Identification of a macrocyclic compound targeting the lassa virus polymerase

Virginia Aida-Ficken; Jamie A Kelly; Payel Chatterjee; M Harley Jenks; Laura K McMullan; César G Albariño; Joel M Montgomery; Katherine L Seley-Radtke; Christina F Spiropoulou; Mike Flint

doi:10.1016/j.antiviral.2024.105923

Identification of a macrocyclic compound targeting the lassa virus polymerase

Antiviral Res. 2024 Aug:228:105923. doi: 10.1016/j.antiviral.2024.105923. Epub 2024 Jun 4.

Affiliations

¹ Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA; Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
² Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA.
³ Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, Baltimore, MD, USA.
⁴ Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA. Electronic address: vfa3@cdc.gov.

PMID: 38844175
DOI: 10.1016/j.antiviral.2024.105923

Abstract

There are no approved vaccines or therapeutics for Lassa virus (LASV) infections. To identify compounds with anti-LASV activity, we conducted a cell-based screening campaign at biosafety level 4 and tested almost 60,000 compounds for activity against an infectious reporter LASV. Hits from this screen included several structurally related macrocycles. The most potent, Mac128, had a sub-micromolar EC₅₀ against the reporter virus, inhibited wild-type clade IV LASV, and reduced viral titers by 4 orders of magnitude. Mechanistic studies suggested that Mac128 inhibited viral replication at the level of the polymerase.

Keywords: Antiviral; Lassa; Macrocycle; Polymerase.

Published by Elsevier B.V.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antiviral Agents* / chemistry
Antiviral Agents* / pharmacology
Cell Line
Chlorocebus aethiops
Drug Evaluation, Preclinical
Humans
Lassa Fever / drug therapy
Lassa Fever / virology
Lassa virus* / drug effects
Macrocyclic Compounds* / chemistry
Macrocyclic Compounds* / pharmacology
Vero Cells
Viral Proteins / antagonists & inhibitors
Viral Proteins / genetics
Viral Proteins / metabolism
Virus Replication* / drug effects

Substances

Antiviral Agents
Macrocyclic Compounds
Viral Proteins