Alkyl hydroxybenzoic acid derivatives that inhibit HIV-1 protease dimerization
| Autor: | Vanderlan da Silva Bolzani, Michèle Reboud-Ravaux, Dulce Helena Siqueira Silva, Laure Dufau, Maicon Segalla Petrônio, Luis Octávio Regasini, Otavio Flausino, Thierry Rose |
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| Přispěvatelé: | Smithsonian Institution National Museum of Natural History (NMNH), Vieillissement Cellulaire Intégré et Inflammation (VCII), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Hydroxybenzoic acid Proteases Stereochemistry medicine.medical_treatment protein-protein interactions non-peptide inhibitors Biochemistry fluorescent probe binding Protocatechuic acid aromatic ring substitutions intermolecularβ-sheet inhibitors chemistry.chemical_compound Structure-Activity Relationship HIV-1 protease HIV Protease Gallic Acid Drug Discovery protocatechuic acid alkyl esters medicine [CHIM]Chemical Sciences Humans Gallic acid Alkyl Alkyl Hydroxybenzoic Acid Pharmacology chemistry.chemical_classification Protease biology Chemistry Organic Chemistry gallic acid alkyl esters Active site HIV Protease Inhibitors biology.protein Molecular Medicine Protein Multimerization dimerization inhibitors HIV-1 protease inhibition |
| Zdroj: | Current Medicinal Chemistry Current Medicinal Chemistry, 2012, 19 (26), pp.4534-4540. ⟨10.2174/092986712803251557⟩ Current Medicinal Chemistry, Bentham Science Publishers, 2012, 19 (26), pp.4534-4540. ⟨10.2174/092986712803251557⟩ ResearcherID |
| ISSN: | 1875-533X 0929-8673 |
| DOI: | 10.2174/092986712803251557⟩ |
| Popis: | International audience; 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. - See more at: http://www.eurekaselect.com/103137/article#sthash.FvTzAG3y.dpuf |
| Databáze: | OpenAIRE |
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