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

$48.00 plus tax (Refund Policy)

Download / Buy Article:



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.

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: October 1, 2008

Related content



Share Content

Access Key

Free Content
Free content
New Content
New content
Open Access Content
Open access content
Subscribed Content
Subscribed content
Free Trial Content
Free trial content
Cookie Policy
Cookie Policy
ingentaconnect website makes use of cookies so as to keep track of data that you have filled in. I am Happy with this Find out more