Alkyl Hydroxybenzoic Acid Derivatives that Inhibit HIV-1 Protease Dimerization

Autor(es)

Flausino, Jr., O. A. ^{[1, 2]} ; Dufau, L. ^[1] ; Regasini, L. O. ^[2] ; Petronio, M. S. ^[2] ; Silva, D. H. S. ^[2] ; Rose, T. ^[3] ; Bolzani, V. S. ^[2] ; Reboud-Ravaux, M. ^[1]

Afiliação do(s) autor(es)

^[1] UPMC Sorbonne Univ, Enzymol Mol & Fonct UR4, F-75252 Paris 05 - France

^[2] Sao Paulo State Univ, Inst Chem, BR-14800060 Sao Paulo - Brazil

^[3] Inst Pasteur, Unite Immunogenet Cellulaire, F-75724 Paris 15 - France

• Tipo de documento: Artigo de Revisão
• Fonte: Current Medicinal Chemistry; v. 19, n. 26, p. 4534-4540, SEP 2012.
• Citações Web of Science: 9

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. (AU)

• Processo FAPESP: 03/02176-7 - Conservação e uso sustentável da diversidade do Cerrado e da Mata Atlântica: diversidade química e prospecção de medicamentos potenciais - fase II
• Beneficiário: Vanderlan da Silva Bolzani
• Linha de fomento: Auxílio à Pesquisa - Programa BIOTA - Temático
• Processo FAPESP: 04/07932-7 - Busca de compostos naturais antitumorais, antioxidantes, antiinflamatórios, antidiabéticos, inibidores de acetilcolinesterase e mieloperoxidase no Cerrado e na Mata Atlântica
• Beneficiário: Dulce Helena Siqueira Silva
• Linha de fomento: Auxílio à Pesquisa - Programa BIOTA - Temático