Related Experiment Video
Updated: Sep 16, 2025
10:16
High-throughput Antiviral Assays to Screen for Inhibitors of Zika Virus Replication
Published on: October 30, 2021
3.8K
Identification of Direct-Acting nsP2 Helicase Inhibitors with Antialphaviral Activity
Bose Muthu Ramalingam1,2, John D Sears2,3, Kacey M Talbot2,3
1Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Journal of Medicinal Chemistry
|July 9, 2025
Summary
Researchers discovered new oxaspiropiperidine inhibitors that target the alphavirus nonstructural protein 2 helicase (nsP2hel). These compounds show broad-spectrum antiviral activity, offering a promising new therapeutic strategy against alphavirus infections.
Area of Science:
- Virology
- Medicinal Chemistry
- Drug Discovery
Background:
- Alphaviruses are mosquito-borne RNA viruses causing significant public health concerns.
- No FDA-approved antiviral drugs currently exist for alphavirus infections.
Purpose of the Study:
- To discover and optimize novel inhibitors targeting the alphavirus nonstructural protein 2 helicase (nsP2hel).
- To evaluate the potential of these inhibitors as broad-spectrum antiviral agents.
Main Methods:
- Structure-activity relationship (SAR) studies were conducted on oxaspiropiperidine derivatives.
- Biochemical assays assessed nsP2hel ATPase and RNA unwindase activities.
- 19F NMR was used to confirm direct binding of inhibitors to nsP2hel.
Main Results:
- Potent cyclic sulfonamide analogs with nanomolar antiviral activity against chikungunya virus (CHIKV) were identified.
- Inhibitors demonstrated noncompetitive, allosteric inhibition of nsP2hel.
- The lead compound, 2o, showed broad-spectrum activity against CHIKV, Mayaro virus (MAYV), and Venezuelan equine encephalitis virus (VEEV).
Conclusions:
- The alphavirus nsP2hel is a viable drug target.
- Oxaspiropiperidine inhibitors represent a promising class of direct-acting, broad-spectrum antialphaviral agents.
