Structural evidence for effectiveness of darunavir and two related antiviral inhibitors against HIV-2 protease.
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-A 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 A 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.
Department of Biology, Molecular Basis of Disease Program, Georgia State University, Atlanta, GA 30303, USA.
Andrey Y
AY
Kovalevsky
John M
JM
Louis
Annie
A
Aniana
Arun K
AK
Ghosh
Irene T
IT
Weber
D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D000069454:Darunavir; D019281:Dimerization; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015498:HIV-2 / Q000187:drug effects / Q000201:enzymology*; D006860:Hydrogen Bonding / Q000187:drug effects; D012997:Solvents; D055672:Static Electricity; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015032:Zinc / Q000378:metabolism
C522027:(2,8-dioxabicyclo(3.3.0)oct-6-yl)-N-(4-((3,4-methylenedioxyphenyl)sulfonyl-(2-methylpropyl)amino)-3-hydroxy-1-phenylbutan-2-yl) carbamate; D000998:Antiviral Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C513858:GRL 06579A; D017320:HIV Protease Inhibitors; D012997:Solvents; D013449:Sulfonamides; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; C065184:p16 protease, Human immunodeficiency virus 2; D015032:Zinc; D000069454:Darunavir