HIV-1 Nef and host proteome analysis: Current perspective.

Proteome represents the set of proteins being produced by an organism at a given time. Comparative proteomic profiling of a healthy and diseased state is likely to reflect the dynamics of a disease process. Proteomic techniques are widely used to discover novel biomarkers and decipher mechanisms of HIV-1 pathogenesis.

N-Alkyl/aryl-4-(3-substituted-3-phenylpropyl)piperazine-1-carbothioamide as dual-action vaginal microbicides with reverse transcriptase inhibition.

The growing population and health-care burden (due to STIs and HIV) imposes a particular economic crisis over resource-poor countries. Thus a novel approach as vaginal microbicides emerges as integrated tool to control both population and anti-STIs/HIV. Our continued efforts in this field led to the synthesis of fifteen N-alkyl/aryl-4-(3-substituted-3-phenylpropyl) piperazine-1-carbothioamide (12-26) derivatives as topical vaginal microbicides which were evaluated for anti-Trichomonas, spermicidal, antifungal and reverse transcriptase (RT) inhibitory activities.

Dithiocarbamate-thiourea hybrids useful as vaginal microbicides also show reverse transcriptase inhibition: design, synthesis, docking and pharmacokinetic studies.

Prophylactic prevention is considered as the most promising strategy to tackle STI/HIV. Twenty-five dithiocarbamate-thiourea hybrids (14-38) were synthesized as woman controlled topical vaginal microbicides to counter Trichomonas vaginalis and sperm along with RT inhibition potential. The four promising compounds (18, 26, 28 and 33) were tested for safety through cytotoxic assay against human cervical cell line (HeLa) and compatibility with vaginal flora, Lactobacillus.

Rational design and synthesis of novel thiazolidin-4-ones as non-nucleoside HIV-1 reverse transcriptase inhibitors.

A series of novel thiazolidin-4-one analogues, characterized by different substitution patterns at positions C-2 and N-3 of the thiazolidin-4-one scaffold for anti-HIV-1 activity has been investigated. Most of the compounds showed anti-HIV-1 activity at micromolar concentrations when tested in TZM-bl cells in vitro. Among the thirty-three compounds tested, compound 16 was the most potent inhibitor of HIV-1 replication against HIV-1IIIB, HIV-1ADA5, HIV-1UG070 and HIV-1VB59 (EC50=0.

One pot efficient diversity oriented synthesis of polyfunctional styryl thiazolopyrimidines and their bio-evaluation as antimalarial and anti-HIV agents.

An efficient one pot synthesis of a series of pluripotent (E)-1-(3-methyl-5-aryl-7-styryl-5H-thiazolo[3,2-a]pyrimidin-6-yl)-3-arylprop-2-en-1-ones is reported. It involves reaction of 5-acetyl-6-methyl-4-aryl-dihydropyrimidine-2-thiones, propargyl bromide and aromatic aldehydes in presence of ethanolic KOH. The newly synthesized compounds were evaluated for antimalarial activity against Plasmodium falciparum and as HIV-RT inhibitors.

Lead optimization at C-2 and N-3 positions of thiazolidin-4-ones as HIV-1 non-nucleoside reverse transcriptase inhibitors.

Based on rational drug design approach, a series of novel thiazolidin-4-ones bearing different aryl/heteroaryl moieties at position C-2 and N-3 are synthesized and evaluated as potent inhibitors for human immunodeficiency virus type-1 reverse transcriptase enzyme (HIV-1 RT). An in vitro HIV-1 RT assay showed that the compounds 4, 5, 6, 8, 12, 13, 14 and 17 have shown high inhibition of reverse transcriptase (75.41, 95.

2-(2,6-Dihalo-phenyl)-3-heteroaryl-2-ylmethyl-1, 3-thiazolidin-4-ones: anti-HIV agents.

A diversity of novel 2-aryl-3-heteroaryl-2-ylmethyl-1,3-thiazolidin-4-ones were designed and synthesized by reacting heteroaryl-2-ylmethyl amine with various 2,6-dihalosubstituted benzaldehydes and mercaptoacetic acid. The title compounds were evaluated for human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT) inhibitory activity. The results of in vitro assays showed that some of the compounds were effective inhibitors of HIV-1 reverse transcriptase enzyme at micromolar concentrations with less cytotoxicity in both MT-4 cells as well as acutely infected human T-lymphoid CEM cells.

Design and synthesis of 2-(2,6-dibromophenyl)-3-heteroaryl-1,3-thiazolidin-4-ones as anti-HIV agents.

A series of 2-(2,6-dibromophenyl)-3-heteroaryl-1,3-thiazolidin-4-ones were designed, synthesized and evaluated as selective human immunodeficiency virus type-1 reverse transcriptase (HIV-1 RT) enzyme inhibitors. The results of the HIV-1 RT kit and in vitro cell based assay showed that eight compounds effectively inhibited HIV-1 replication at 20-320 nM concentrations with minimal cytotoxicity in MT-4 as well as in CEM cells.

Synthesis and evaluation of 2-(2,6-dihalophenyl)-3-pyrimidinyl-1,3-thiazolidin-4-one analogues as anti-HIV-1 agents.

A series of 2-(2,6-dihalophenyl)-3-(substituted pyrimidinyl)-1,3-thiazolidin-4-ones were designed on the prediction of quantitative structure-activity relationship (QSAR) studies, synthesized, and evaluated as HIV-1 reverse transcriptase inhibitors. Our attempts in correlating the identified molecular surface features related properties for modeling the HIV-1 RT inhibitory activity resulted in some statistically significant QSAR models with good predictive ability. The results showed that compounds 4m and 4n were highly active in inhibiting HIV-1 replication with EC(50) values in the range of 22-28 nM in MT-4 as well as in CEM cells with selectivity indexes of >10,000.

Design, synthesis, and evaluation of 2-aryl-3-heteroaryl-1,3-thiazolidin-4-ones as anti-HIV agents.

Compounds having isothiourea or thiourea functional group have shown high anti-HIV-1 activity. Therefore, a series of 2-aryl-3-heteroaryl-1,3-thiazolidin-4-ones were designed, synthesized, and evaluated for anti-HIV-1 RT activity. The results of in vitro tests showed that the compound 9 exhibited EC50 at 0.

Regulation of V(D)J recombination: a dominant role for promoter positioning in gene segment accessibility.

Antigen receptor gene assembly is regulated by transcriptional promoters and enhancers, which control the accessibility of gene segments to a lymphocyte-specific V(D)J recombinase. However, it remained unclear whether accessibility depends on the process of transcription itself or chromatin modifications that accompany transcription. By using T cell receptor beta substrates that integrate stably into nuclear chromatin, we show that promoter location, rather than germ-line transcription or histone acetylation, is a primary determinant of recombination efficiency.

A change in the structure of Vbeta chromatin associated with TCR beta allelic exclusion.

To investigate chromatin control of TCR beta rearrangement and allelic exclusion, we analyzed TCR beta chromatin structure in double negative (DN) thymocytes, which are permissive for TCR beta recombination, and in double positive (DP) thymocytes, which are postallelic exclusion and nonpermissive for Vbeta to DbetaJbeta recombination. Histone acetylation mapping and DNase I sensitivity studies indicate Vbeta and DbetaJbeta segments to be hyperacetylated and accessible in DN thymocytes. However, they are separated from each other by hypoacetylated and inaccessible trypsinogen chromatin.