Abstract 2738 Motion-Based Drug Discovery of Human 5-Lipoxygenase

NSP14 is a dual-function enzyme which plays a key role in SARS-CoV-2 replication.Its C-terminal 3`to 5`exonuclease (ExoN) domain is important for proofreading nascent RNA.At the N-terminus the methyltransferase (MTase) domain performs the N7-methylation of the forming RNA cap, promoting stability of the genome and aiding in host evasion.Curiously, these domains function independently.Additionally, the ExoN activity depends on an accessory protein, NSP10 while the MTase domain is not.Both activities are enticing drug development targets.Toward this end, we developed biochemical high-throughput screening (HTS) assays for the ExoN and MTase activities.We screened both ExoN and MTase activities against 40,664 unique compounds from NCATS libraries to identify potential lead compounds for further drug development.Through this screening platform we identified inhibitors specific to ExoN and MTase activities as well as a novel dualactivity inhibitor of NSP14.