Integrated Computational and Experimental Approach for Lead Optimization and Design of Compstatin Variants with Improved Activity

A novel structure−activity-based combinatorial computational optimization methodology for the design of peptides that are candidates to become therapeutics is presented. This methodology has been successfully applied in the design of a 7-fold more active analogue, among other active analogues, in the case of the complement inhibitor compstatin. The main steps of the approach involve the availability of NMR-derived structural templates, combinatorial selection of sequences based on optimization of parametrized pairwise residue interaction potentials, prediction of fold stabilities using deterministic global optimization, and experimental validation with immunological activity measurements. This work is direct evidence that an integrated experimental and theoretical approach can make the engineering of compounds with enhanced immunological properties possible.