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

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.

doi:10.1016/j.antiviral.2016.12.016

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

Journal Article · Mon Dec 26 00:00:00 EST 2016 · Antiviral Research

DOI:https://doi.org/10.1016/j.antiviral.2016.12.016· OSTI ID:1352271

Lee, Hyun ^[1]; Ren, Jinhong ^[2]; Nocadello, Salvatore ^[3]; Rice, Amy J. ^[2]; Ojeda, Isabel ^[2]; Light, Samuel ^[3]; Minasov, George ^[3]; Vargas, Jason ^[2]; Nagarathnam, Dhanapalan ^[4]; Anderson, Wayne F. ^[3]; Johnson, Michael E. ^[1]

Novalex Therapeutics, Inc., Chicago, IL (UnitedStates)
Univ. of Illinois, Chicago, IL (United States)
Northwestern Univ., Chicago, IL (United States). Feinberg School of Medicine
DNSK International, LLC, Hamden, CT (United States)

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. We report our studies have identified several compounds with inhibitory activity (IC₅₀) and binding affinity (K_D) 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 $$K_i$$ 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID)

Grant/Contract Number:: HHSN272201200026C; AI112114

OSTI ID:: 1352271

Journal Information:: Antiviral Research, Vol. 139, Issue C; ISSN 0166-3542

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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

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