A CDR-Based Approach to Generate Covalent Inhibitory Antibodyfor Human Rhinovirus Protease

摘要: Abstract Covalent target modulation with small molecules has been emerging as a promising strategy for drug discovery. However, covalent inhibitory antibodyremains unexplored due to the lack of efficient strategies engineer antibody desired bioactivity. Herein, we developed an intracellular selection method generate antibodyagainst human rhinovirus 14 (HRV14) 3C proteasethrough unnatural amino acid mutagenesis along heavy chain complementarity-determining region 3 (CDR-H3). A library mutants wasthus constructedand screened in vivo through co-expression withthe targetprotease. Using this screening strategy, six antibodies proximity-enabled bioactivity were identified, which shown covalently HRV14-3C protease highinhibitory potency and exquisite selectivity. Compared structure-based rational design, library-based provides simple wayfor thediscovery engineering ofcovalentantibody enzyme inhibition.