skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Identification of novel small molecule inhibitors against NS2B/NS3 serine protease from Zika virus

Abstract

Zika flavivirus infection during pregnancy appears to produce higher risk of microcephaly, and also causes multiple neurological problems such as Guillain–Barré syndrome. The Zika virus is now widespread in Central and South America, and is anticipated to become an increasing risk in the southern United States. With continuing global travel and the spread of the mosquito vector, the exposure is expected to accelerate, but there are no currently approved treatments against the Zika virus. The Zika NS2B/NS3 protease is an attractive drug target due to its essential role in viral replication. Our studies have identified several compounds with inhibitory activity (IC50) and binding affinity (KD) of ~5–10 μM against the Zika NS2B-NS3 protease from testing 71 HCV NS3/NS4A inhibitors that were initially discovered by high-throughput screening of 40,967 compounds. Competition surface plasmon resonance studies and mechanism of inhibition analyses by enzyme kinetics subsequently determined the best compound to be a competitive inhibitor with a Ki value of 9.5 μM. We also determined the X-ray structure of the Zika NS2B-NS3 protease in a “pre-open conformation”, a conformation never observed before for any flavivirus proteases. This provides the foundation for new structure-based inhibitor design.

Authors:
; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE; National Institutes of Health (NIH)
OSTI Identifier:
1352271
Resource Type:
Journal Article
Resource Relation:
Journal Name: Antiviral Research; Journal Volume: 139; Journal Issue: C
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Lee, Hyun, Ren, Jinhong, Nocadello, Salvatore, Rice, Amy J., Ojeda, Isabel, Light, Samuel, Minasov, George, Vargas, Jason, Nagarathnam, Dhanapalan, Anderson, Wayne F., and Johnson, Michael E. Identification of novel small molecule inhibitors against NS2B/NS3 serine protease from Zika virus. United States: N. p., 2016. Web. doi:10.1016/j.antiviral.2016.12.016.
Lee, Hyun, Ren, Jinhong, Nocadello, Salvatore, Rice, Amy J., Ojeda, Isabel, Light, Samuel, Minasov, George, Vargas, Jason, Nagarathnam, Dhanapalan, Anderson, Wayne F., & Johnson, Michael E. Identification of novel small molecule inhibitors against NS2B/NS3 serine protease from Zika virus. United States. doi:10.1016/j.antiviral.2016.12.016.
Lee, Hyun, Ren, Jinhong, Nocadello, Salvatore, Rice, Amy J., Ojeda, Isabel, Light, Samuel, Minasov, George, Vargas, Jason, Nagarathnam, Dhanapalan, Anderson, Wayne F., and Johnson, Michael E. Mon . "Identification of novel small molecule inhibitors against NS2B/NS3 serine protease from Zika virus". United States. doi:10.1016/j.antiviral.2016.12.016.
@article{osti_1352271,
title = {Identification of novel small molecule inhibitors against NS2B/NS3 serine protease from Zika virus},
author = {Lee, Hyun and Ren, Jinhong and Nocadello, Salvatore and Rice, Amy J. and Ojeda, Isabel and Light, Samuel and Minasov, George and Vargas, Jason and Nagarathnam, Dhanapalan and Anderson, Wayne F. and Johnson, Michael E.},
abstractNote = {Zika flavivirus infection during pregnancy appears to produce higher risk of microcephaly, and also causes multiple neurological problems such as Guillain–Barré syndrome. The Zika virus is now widespread in Central and South America, and is anticipated to become an increasing risk in the southern United States. With continuing global travel and the spread of the mosquito vector, the exposure is expected to accelerate, but there are no currently approved treatments against the Zika virus. The Zika NS2B/NS3 protease is an attractive drug target due to its essential role in viral replication. Our studies have identified several compounds with inhibitory activity (IC50) and binding affinity (KD) of ~5–10 μM against the Zika NS2B-NS3 protease from testing 71 HCV NS3/NS4A inhibitors that were initially discovered by high-throughput screening of 40,967 compounds. Competition surface plasmon resonance studies and mechanism of inhibition analyses by enzyme kinetics subsequently determined the best compound to be a competitive inhibitor with a Ki value of 9.5 μM. We also determined the X-ray structure of the Zika NS2B-NS3 protease in a “pre-open conformation”, a conformation never observed before for any flavivirus proteases. This provides the foundation for new structure-based inhibitor design.},
doi = {10.1016/j.antiviral.2016.12.016},
journal = {Antiviral Research},
number = C,
volume = 139,
place = {United States},
year = {Mon Dec 26 00:00:00 EST 2016},
month = {Mon Dec 26 00:00:00 EST 2016}
}