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Identification of novel small molecule inhibitors against NS2B/NS3 serine protease from Zika virus
- Source :
- Antiviral Research
- Publication Year :
- 2016
-
Abstract
- Zika flavivirus infection during pregnancy appears to produce higher risk of microcephaly, and also causes multiple neurological problems such as Guillain–Barre 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.
- Subjects :
- 0301 basic medicine
Microcephaly
Proteases
Serine Proteinase Inhibitors
Protein Conformation
medicine.medical_treatment
viruses
030106 microbiology
Viral Nonstructural Proteins
Virus Replication
Antiviral Agents
Article
Zika virus
03 medical and health sciences
Inhibitory Concentration 50
Virology
Drug Discovery
medicine
Pharmacology
Serine protease
NS3
Protease
biology
Zika Virus
Surface Plasmon Resonance
biology.organism_classification
medicine.disease
Flavivirus
Kinetics
030104 developmental biology
Viral replication
biology.protein
Serine Proteases
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Antiviral Research
- Accession number :
- edsair.doi.dedup.....eab38484eeac867b299bd934cab0b52f