Four-tiered pi interaction at the dimeric interface of HIV-1 integrase critical for DNA integration and viral infectivity

HIV-1 integrase (IN) is an essential enzyme for viral infection. Here, we report an extensive pi electron orbital interaction between four amino acids, W132, M178, F181 and F185, located at the dimeric interface of IN that is critical for the strand transfer activity alone. Catalysis of nine different mutant IN proteins at these positions were evaluated. Whereas the 3'-processing activity is predominantly strong, the strand transfer activity of each enzyme was completely dependent on an intact pi electron orbital interaction at the dimeric interface. Four representative IN mutants were constructed in the context of the infectious NL4.3 HIV-1 viral clone. Whereas viruses with an intact pi electron orbital interaction at the IN dimeric interface replicated comparable to wild type, viruses containing an abolished pi interaction were non-infectious. Q-PCR analysis of viral DNA forms during viral replication revealed pleiotropic effects of most mutations. We hypothesize that the pi interaction is a critical contact point for the assembly of functional IN multimeric complexes, and that IN multimerization is required for a functional pre-integration complex. The rational design of small molecule inhibitors targeting the disruption of this pi-pi interaction should lead to powerful anti-retroviral drugs. (C) 2008 Elsevier Inc. All rights reserved.status: publishe

Napthoxazepine Inhibitors of HIV-1 Integrase: Synthesis and Biological Evaluation

HIV-1 integrase is an important target for the identification of novel antiretroviral compounds potentially active against HIV-1 replication. Previously, we discovered several novel thiazolothiazepine derivatives as IN inhibitors with antiviral activity on cell-based assays. Due to their low cytotoxicity, low molecular weight, drug-like properties, and structural novelty, we embarked on a study to optimize the original lead compounds

Discovery of novel non-cytotoxic salicylhydrazide containing HIV-1 integrase inhibitors

The previously discovered salicylhydrazide class of compounds displayed potent HIV-1 integrase (IN) inhibitory activity. The development of this class of compounds as antiretroviral agents was halted due to cytotoxicity in the nanomolar to sub-micromolar range. We identified a novel class of non-cytotoxic hydrazide IN inhibitors utilizing the minimally required salicylhydrazide substructure as a template in a small-molecule database search. The novel hydrazides displayed low micromolar IN inhibitory activity and are several hundred-fold less cytotoxic than previously disclosed salicylhydrazide IN inhibitors.status: publishe

Three-Dimensional Quantitative Structural Activity Relationship (3D-QSAR) Studies of Some 1,5-Diarylpyrazoles: Analogue Based Design of Selective Cyclooxygenase-2 Inhibitors

Selective cyclooxygenase inhibitors have attracted much attention in recent times in the design of new non-steroidal anti-inflammatory drugs (NSAID). 3D-QSAR studies have been performed on a series of 1,5-diarylpyrazoles that act as selective cyclooxygenase-2 (COX-2) inhibitors, using three different methods: comparative molecular field analysis (CoMFA) with partial least squares (PLS) fit; molecular field analysis (MFA) and; receptor surface analysis (RSA) with genetic function algorithms (GFA). The analyses were carried out on 30 analogues of which 25 were used in the training set and the rest considered for the test set. These studies produced reasonably good predictive models with high cross-validated and conventional r2 values in all the three cases

Three-Dimensional Quantitative Structural Activity Relationship (3D-QSAR) Studies of Some 1,5-Diarylpyrazoles: Analogue Based Design of Selective Cyclooxygenase-2 Inhibitors

Selective cyclooxygenase inhibitors have attracted much attention in recent times in the design of new non-steroidal anti-inflammatory drugs (NSAID). 3D-QSAR studies have been performed on a series of 1,5-diarylpyrazoles that act as selective cyclooxygenase-2 (COX-2) inhibitors, using three different methods: comparative molecular field analysis (CoMFA) with partial least squares (PLS) fit; molecular field analysis (MFA) and; receptor surface analysis (RSA) with genetic function algorithms (GFA). The analyses were carried out on 30 analogues of which 25 were used in the training set and the rest considered for the test set. These studies produced reasonably good predictive models with high cross-validated and conventional r2 values in all the three cases

Design and synthesis of novel dihydroquinoline-3-carboxylic acids as HIV-1 integrase inhibitors

Previously, we discovered linomide analogues as novel HIV-1 integrase (IN) inhibitors. Here, to make possible structure–activity relationships, we report on the design and synthesis of a series of substituted dihydroquinoline-3-carboxylic acids. The crystal structure of the representative compound 2c has also been solved. Among the eight new analogues, 2e showed a potency in inhibiting IN strand transfer catalytic activity similar to the reference diketo acid inhibitor L-731,988 (IC50 = 0.9 µM vs. 0.54 µM, for 2e and L-731,988, respectively). Furthermore, none of the compounds showed significant cytotoxicity in two tested cancer cell lines. These compounds represent an interesting prototype of IN inhibitors, potentially involved in a metal chelating mechanism, and further optimization is warranted