Identification of novel small molecule inhibitors against NS2B/NS3 serine protease from Zika virus [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 571 Physiology and related subjects
• Thông tin xuất bản: Argonne, Ill. : Oak Ridge, Tenn. : Argonne National Laboratory ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2016
• Mô tả vật lý: Size: p. 49-58 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260646
• Chủ đề: 1. 59 basic biological sciences; 2. 60 applied life sciences; 3. Apo zikv ns2b-ns3pro structure; 4. Ns2bns3 serine protease; 5. Small molecule inhibitor; 6. Zika flavivirus

Tóm tắt

 Zika flavivirus infection during pregnancy appears to produce higher risk of microcephaly, and also causes multiple neurological problems such as Guillain?Barr� 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 (IC<
 sub>
 50<
 /sub>
 ) and binding affinity (K<
 sub>
 D<
 /sub>
 ) of ~5?10 ?M 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 ?M. 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.