Abstract
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 β-sheet and disrupt the dimeric enzyme. The best gallic ester (14 carbon atoms, Kid 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 β-sheets involved in protein-protein interactions.
Keywords: dimerization inhibitors, gallic acid alkyl esters, HIV-1 protease inhibition, intermolecularβ-sheet inhibitors, protocatechuic acid alkyl esters, Alkyl Hydroxybenzoic Acid, fluorescent probe binding, non-peptide inhibitors, protein-protein interactions, aromatic ring substitutions.
Current Medicinal Chemistry
Title:Alkyl Hydroxybenzoic Acid Derivatives that Inhibit HIV-1 Protease Dimerization
Volume: 19 Issue: 26
Author(s): O. A. Flausino, L. Dufau, L. O. Regasini, M. S. Petronio, D. H.S. Silva, T. Rose, V. S. Bolzani and M. Reboud-Ravaux
Affiliation:
Keywords: dimerization inhibitors, gallic acid alkyl esters, HIV-1 protease inhibition, intermolecularβ-sheet inhibitors, protocatechuic acid alkyl esters, Alkyl Hydroxybenzoic Acid, fluorescent probe binding, non-peptide inhibitors, protein-protein interactions, aromatic ring substitutions.
Abstract: 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 β-sheet and disrupt the dimeric enzyme. The best gallic ester (14 carbon atoms, Kid 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 β-sheets involved in protein-protein interactions.
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Cite this article as:
A. Flausino O., Dufau L., O. Regasini L., S. Petronio M., H.S. Silva D., Rose T., S. Bolzani V. and Reboud-Ravaux M., Alkyl Hydroxybenzoic Acid Derivatives that Inhibit HIV-1 Protease Dimerization, Current Medicinal Chemistry 2012; 19 (26) . https://dx.doi.org/10.2174/092986712803251557
DOI https://dx.doi.org/10.2174/092986712803251557 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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