In Silico Identification and In Vitro Validation of Repurposed Compounds Targeting the RSV Polymerase.

• Type of Material: Article
• Authors: Eric Xu, Emory University; Seohyun Park, Emory University; Juan Calderon, Emory University; Dongdong Cao, Emory University; Bo Liang, Emory University
• Language: English
• Date: 2023-06-18
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2023 by the authors. Licensee MDPI, Basel, Switzerland.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/microorganisms11061608
• Title of Journal or Parent Work: Microorganisms
• Volume: 11
• Issue: 6
• Grant/Funding Information: The research programs in the Liang laboratory at Emory are supported by the US National Institute of General Medical Sciences (NIGMS), the National Institutes of Health (NIH) under award number R01GM130950, and the American Lung Association Innovation Award, grant number IA-831472.
• Keywords: RNA-dependent RNA Polymerase (RdRP); totrombopag; in vitro transcription assay; in silico simulation; Respiratory Syncytial Virus (RSV); micafungin; verubecestat
• Research Categories: Biology, Genetics

Abstract

Respiratory Syncytial Virus (RSV) is the top cause of infant hospitalization globally, with no effective treatments available. Researchers have sought small molecules to target the RNA-dependent RNA Polymerase (RdRP) of RSV, which is essential for replication and transcription. Based on the cryo-EM structure of the RSV polymerase, in silico computational analysis including molecular docking and the protein-ligand simulation of a database, including 6554 molecules, is currently undergoing phases 1-4 of clinical trials and has resulted in the top ten repurposed compound candidates against the RSV polymerase, including Micafungin, Totrombopag, and Verubecestat. We performed the same procedure to evaluate 18 small molecules from previous studies and chose the top four compounds for comparison. Among the top identified repurposed compounds, Micafungin, an antifungal medication, showed significant inhibition and binding affinity improvements over current inhibitors such as ALS-8112 and Ribavirin. We also validated Micafungin's inhibition of the RSV RdRP using an in vitro transcription assay. These findings contribute to RSV drug development and hold promise for broad-spectrum antivirals targeting the non-segmented negative-sense (NNS) RNA viral polymerases, including those of rabies (RABV) and Ebola (EBOV).