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Symmetrical 1-pyrrolidineacetamide showing anti-HIV activity through a new binding site on HIV-1 integrase

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Aim: To characterize the functional and pharmacological features of a symmetrical 1-pyrrolidineacetamide, N,N′-(methylene-di-4,1-phenylene) bis-1-pyrrolidineacetamide, as a new anti-HIV compound which could competitively inhibit HIV-1 integrase (IN) binding to viral DNA. Methods: A surface plasma resonance (SPR)-based competitive assay was employed to determine the compound's inhibitory activity, and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell assay was used to qualify the antiviral activity. The potential binding sites were predicted by molecular modeling and determined by site-directed mutagenesis and a SPR binding assay. Results: 1-pyrrolidineacetamide, N,N′-(methylene-di-4,1-phenylene) bis- 1-pyrrolidineacetamide could competitively inhibit IN binding to viral DNA with a 50% inhibitory concentration (IC50) value of 7.29±0.68 mol/L as investigated by SPR-based investigation. Another antiretroviral activity assay showed that this compound exhibited inhibition against HIV-1(IIIB) replication with a 50% effective concentration (EC50) value of 40.54 mol/L in C8166 cells, and cytotoxicity with a cytotoxic concentration value of 173.84 mol/L in mock-infected C8166 cells. Molecular docking predicted 3 potential residues as 1-pyrrolidineacetamide, N,N′-(methylene-di-4,1-phenylene)bis-1-pyrrolidineacetamide binding sites. The importance of 3 key amino acid residues (Lys 103, Lys 173, and Thr 174) involved in the binding was further identified by site-directed mutagenesis and a SPR binding assay. Conclusion: This present work identified a new anti-HIV compound through a new IN-binding site which is expected to supply new potential drug-binding site information for HIV-1 integrase inhibitor discovery and development.
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Keywords: HIV-1 integrase inhibitor; molecular docking; site-directed mutagenesis; surface plasma resonance

Document Type: Research Article

Affiliations: 1: Laboratory of Molecular Immunopharmacology, Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China 2: School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China

Publication date: 2008-10-01

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