Scientific Reports (Mar 2025)
A covalent chemical probe for Chikungunya nsP2 cysteine protease with antialphaviral activity and proteome-wide selectivity
- Anirban Ghoshal,
- Edwin G. Tse,
- Mohammad Anwar Hossain,
- Kesatebrhan Haile Asressu,
- Eric M. Merten,
- John D. Sears,
- Stefanie Howell,
- Sumera Perveen,
- Jane Burdick,
- Noah L. Morales,
- Sabian A. Martinez,
- Isabella Law,
- Bennett J. Davenport,
- Thomas E. Morrison,
- Zachary J. Streblow,
- Daniel N. Streblow,
- Angie L. Mordant,
- Thomas S. Webb,
- Aurora Cabrera,
- Laura E. Herring,
- Cheryl H. Arrowsmith,
- Kenneth H. Pearce,
- Nathaniel J. Moorman,
- Mark T. Heise,
- Rafael M. Couñago,
- Peter J. Brown,
- Timothy M. Willson
Affiliations
- Anirban Ghoshal
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
- Edwin G. Tse
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
- Mohammad Anwar Hossain
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
- Kesatebrhan Haile Asressu
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
- Eric M. Merten
- READDI Avidd Center, University of North Carolina at Chapel Hill
- John D. Sears
- READDI Avidd Center, University of North Carolina at Chapel Hill
- Stefanie Howell
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
- Sumera Perveen
- READDI Avidd Center, University of North Carolina at Chapel Hill
- Jane Burdick
- READDI Avidd Center, University of North Carolina at Chapel Hill
- Noah L. Morales
- READDI Avidd Center, University of North Carolina at Chapel Hill
- Sabian A. Martinez
- READDI Avidd Center, University of North Carolina at Chapel Hill
- Isabella Law
- READDI Avidd Center, University of North Carolina at Chapel Hill
- Bennett J. Davenport
- READDI Avidd Center, University of North Carolina at Chapel Hill
- Thomas E. Morrison
- READDI Avidd Center, University of North Carolina at Chapel Hill
- Zachary J. Streblow
- READDI Avidd Center, University of North Carolina at Chapel Hill
- Daniel N. Streblow
- READDI Avidd Center, University of North Carolina at Chapel Hill
- Angie L. Mordant
- UNC Metabolomics and Proteomics Core, University of North Carolina at Chapel Hill
- Thomas S. Webb
- UNC Metabolomics and Proteomics Core, University of North Carolina at Chapel Hill
- Aurora Cabrera
- UNC Metabolomics and Proteomics Core, University of North Carolina at Chapel Hill
- Laura E. Herring
- UNC Metabolomics and Proteomics Core, University of North Carolina at Chapel Hill
- Cheryl H. Arrowsmith
- READDI Avidd Center, University of North Carolina at Chapel Hill
- Kenneth H. Pearce
- READDI Avidd Center, University of North Carolina at Chapel Hill
- Nathaniel J. Moorman
- READDI Avidd Center, University of North Carolina at Chapel Hill
- Mark T. Heise
- READDI Avidd Center, University of North Carolina at Chapel Hill
- Rafael M. Couñago
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
- Peter J. Brown
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
- Timothy M. Willson
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
- DOI
- https://doi.org/10.1038/s41598-025-91673-x
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 14
Abstract
Abstract Chikungunya is a mosquito-borne viral disease that causes fever and severe joint pain for which there is no direct acting drug treatments. Vinyl sulfone SGC-NSP2PRO-1 (3) was identified as a potent inhibitor of the nsP2 cysteine protease (nsP2pro) that reduced viral titer against infectious isolates of Chikungunya and other alphaviruses. The covalent warhead in 3 captured the active site C478 and inactivated nsP2pro with a k inact/K i ratio of 5950 M–1 s–1. The vinyl sulfone 3 was inactive across a panel of 23 other cysteine proteases and demonstrated remarkable proteome-wide selectivity by two chemoproteomic methods. A negative control analog SGC-NSP2PRO-1N (4) retained the isoxazole core and covalent warhead but demonstrated > 100-fold decrease in enzyme inhibition. Both 3 and 4 were stable across a wide range of pH in solution and upon prolonged storage as solids. Vinyl sulfone 3 and its negative control 4 will find utility as high-quality chemical probes to study the role of the nsP2pro in cellular studies of alphaviral replication and virulence.
Keywords
