Project 5: Pandemic Virus Helicase Inhibitors Abstract

SARS-CoV2 viral helicase (purple) is a key component in the viral replicase complex interacting with other viral proteins (e.g., viral RNA-dependent RNA polymerase shown in green) to generate viral RNAs (shown in orange and blue wires).

Project 5: Pandemic Virus Helicase Inhibitors Abstract

The goal of Project 5 is to develop antiviral drug candidates that target the viral enzymes (i.e., helicases) involved in virus replication. All priority RNA viruses have a viral helicase domain in their genomes that are similar in structure and biochemical features.

Viral RNA helicases are essential for RNA virus replication. In addition, these helicases share an evolutionary origin.

Viral RNA helicases can serve as an antiviral target with a high barrier to drug resistance. Therefore, we hypothesize that viral helicases can be a target for safe and effective antivirals.

With our first aim, we propose an antiviral discovery campaign that targets viral helicase by combining ultra-high-throughput screening and DNA-encoded chemistry technology. A validation scheme with antiviral testing, structural biology, and biochemical approaches would occur after the screening.

In our second aim, we propose to advance promising inhibitors through hit-to-lead development. Validated leads for drug development will undergo medicinal chemistry, AI-based drug design, drug metabolism and pharmacokinetics, and in vivo antiviral efficacy studies.

Our third aim is to deliver one to two orally bioavailable, patentable small molecules suited for development by a pharma partner.

Our efforts will deliver new classes of direct helicase-targeting antiviral agents for SARS2 infection and other high-priority viral pathogens.