Suppression of HIV-1 protease inhibitor resistance by phosphonate-mediated solvent anchoring.
J Mol Biol
; 363(3): 635-47, 2006 Oct 27.
Article
en En
| MEDLINE
| ID: mdl-16979654
The introduction of human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) markedly improved the clinical outcome and control of HIV-1 infection. However, cross-resistance among PIs due to a wide spectrum of mutations in viral protease is a major factor limiting their broader clinical use. Here we report on the suppression of PI resistance using a covalent attachment of a phosphonic acid motif to a peptidomimetic inhibitor scaffold. The resulting phosphonate analogs maintain high binding affinity to HIV-1 protease, potent antiretroviral activity, and unlike the parent molecules, display no loss of potency against a panel of clinically important PI-resistant HIV-1 strains. As shown by crystallographic analysis, the phosphonate moiety is highly exposed to solvent with no discernable interactions with any of the enzyme active site or surface residues. We term this effect "solvent anchoring" and demonstrate that it is driven by a favorable change in the inhibitor binding entropy upon the interaction with mutant enzymes. This type of thermodynamic behavior, which was not found with the parent scaffold fully buried in the enzyme active site, is a result of the increased degeneracy of inhibitor binding states, allowing effective molecular adaptation to the expanded cavity volume of mutant proteases. This strategy, which is applicable to various PI scaffolds, should facilitate the design of novel PIs and potentially other antiviral therapeutics.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Solventes
/
Diseño de Fármacos
/
Proteasa del VIH
/
Inhibidores de la Proteasa del VIH
/
Farmacorresistencia Viral Múltiple
/
Organofosfonatos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Mol Biol
Año:
2006
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Países Bajos