chicoric-acid and HIV-Infections

Current strategies for the treatment of HIV infection are based on cocktails of drugs that target the viral reverse transcriptase or protease enzymes. At present, the clinical benefit of this combination therapy for HIV-infected patients is considerable, although it is not clear how long this effect will last taking into account the emergence of multiple drug-resistant viral strains. Addition of new anti-HIV drugs targeting additional steps of the viral replication cycle may increase the potency of inhibition and prevent resistance development. During HIV replication, integration of the viral genome into the cellular chromosome is an essential step catalysed by the viral integrase. Although HIV integrase is an attractive target for antiviral therapy, so far all research efforts have led to the identification of only one series of compounds that selectively inhibit the integration step during HIV replication, namely the diketo acids. In this review we try to address the question why it has proven so difficult to find potent and selective integrase inhibitors. We point to potential pitfalls in defining an inhibitor as an authentic integrase inhibitor, and propose new strategies and technologies for the discovery of authentic HIV integration inhibitors.

Topics: Anti-HIV Agents; Caffeic Acids; DNA, Viral; Drug Design; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Oligonucleotides; Succinates; Virus Integration

Resolving the chemo-diversity of plant extract samples is an essential step for in-depth analyses of natural products which often exhibit promising biological activities. One of the challenges in this endeavor has been the confident differentiation of geometrical isomers. In this study, we investigated these aspects in chromatography (column chemistry and mobile phase composition) and mass spectrometry settings with regards to better differentiation of geometrical isomers. A standard of a hydroxycinnamic acid (HCA) derivative, L-chicoric acid (L-CA) - a di-acylated caffeoyltartaric acid ester found in a number of plant families - was used. Geometrical isomers of L-CA were formed by exposing the compound to ultraviolet (UV) radiation, to mimic the natural environment. The high performance liquid chromatography photo-diode array (HPLC-PDA) and ultra-high performance liquid chromatography mass spectrometry (UHPLC-MS) platforms were used to analyze the trans and cis geometrical isomers of L-CA. The HPLC-PDA results confirmed the generation of two cis geometrical isomers following UV exposure of the authentic trans-L-CA standard. Furthermore, the HPLC-PDA analyses demonstrated that the changes in both column chemistry (reverse-phase: C

Topics: Caffeic Acids; Chromatography, High Pressure Liquid; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Isomerism; Mass Spectrometry; Molecular Docking Simulation; Succinates

A series of 13 hydroxylated 2-arylnaphthalenes have been synthesized and evaluated as HIV-1 integrase inhibitors. 7-(3,4,5-trihydroxyphenyl)naphthalene-1,2,3-triol 1c revealed chemical instability upon storage, leading to the isolation of a dimer 5c which was also tested. In the 2-arylnaphthalene series, all compounds were active against HIV-1 IN with IC50's within the 1-10 microM range, except for 1c and 5c which displayed submicromolar activity. Antiviral activity against HIV-1 replication was measured on 1b-c and 5c. Amongst the tested molecules, only 5c was found to present antiviral properties with a low cytotoxicity on two different cell lines.

Topics: Anti-HIV Agents; Cell Line; Cell Survival; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Naphthalenes

Integration of the HIV genome by integrase is absolutely required for productive infection.. To determine the role of natural selection on HIV integrase biology.. To study the activities of HIV integrases from a limited panel of North American clinical isolates from HIV-infected patients and to compare these proteins with integrases from two laboratory adapted reference strains (HI(VIIIRF) and HIV(NL4--3)).. HIV was isolated and the particle-associated RNA was reverse transcribed and sequenced. Replication kinetics of molecularly cloned viruses containing each variant integrase were studied in tissue culture. The mutant integrase proteins were expressed, purified and specific activities of the enzymes were derived for both 3' end-processing and disintegration reactions.. Despite 3--5% variability in integrase at the amino acid level, viruses showed no statistically significant differences in growth kinetics compared with the reference HIV(NL4--3) virus and only minor differences were observed in 3' end-processing and disintegration activities. All integrase proteins demonstrated similar sensitivity to an integrase inhibitor l-chicoric acid.. These results demonstrate that integrase genes derived from HIV-infected individuals can differ from reference sequences but these mutations do not result in loss of function, including susceptibility to an integrase inhibitor; therefore, integrase remains an attractive target for antiviral drug design, as mutability appears to be restricted by function.

Topics: Anti-HIV Agents; Caffeic Acids; Gene Expression; Genetic Variation; HeLa Cells; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Kinetics; Phylogeny; RNA Processing, Post-Transcriptional; Selection, Genetic; Sequence Analysis, DNA; Succinates; Tumor Cells, Cultured; Virus Integration

Topics: Anti-HIV Agents; Caffeic Acids; Coffee; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Succinates; Virus Replication