Explore a key nucleotide synthesis enzyme to develop a broad-spectrum antiviral therapy.

Title: Explore a key nucleotide synthesis enzyme to develop a broad-spectrum antiviral therapy Co-PI: Pinghui Feng (contact) and Chao Zhang With highly infectious viruses rapidly emerging and re-emerging (such as SARS-Coronavirus, influenza virus and drug-resistant herpes simplex viruses), the human society is challenged with limited options to treat diseases associated with these human viruses. In fact, antiviral therapies that effectively thwart the infection of a broad spectrum of viral pathogens are long sought in the antiviral community. In studying viral immune evasion, we have discovered that diverse viruses, including SARS- CoV-2, herpes simplex virus 1 (HSV-1) and influenza A virus (IAV), activate a key nucleotide synthesis enzyme not only to fuel nucleotide supply, but also block antiviral inflammatory cytokine production, thus efficiently promoting viral replication. We aim to target the key nucleotide synthesis enzyme for inhibition, which will deplete nucleotide supply and restore antiviral immune response to impede their replication. To achieve this goal, we have engineered conditional knockout and knockin mouse strains that will enable the genetic interrogation of the enzyme- mediated evasion of inflammatory response and metabolic reprogramming during the infection of SARS-CoV-2, IAV and HSV-1. Teaming up with a chemical biologist (Dr. Chao Zhang, University of Southern California), we have synthesized a library of small molecules and characterized specific inhibitors of the nucleotide enzyme. Furthermore, we will collaborate with a structural biologist (Dr. Santiago Ramon-Maiques, Instituto de Biomedicina de Valencia, Spain) to perform structure-activity relationship (SAR) analysis to further improve the lead small-molecule inhibitors. This study will provide a proof-of-concept to target a nucleotide synthesis enzyme in an effort to combat the infection of key human viral pathogens.