2. Academic Validation
  3. Identification of a macrocyclic compound targeting the lassa virus polymerase

Identification of a macrocyclic compound targeting the lassa virus polymerase

  • Antiviral Res. 2024 Jun 4:228:105923. doi: 10.1016/j.antiviral.2024.105923.
Virginia Aida-Ficken 1,  Jamie A Kelly 2,  Payel Chatterjee 2,  M Harley Jenks 2,  Laura K McMullan 2,  César G Albariño 2,  Joel M Montgomery 2,  Katherine L Seley-Radtke 3,  Christina F Spiropoulou 2,  Mike Flint 4
Affiliations

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.

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