Michellamine B, a novel plant alkaloid, inhibits human immunodeficiency virus-induced cell killing by at least two distinct mechanisms

McMahon, James B.; Currens, Michael J.; Gulakowski, Robert J.; Buckheit, Robert W.; Lackman-Smith, Carol; Hallock, Yali F.; Boyd, Michael R.

doi:10.1128/aac.39.2.484

Cited by 109 publications

(68 citation statements)

References 25 publications

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“…Certainly, the anti-HIV activity of gossypol cannot be attributed solely to its RT inhibition -indeed notable compounds have been shown to have multiple modes of action, including the michellamine class of compounds that are also reverse transcriptase inhibitors, but are known to act at two additional sites to account for their anti-HIV activity. 21 The results from our study conclusively demonstrate that gossypol is a weak reverse transcriptase inhibitor, and strongly suggest that the site of this action is the non-nucleoside inhibitor binding pocket. …”

Section: Biological Testingsupporting

confidence: 61%

Novel pharmacophore-based methods reveal gossypol as a reverse transcriptase inhibitor

Keller

Birch

Leach

et al. 2003

Journal of Molecular Graphics and Modelling

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In a program to identify new structural entities for the inhibition of the HIV-1 reverse transcriptase (RT) enzyme via database searching, a series of RT pharmacophores were developed. By utilising a novel filtering technique, the National Cancer Institute database of compounds was scanned producing 15 compounds to be screened for activity. A notable inclusion was a series of gossypol derivatives. The testing of a series of compounds revealed the parent compound gossypol to be an HIV-1 reverse transcriptase inhibitor. These results suggest that at least part of its anti-HIV activity is due to gossypol targeting the non-nucleoside inhibitor binding pocket of RT. AbstractIn a program to identify new structural entities for the inhibition of the HIV-1 reverse transcriptase (RT) enzyme via database searching, a series of RT pharmacophores were developed. By utilising a novel filtering technique, the National Cancer Institute database of compounds was scanned producing 15 compounds to be screened for activity. A notable inclusion was a series of gossypol derivatives. The testing of a series of compounds revealed the parent compound gossypol to be an HIV-1 reverse 2 transcriptase inhibitor. These results suggest that at least part of its anti-HIV activity is due to gossypol targeting the non-nucleoside inhibitor binding pocket of RT.

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Section: Biological Testingsupporting

confidence: 61%

Novel pharmacophore-based methods reveal gossypol as a reverse transcriptase inhibitor

Keller

Birch

Leach

et al. 2003

Journal of Molecular Graphics and Modelling

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“…It has antioxidation properties (78) and inhibitory activity against the arachidonic acid-metabolizing lipoxygenase (hLO) enzymes (17), which catalyze the dioxygenation of polyunsaturated fatty acids to their hydroperoxy acids (66). Michellamine B has also been shown to inhibit HIV reverse transcriptase and virus-mediated cellular fusion (77) as well as HIV-induced cell killing in a variety of human cell lines (11,51,52). Here we show that NSC 661755 reduced infectious HCVcc production in persistently infected cells (Table 4) without affecting intracellular RNA levels (Table 3; Fig.…”

Section: Discussionmentioning

confidence: 99%

Identification of Hepatitis C Virus Inhibitors Targeting Different Aspects of Infection Using a Cell-Based Assay

Sáinz

Petukhov

et al. 2012

Antimicrob Agents Chemother

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With 2 to 3% of the worldwide population chronically infected, hepatitis C virus (HCV) infection continues to be a major health care burden. Unfortunately, current interferon-based treatment options are not effective in all patients and are associated with significant side effects. Consequently, there is an ongoing need to identify and develop new anti-HCV therapies. Toward this goal, we previously developed a cell-based HCV infection assay for antiviral compound screening based on a low-multiplicity-of-infection approach that uniquely allows for the identification of antiviral compounds that target cell culture-derived HCV (HCVcc) at any step of the viral infection cycle. Using this assay, here we report the screening of the NCI Diversity Set II library, containing 1,974 synthesized chemical compounds, and the identification of compounds with specific anti-HCV activity. In combination with toxicity counterscreening, we identified 30 hits from the compound library, 13 of which showed reproducible and dose-dependent inhibition of HCV with mean therapeutic indices (50% cytotoxic concentration [CC 50 ]/50% effective concentration [EC 50 ]) of greater than 6. Using HCV pseudotype and replicon systems of multiple HCV genotypes, as well as infectious HCVcc-based assembly and secretion analysis, we determined that different compounds within this group of candidate inhibitors target different steps of viral infection. The compounds identified not only will serve as biological probes to study and further dissect the biology of viral infection but also should facilitate the development of new anti-HCV therapeutic treatments. Hepatitis C virus (HCV) is a hepatotropic enveloped positivestrand RNA virus (family Flaviviridae) that infects the parenchymal cells of the liver (i.e., hepatocytes) (69, 70). HCV infection begins with interaction of the viral particle with the target cell via a relatively undefined multistep process of binding between the virion and multiple cell surface receptors, which include the cluster of differentiation 81 (CD81) tetraspanin protein (7,34,56,80,84), the scavenger receptor class B member I (SR-BI) (also known as SCARB1) (7,30,38,63,83), and the tight-junction proteins claudin-1 (CLDN1) (20) and occludin (OCLN) (8,47,57). In addition to these four host factors, we more recently showed that the cellular Niemann-Pick C1-like 1 (NPC1L1) cholesterol uptake receptor also functions as an HCV entry factor via a virion particle cholesterol-associated mechanism (60), and Lupberger et al. have recently shown that the host cellular epidermal growth factor receptor (EGFR) and ephrin receptor A2 (EphA2) function as cofactors during viral cell entry (49).Following entry, the viral genome (ϳ9.6 kb) is translated by an internal ribosome entry site (IRES)-dependent process into a single viral polyprotein that is subsequently co-and posttranslationally cleaved into structural (core, E1, E2, and p7) and nonstructural (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) proteins by host and viral proteases (29,46). The NS prote...

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“…This assay is sensitive to inhibitors of gp120 to CD4/CCR5/CXCR4 binding and inhibitors of gp41-mediated fusion. The CXCR4-tropic assay was performed as described previously (25). The CCR5-tropic fusion assay was set up in the same manner except that 1.5 ϫ 10 before the assay.…”

Section: Cells and Virusesmentioning

confidence: 99%

“…This assay is designed to identify compounds that inhibit cell-free HIV-1 entry into HeLa CD4 LTR ␤-Gal (MAGI) or MAGI-CCR5 cells (7,22). The CCR5-tropic HIV-1 entry assay is one of the primary screening assays and is performed as described previously, with the modifications outlined below (25).…”

Section: Cells and Virusesmentioning

confidence: 99%

Development of a Comprehensive Human Immunodeficiency Virus Type 1 Screening Algorithm for Discovery and Preclinical Testing of Topical Microbicides

Lackman-Smith

Osterling

Luckenbaugh

et al. 2008

Antimicrob Agents Chemother

102

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Topical microbicides are self-administered, prophylactic products for protection against sexually transmitted pathogens. A large number of compounds with known anti-human immunodeficiency virus type 1 (HIV-1) inhibitory activity have been proposed as candidate topical microbicides. To identify potential leads, an in vitro screening algorithm was developed to evaluate candidate microbicides in assays that assess inhibition of cell-associated and cell-free HIV-1 transmission, entry, and fusion. The algorithm advances compounds by evaluation in a series of defined assays that generate measurements of relative antiviral potency to determine advancement or failure. Initial testing consists of a dual determination of inhibitory activity in the CD4-dependent CCR5-tropic cell-associated transmission inhibition assay and in the CD4/CCR5-mediated HIV-1 entry assay. The activity is confirmed by repeat testing, and identified actives are advanced to secondary screens to determine their effect on transmission of CXCR4-tropic viruses in the presence or absence of CD4 and their ability to inhibit CXCR4-and CCR5-tropic envelopemediated cell-to-cell fusion. In addition, confirmed active compounds are also evaluated in the presence of human seminal plasma, in assays incorporating a pH 4 to 7 transition, and for growth inhibition of relevant strains of lactobacilli. Leads may then be advanced for specialized testing, including determinations in human cervical explants and in peripheral blood mononuclear cells against primary HIV subtypes, combination testing with other inhibitors, and additional cytotoxicity assays. PRO 2000 and SPL7013 (the active component of VivaGel), two microbicide products currently being evaluated in human clinical trials, were tested in this in vitro algorithm and were shown to be highly active against CCR5-and CXCR4-tropic HIV-1 infection.

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Michellamine B, a novel plant alkaloid, inhibits human immunodeficiency virus-induced cell killing by at least two distinct mechanisms

Cited by 109 publications

References 25 publications

Novel pharmacophore-based methods reveal gossypol as a reverse transcriptase inhibitor

Novel pharmacophore-based methods reveal gossypol as a reverse transcriptase inhibitor

Identification of Hepatitis C Virus Inhibitors Targeting Different Aspects of Infection Using a Cell-Based Assay

Development of a Comprehensive Human Immunodeficiency Virus Type 1 Screening Algorithm for Discovery and Preclinical Testing of Topical Microbicides

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