway, NJ, USA (United States)
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: bronze
OpenAlex ID: W7214401190