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 pervasive pathogen that establishes lifelong latent infections, and the emergence of drug resistance necessitates novel therapeutic strategies. This study puts forth a first-in-class antiviral concept: a bivalent degrader designed to force the virus to destroy its own critical machinery. Methods: We target the viral E3 ubiquitin ligase, Infected Cell Protein 0 (ICP0), a crucial factor for both lytic replication and reactivation from latency. Our strategy is to induce the dimerization of ICP0, forcing one molecule to catalyze the ubiquitination and subsequent proteasomal degradation of another. This study details a comprehensive in silico pipeline, initiated by an iterative de novo design campaign against a single, druggable pocket on an AI-predicted structure of ICP0. 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 robust computational blueprint for a novel class of anti-herpetic agents, laying the foundation for future molecular dynamics simulations and experimental validation required to advance this therapeutic concept.