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
  • 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: [email protected].
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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