Alkyl Hydroxybenzoic Acid Derivatives that Inhibit HIV-1 Protease Dimerization
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Data
2012-09-01
Autores
Flausino, O. A. [UNESP]
Dufau, L.
Regasini, L. O. [UNESP]
Petronio, M. S. [UNESP]
Silva, Dulce Helena Siqueira [UNESP]
Rose, T.
Bolzani, Vanderlan da Silva [UNESP]
Reboud-Ravaux, M.
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Editor
Bentham Science Publ Ltd
Resumo
The therapeutic potential of gallic acid and its derivatives as anti-cancer, antimicrobial and antiviral agents is well known. We have examined the mechanism by which natural gallic acid and newly synthesized gallic acid alkyl esters and related protocatechuic acid alkyl esters inhibit HIV-1 protease to compare the influence of the aromatic ring substitutions on inhibition. We used Zhang-Poorman's kinetic analysis and fluorescent probe binding to demonstrate that several gallic and protecatechuic acid alkyl esters inhibited HIV-1 protease by preventing the dimerization of this obligate homodimeric aspartic protease rather than targeting the active site. The tri-hydroxy substituted benzoic moiety in gallates was more favorable than the di-substituted one in protocatechuates. In both series, the type of inhibition, its mechanism and the inhibitory efficiency dramatically depended on the length of the alkyl chain: no inhibition with alkyl chains less than 8 carbon atoms long. Molecular dynamics simulations corroborated the kinetic data and propose that gallic esters are intercalated between the two N- and C-monomer ends. They complete the beta-sheet and disrupt the dimeric enzyme. The best gallic ester (14 carbon atoms, K-id of 320 nM) also inhibited the multi-mutated protease MDR-HM. These results will aid the rational design of future generations of non-peptide inhibitors of HIV-1 protease dimerization that inhibit multi-mutated proteases. Finally, our work suggests the wide use of gallic and protocatechuic alkyl esters to dissociate intermolecular beta-sheets involved in protein-protein interactions.
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Palavras-chave
dimerization inhibitors, gallic acid alkyl esters, HIV-1 protease inhibition, intermolecular beta-sheet inhibitors, protocatechuic acid alkyl esters
Como citar
Current Medicinal Chemistry. Sharjah: Bentham Science Publ Ltd, v. 19, n. 26, p. 4534-4540, 2012.