New Analogs of the Compstatin Family of Clinical Complement Inhibitors with Low Picomolar Target Affinity

Macrocyclic peptides of the compstatin family have emerged as therapeutic complement system modulators. Alongside an approved PEGylated derivative, sequence-optimized compstatin analogs with enhanced PK/PD properties have shown clinical promise. By extending the structure-activity relationship of compstatin, we characterized a highly beneficial V3I modification that enhances compstatin’s target affinity up to 30-fold and show that the additional gamma-methyl group addresses a specific target pocket. Novel analog Cp01-V3I represents the most potent analog comprised entirely of canonical amino acids (KD = 20 nM), opening a path toward recombinant applications. Meanwhile, the V3I modification can be transferred to late-generation analogs to obtain a low-picomolar-affinity derivative (KD = 0.08 nM), termed Cp60, with potent complement inhibition in vitro. Lastly, we demonstrate that Cp60’s ultra-long target residence enables new applications as a diagnostic tool for the detection of complement opsonins on biosurfaces. Collectively, this work highlights the importance of vigorous optimization of de novo peptide inhibitors to improve PK/PD properties and enable novel applications.