Increased activity of unlinked Zika virus NS2B/NS3 protease compared to linked Zika virus protease

• Type of Material: Article
• Authors: Benjamin D. Kuiper, Wayne State University; Kristin Slater, Wayne State University; Nicholas Spellmon, Wayne State University; Joshua Holcomb, Wayne State University; Prasanna Medapureddy, Wayne State University; Kendall M. Muzzarelli, Wayne State University; Zhe Yang, Wayne State University; Reuben Ovadia, Emory University; Franck Amblard, Emory University; Iulia A. Kovari, Wayne State University; Raymond Schinazi, Emory University; Ladislau C. Kovari, Wayne State University
• Language: English
• Date: 2017-10-28
• Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2017
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bbrc.2017.03.108
• Title of Journal or Parent Work: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• Volume: 492
• Issue: 4
• Start Page: 668
• End Page: 673
• Grant/Funding Information: We thank Wayne State University for a Rumble Fellowship supporting the Ph.D. studies of BDK. RFS is supported in part by NIH grant 1R21AI-129607 and by the Center for AIDS Research NIH grant 2P30AI-050409.
• Keywords: Zika virus; NS2B-NS3 PROTEASE; CRYSTAL-STRUCTURE; Biophysics; NS2B/NS3 protease; Science & Technology; Biochemistry & Molecular Biology; Life Sciences & Biomedicine; Flavivirus; AMERICA; Protease inhibitor; DENGUE; INHIBITORS
• Research Categories: Engineering, Biomedical; Biology, Virology

Abstract

Zika virus (ZIKV) is a flavivirus spread by daytime-active Aedes spp. mosquitoes such as A. aegypti and A. albopictus. Previously thought to be a mild infection, the latest ZIKV outbreak in the Americas is causally associated with more severe symptoms as well as severe birth defects, such as microcephaly. Currently no vaccine or antiviral exists. However, recent progress has demonstrated the viral NS2B/NS3 protease may be a suitable target for the development of small-molecule antiviral agents. To better understand the ZIKV protease, we expressed, purified, and characterized unlinked and linked NS2B/NS3 protease corresponding to an isolate from the recent outbreak in Puerto Rico. Unlinked ZIKV protease is more active and binds substrate with greater affinity than linked ZIKV protease. Therefore, we propose that unlinked ZIKV protease be used when evaluating or designing ZIKV protease inhibitors. Additionally, potent inhibitors of related viral proteases, like West Nile Virus and Dengue virus, may serve as advanced starting points to identify and develop ZIKV protease inhibitors.