Inhibition of Human Immunodeficiency Virus Infection of CD4 + Cells by CD4-Free Glycopeptides from Monocytic U937 Cells (original) (raw)
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Design and Development of Integrase Inhibitors as Anti-HIV Agents
Current Medicinal Chemistry, 2003
A review is presented on different categories of compounds that have been studied for the inhibition of the HIV-1 integrase to develop anti-HIV agents. These compounds are: oligonucleotides (double-stranded, triplex, and G-quartet), curcumin analogues, polyhydroxylated aromatic compounds, diketo acids, caffeoyl-and galloylbased compounds, hydrazides and amides, tetracyclines, and depsides and depsidones. For all these compounds, the important structural features essential for the inhibition of the integrase are pointed out.
Progress in development of HIV-1 integrase inhibitor
2010
AIDS (Acquired Immuno Deficiency Syndrome) has found to be most fatal syndrome. The main causative agent of AIDS is HIV-1 integrase. Incorporation of viral DNA into the host cell genome could be translated as the basis of life-long infection. Therefore, this biochemical event, catalyzed by the enzyme integrase, is a pivotal step in viral life cycle and thus worthy of being exploited to develop anti-HIV chemotherapy. The review presented on different categories of compounds that have been studied for the inhibition of the HIV-1 integrase to develop anti-HIV agents. The categories are Oligonucleotides, Curcumin Analogues, Polyhydroxylated Aromatic Compounds, Diketo Acid,) Caffeoyl-based Inhibitors, Hydrazides and Amides, Tetracycline, Depsides and Depsidones.
Antimicrobial Agents and Chemotherapy, 2008
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European Journal of Immunology, 1993
. This observation suggests that chemical inhibitors of integrase may prevent the spread of HIV in infected individuals. In our search for such potential chemotherapeutic agents, we observed that -conidendrol inhibits both the sequence-dependent and sequenceindependent endonucleolytic activities of integrase with comparable potencies in vitro (50% inhibitory concentration, 500 nM). Structurally related compounds tested for their abilities to inhibit integrase generated a limited structure-activity analysis which demonstrated that potency is associated with the bis-catechol structure: two pairs of adjacent hydroxyls on separate benzene rings. -Conidendrol did not inhibit several other endonucleases and/or phosphoryltransferases. Although -conidendrol was not effective in preventing HIV-1 infection in cell culture, the in vitro data demonstrate that it is possible to identify selective agents targeted against this essential HIV-1 function.
Pure and Applied Chemistry, 2003
Combination therapy using reverse transcriptase (RT) and protease (PR) inhibitors is currently the best clinical approach in combatting acquired immunodeficiency syndrome (AIDS), caused by infection from the human immunodeficiency virus type 1 (HIV-1). However, the emergence of resistant strains calls urgently for research on inhibitors of further viral targets such as integrase (IN), the enzyme that catalyzes the integration of the proviral DNA into the host chromosomes. Recently, we started studies on new IN inhibitors as analogs of natural products, characterized by one or two 3,4-dihydroxycinnamoyl moieties, which were proven to be IN inhibitors in vitro. Then, we designed and synthesized a number of derivatives sharing 3,4-dihydroxycinnamoyl groups, obtaining potent IN inhibitors active at submicromolar concentrations. Unfortunately, these derivatives lacked antiretroviral activity, probably owing to their high cytotoxicity. So we designed a number of 3,4,5-trihydroxycinnamoyl derivatives as less-cytotoxic IN inhibitors, which were proven to be antiretrovirals in cell-based assays. Finally, we designed and synthesized a number of aryldiketohexenoic acids, strictly related to the aryldiketo acid series recently reported by Merck Company, which were shown to be potent antiretroviral agents endowed with anti-IN activities either in 3′ processing or in strand transfer steps.
Inhibitors of human immunodeficiency virus integrase
Proceedings of the National Academy of Sciences, 1993
In an effort to further extend the number of targets for development of antiretroviral agents, we have used an in vitro integrase assay to investigate a variety of chemicals, including topoisomerase inhibitors, antimalarial agents, DNA binders, naphthoquinones, the flavone quercetin, and caffeic acid phenethyl ester as potential human immunodericiency virus type 1 integrase inhibitors. Our results show that although several topoisomerase inhibitors-including doxorubicin, mitoxantrone, ellipticines, and quercetin-are potent integrase inhibitors, other topoisomerase inhibitors-such as amsacrine, etoposide, teniposide, and camptothecin-are inactive. Other intercalators, such as chloroquine and the bifunctional intercalator ditercalinium, are also active. However, DNA binding does not correlate closely with integrase inhibition. The intercalator 9-aminoacridine and the polyamine DNA minor-groove binders spermine, spermidine, and distamycin have no effect, whereas the non-DNA binders primaquine,
HIV-1 integrase inhibitors: a review of their chemical development
Antiviral Chemistry & Chemotherapy, 2011
Highly active antiretroviral therapy (HAART) significantly decreases plasma viral load, increases CD4+ T-cell counts in HIV-1-infected patients and has reduced progression to AIDS in developed countries. However, adverse side effects, and emergence of drug resistance, mean there is still a demand for new anti-HIV agents. The HIV integrase (IN) is a target that has been the focus of rational drug design over the past decade. In 2007, raltegravir was the first IN inhibitor approved by the US Food and Drug Administration for antiretroviral combination therapy, while another IN inhibitor, elvitegravir, is currently in Phase III clinical trials. This article reviews the development and resistance profiling of small molecule HIV-1 IN inhibitors.
Progress in HIV-1 Integrase Inhibitors: A Review of their Chemical Structure Diversity
Iranian journal of pharmaceutical research : IJPR, 2016
HIV-1 integrase (IN) enzyme, one of the three main enzymes of HIV-1, catalyzed the insertion of the viral DNA into the genome of host cells. Because of the lack of its homologue in human cells and its essential role in HIV-1 replication, IN inhibition represents an attractive therapeutic target for HIV-1 treatment. Since identification of IN as a promising therapeutic target, a major progress has been made, which has facilitated and led to the approval of three drugs. This review focused on the structural features of the most important IN inhibitors and categorized them structurally in 10 scaffolds. We also briefly discussed the structural and functional properties of HIV-1 IN and binding modes of IN inhibitors. The SAR analysis of the known IN inhibitors provides some useful clues to the possible future discovery of novel IN inhibitors.
2004
A series of 6-aryl-2,4-dioxo-5-hexenoic acids, were synthesized and tested against HIV-1 in cell-based assays and against recombinant HIV-1 integrase (rIN) in enzyme assays. Compound 8a showed potent antiretroviral activity (EC 50 =1.5 mM) and significant inhibition against rIN (strand transfer: IC 50 =7.9 mM; 3 0 -processing: IC 50 =7.0 mM). A preliminary molecular modeling study was carried out to compare the spatial conformation of 8a with those of L-731,988 (4) and 5CITEP (7) in the IN core. #