Alkyl hydroxybenzoic acid derivatives that inhibit HIV-1 protease dimerization
| العنوان: | Alkyl hydroxybenzoic acid derivatives that inhibit HIV-1 protease dimerization |
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| المؤلفون: | Vanderlan da Silva Bolzani, Michèle Reboud-Ravaux, Dulce Helena Siqueira Silva, Laure Dufau, Maicon Segalla Petrônio, Luis Octávio Regasini, Otavio Flausino, Thierry Rose |
| المساهمون: | 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) |
| المصدر: | 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 |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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 |
| تدمد: | 1875-533X 0929-8673 |
| DOI: | 10.2174/092986712803251557⟩ |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::28e5d588e20746ddc89412f8757340ff https://pubmed.ncbi.nlm.nih.gov/22963666 |
| رقم الانضمام: | edsair.doi.dedup.....28e5d588e20746ddc89412f8757340ff |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1875533X 09298673 |
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| DOI: | 10.2174/092986712803251557⟩ |