Identification of Novel Small Molecule Inhibitors against NS2B/NS3 Serine Protease from Zika Virus and Various SPR Applications

Speaker:

Hyun Lee, Director of Biophysics Core
Research Resources Center
Research Assistant Professor
Department of Pharmaceutical Science
Center for Structural Biology
University of Illinois at Chicago

 

Description:

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 (IC 50 ) 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.