2. Academic Validation
  3. Identification of Direct-Acting nsP2 Helicase Inhibitors with Antialphaviral Activity

Identification of Direct-Acting nsP2 Helicase Inhibitors with Antialphaviral Activity

  • J Med Chem. 2025 Jul 24;68(14):14514-14536. doi: 10.1021/acs.jmedchem.5c00635.
Bose Muthu Ramalingam 1 2,  John D Sears 2 3,  Kacey M Talbot 2 3,  Yuan-Wei Norman Su 2 3,  Scott Houliston 4,  Mohammed Anwar Hossain 1 2,  Zachary W Davis-Gilbert 1 2,  Chunqing Zhao 5,  Hans J Oh 1 2,  Peter J Brown 1 2,  Marcia K Sanders 2 6,  Stella R Moorman 2 3,  Durbadal Ojha 2 3,  Jane E Burdick 2 6,  Isabella Law 2 6,  Noah L Morales 2 6,  Sabian A Martinez 2 6,  Peter Loppnau 4,  Julia Garcia Perez 4,  Adam M Drobish 7,  Thomas E Morrison 2 7,  Zachary J Streblow 8,  Daniel N Streblow 2 8,  Cheryl H Arrowsmith 2 4,  Ava Vargason 2 9,  Rafael M Couñago 1 2 10,  Levon Halabelian 4 11,  Jamie J Arnold 2 3,  Craig E Cameron 2 3,  Nathaniel J Moorman 2 3,  Mark T Heise 2 3 6,  Timothy M Willson 1 2
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 2 READDI AViDD Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 3 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 4 Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • 5 NMR Facility, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 6 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 7 Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado 80045, United States.
  • 8 Vaccine & Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon 97006, United States.
  • 9 Eshelman Innovation, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 10 Center of Medicinal Chemistry, Center for Molecular Biology and Genetic Engineering, University of Campinas, 13083-886 Campinas, SP, Brazil.
  • 11 Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5G 2C8, Canada.
PMID: 40634283 DOI: 10.1021/acs.jmedchem.5c00635
Abstract

Alphaviruses are mosquito-borne RNA viruses that pose a significant public health threat, with no FDA-approved Antiviral therapeutics available. The nonstructural protein 2 helicase (nsP2hel) is an enzyme involved in unwinding dsRNA essential for alphavirus replication. This study reports the discovery and optimization of first-in-class oxaspiropiperidine inhibitors targeting nsP2hel. Structure-activity relationship (SAR) studies identified potent cyclic sulfonamide analogs with nanomolar Antiviral activity against chikungunya virus (CHIKV). Biochemical analyses of nsP2hel ATPase and RNA unwindase activities showed these compounds act in a noncompetitive mode, suggesting that they are allosteric inhibitors. Viral resistance mutations mapped to nsP2hel and a fluorine-labeled analog exhibited direct binding to the protein by 19F NMR. The lead inhibitor, 2o, demonstrated broad-spectrum antialphaviral activity, reducing titers of CHIKV, Mayaro virus (MAYV), and Venezuelan equine encephalitis virus (VEEV). These findings support nsP2hel as a viable target for the development of broad-spectrum, direct-acting antialphaviral drugs.

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