Structural Evidence for Effectiveness of Darunavir and Two Related Antiviral Inhibitors against HIV-2 Protease
- GSU
No drug has been targeted specifically for HIV-2 (human immunodeficiency virus type 2) infection despite its increasing prevalence worldwide. The antiviral HIV-1 (human immunodeficiency virus type 1) protease (PR) inhibitor darunavir and the chemically related GRL98065 and GRL06579A were designed with the same chemical scaffold and different substituents at P2 and P2' to optimize polar interactions for HIV-1 PR (PR1). These inhibitors are also effective antiviral agents for HIV-2-infected cells. Therefore, crystal structures of HIV-2 PR (PR2) complexes with the three inhibitors have been solved at 1.2-{angstrom} resolution to analyze the molecular basis for their antiviral potency. Unusually, the crystals were grown in imidazole and zinc acetate buffer, which formed interactions with the PR2 and the inhibitors. Overall, the structures were very similar to the corresponding inhibitor complexes of PR1 with an RMSD of 1.1 {angstrom} on main-chain atoms. Most hydrogen-bond and weaker C-H...O interactions with inhibitors were conserved in the PR2 and PR1 complexes, except for small changes in interactions with water or disordered side chains. Small differences were observed in the hydrophobic contacts for the darunavir complexes, in agreement with relative inhibition of the two PRs. These near-atomic-resolution crystal structures verify the inhibitor potency for PR1 and PR2 and will provide the basis for the development of antiviral inhibitors targeting PR2.
- Research Organization:
- Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 1006995
- Journal Information:
- J. Mol. Biol., Journal Name: J. Mol. Biol. Journal Issue: (1) ; 12, 2008 Vol. 384; ISSN JMOBAK; ISSN 0022-2836
- Country of Publication:
- United States
- Language:
- ENGLISH
Similar Records
Molecular Characterization of Clinical Isolates of Human Immunodeficiency Virus Resistant to the Protease Inhibitor Darunavir
Effect of Flap Mutations on Structure of HIV-1 Protease and Inhibition by Sanquinavir and Darunavir
The higher barrier of darunavir and tipranavir resistance for HIV-1 protease
Journal Article
·
Wed Mar 03 23:00:00 EST 2010
· J. Virol.
·
OSTI ID:1005987
Effect of Flap Mutations on Structure of HIV-1 Protease and Inhibition by Sanquinavir and Darunavir
Journal Article
·
Mon Aug 25 00:00:00 EDT 2008
· J. Mol. Biol.
·
OSTI ID:1006792
The higher barrier of darunavir and tipranavir resistance for HIV-1 protease
Journal Article
·
Wed Nov 16 23:00:00 EST 2011
· Biochem. Biophys. Res. Commun.
·
OSTI ID:1024491