In:
Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 58, No. 7 ( 2014-07), p. 3679-3688
Abstract:
In the present study, GRL008, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI), and darunavir (DRV), both of which contain a P2- bis -tetrahydrofuranyl urethane ( bis -THF) moiety, were found to exert potent antiviral activity (50% effective concentrations [EC 50 s], 0.029 and 0.002 μM, respectively) against a multidrug-resistant clinical isolate of HIV-1 (HIV A02 ) compared to ritonavir (RTV; EC 50 , 〉 1.0 μM) and tipranavir (TPV; EC 50 , 0.364 μM). Additionally, GRL008 showed potent antiviral activity against an HIV-1 variant selected in the presence of DRV over 20 passages (HIV DRV R P20 ), with a 2.6-fold increase in its EC 50 (0.097 μM) compared to its corresponding EC 50 (0.038 μM) against wild-type HIV-1 NL4-3 (HIV WT ). Based on X-ray crystallographic analysis, both GRL008 and DRV showed strong hydrogen bonds (H-bonds) with the backbone-amide nitrogen/carbonyl oxygen atoms of conserved active-site amino acids G27, D29, D30, and D30′ of HIV A02 protease (PR A02 ) and wild-type PR in their corresponding crystal structures, while TPV lacked H-bonds with G27 and D30′ due to an absence of polar groups. The P2′ thiazolyl moiety of RTV showed two conformations in the crystal structure of the PR A02 -RTV complex, one of which showed loss of contacts in the S2′ binding pocket of PR A02 , supporting RTV's compromised antiviral activity (EC 50 , 〉 1 μM). Thus, the conserved H-bonding network of P2- bis -THF-containing GRL008 with the backbone of G27, D29, D30, and D30′ most likely contributes to its persistently greater antiviral activity against HIV WT , HIV A02 , and HIV DRV R P20 .
Type of Medium:
Online Resource
ISSN:
0066-4804
,
1098-6596
DOI:
10.1128/AAC.00107-14
Language:
English
Publisher:
American Society for Microbiology
Publication Date:
2014
detail.hit.zdb_id:
1496156-8
SSG:
12
SSG:
15,3
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