Development of chemokine network inhibitors using combinatorial saturation mutagenesis.

ABSTRACT: Targeting chemokine-driven inflammation has been elusive due to redundant pathways constituting chemokine-immune cell networks. Tick evasins overcome redundant pathways by broadly targeting either CC or CXC-chemokine classes. Recently identified evasin-derived peptides inhibiting both chemokine classes provide a starting point for developing agents with enhanced potency and breadth of action. Structure-guided and affinity maturation approaches to achieve this are unsuitable when multiple targets are concerned. Here we develop a combinatorial saturation mutagenesis optimisation strategy (CoSMOS). This identifies a combinatorially mutated evasin-derived peptide with significantly enhanced pIC₅₀ against three different inflammatory disease chemokine pools. Using AlphaFold 3 to mode

SUBMITTER: Kryukova J 

PROVIDER: S-EPMC11969024 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature