Structural studies of antiviral inhibitor with HIV-1 protease bearing drug resistant substitutions of V32I, I47V and V82I [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 574.8 [Unassigned]
• Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2019
• Mô tả vật lý: Size: p. 974-978 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260033
• Chủ đề: 1. 60 applied life sciences; 2. Antiviral inhibitors; 3. Drug resistance; 4. Hiv-1 protease; 5. X-ray crystallography

Tóm tắt

 HIV-1 protease inhibitors are effective in HIV/AIDS therapy, although drug resistance is a severe problem. This study examines the effects of four investigational inhibitors against HIV-1 protease with drug resistant mutations of V32I, I47V and V82I (PR<
 sub>
 Tri<
 /sub>
 ) that model the inhibitor-binding site of HIV-2 protease. These inhibitors contain diverse chemical modifications on the darunavir scaffold and form new interactions with wild type protease, however, the measured inhibition constants for PR<
 sub>
 Tri<
 /sub>
  mutant range from 17 to 40 nM or significantly worse than picomolar values reported for wild type enzyme. The X-ray crystal structure of PR<
 sub>
 Tri<
 /sub>
  mutant in complex with inhibitor 1 at 1.5 � resolution shows minor changes in interactions with inhibitor compared with the corresponding wild type PR complex. Instead, the basic amine at P2 of inhibitor together with mutation V82I induces two alternate conformations for the side chain of Arg8 with new interactions with inhibitor and Leu10. Hence, inhibition is influenced by small coordinated changes in hydrophobic interactions.