Identification of spirodioxolane nsP2 helicase inhibitors with antialphaviral activity
We describe the design, synthesis, and antialphaviral activity of spirodioxolane inhibitors targeting the alphavirus nsP2 helicase (nsP2hel). The spirodioxolanes are a new series of direct-acting antivirals that retain key molecular features required for inhibition of nsP2hel, including a highly substituted piperidine acetamide with its associated conformational isomerism and thermal mobility. Unlike the related oxaspiropiperidine nsP2hel inhibitors, the spirodioxolanes showed no enantioselectivity in their antiviral activity. The spirodioxolanes demonstrated antialphaviral activity against the Old World alphavirus Chikungunya virus, with some analogs also showing activity against the New World alphavirus Venezuelan equine encephalitis virus. Importantly, certain spirodioxolane analogs, such as 6b, maintained activity against viral mutants that displayed resistance to first-generation oxaspiropiperidine inhibitors, indicating their potential for optimization as a new class of broad-spectrum antialphaviral drugs.
Authors
- Rahman Shah Zaib Saleem (ORCID: https://orcid.org/0000-0002-9615-4471)
- John D. Sears (ORCID: https://orcid.org/0000-0002-4713-2241)
- Mark T. Heise (ORCID: https://orcid.org/0000-0001-5829-8477)
- Zachary W. Davis‐Gilbert (ORCID: https://orcid.org/0000-0002-4070-0832)
- Sabian A. Martinez (ORCID: https://orcid.org/0000-0002-1333-5083)
- Rafael M. Couñago (ORCID: https://orcid.org/0000-0003-1847-5090)
- Durbadal Ojha (ORCID: https://orcid.org/0000-0001-5032-7173)
- Matthew H. Todd (ORCID: https://orcid.org/0000-0001-7096-4751)
- Timothy M. Willson (ORCID: https://orcid.org/0000-0003-4181-8223)
- Mohammad Anwar Hossain (ORCID: https://orcid.org/0000-0001-8684-8755)
- Hans J. Oh (ORCID: https://orcid.org/0009-0007-2354-080X)
- Jane Burdick (ORCID: https://orcid.org/0009-0001-9719-8302)
- M. Bose (ORCID: https://orcid.org/0000-0002-0916-3784)
- Stella R. Moorman (ORCID: https://orcid.org/0009-0008-0070-5955)
- Nathaniel J. Moorman (ORCID: https://orcid.org/0009-0008-6391-3268)
Institutions
- University of North Carolina at Chapel Hill (US)
- University of North Carolina Health Care (US)
- Universidade Estadual de Campinas (UNICAMP) (BR)
- Genomics England (GB)
- University College London (GB)
Publication Details
- Journal
- RSC Medicinal Chemistry
- Published
- 2025-10-31
- DOI
- https://doi.org/10.1039/d5md00772k
- Primary Topic
- Mosquito-borne diseases and control
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Bristol-Myers Squibb
- Pfizer
- Bayer
- McGill University
- Genome Canada
- Merck KGaA
- Ontario Genomics
- European Federation of Pharmaceutical Industries and Associations
- Ontario Genomics Institute
- National Institutes of Health
- Genentech