Design of a First-in-Class homoPROTAC to Induce ICP0 Degradation in Human Herpes Simplex Virus 1

Background/Objectives: Human Herpes Simplex Virus 1 (HSV-1) is a common pathogen that establishes lifelong latent infections. The emergence of drug resistance necessitates novel therapeutic strategies. This study introduces a novel antiviral approach: a bivalent degrader designed to induce the degradation of an essential protein. Methods: A structural model of ICP0, generated via the Chai-1 AI platform, was analyzed with fpocket, P2Rank, and KVFinder to identify a superior allosteric target site. An iterative de novo design workflow with CReM-dock then yielded a lead scaffold based on its predicted affinity and drug-like properties. This selected “warhead” was used to rationally design the final bivalent degrader, ICP0-deg-01, for the ICP0 dimer model. Results: The generative process yielded a lead chemical scaffold that was selected based on its predicted binding affinity and favorable drug-like properties. This scaffold was used to rationally design a single candidate bivalent degrader, ICP0-deg-01. Our structural model predicts that ICP0-deg-01 can successfully bridge two ICP0 protomers, forming an energetically favorable ternary complex. Conclusions: This work provides a computational proof-of-concept for a novel class of anti-herpetic agents and identifies a lead candidate for future molecular dynamics simulations and experimental validation.