The Connection Domain Is Implicated in Metalloporphyrin Binding and Inhibition of HIV Reverse Transcriptase

Argyris, Elias G.; Vanderkooi, Jane M.; Venkateswaran, P. S.; Kay, Brian K.; Paterson, Yvonne

doi:10.1074/jbc.274.3.1549

Cited by 26 publications

(22 citation statements)

References 46 publications

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“…No significant cytotoxicity was observed when healthy human T-cells and fibroblasts were used as models for toxicity determination using [Au III (TMPyP)]Cl 5 . Further UV/ Vis absorption titration analysis revealed that the HIV-1 RT inhibition by [Au III (TMPyP)]Cl 5 is related to it being bound to connection domain sequence 398-407 (WETWWTWYWQ; Argyris et al 1999). This is in agreement with the fact that gold(III) porphyrin binds to certain sites near the active site of the enzyme.…”

Section: Gold(iii) Compoundssupporting

confidence: 72%

HIV therapeutic possibilities of gold compounds

2010

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Highly active antiretroviral therapy (HAART) has resulted in decreased mortality and morbidity from the acquired immune deficiency syndrome caused by the human immunodeficiency virus (HIV). Drug resistance and toxicity of HAART has led to the search for novel inhibitors of HIV infection. Gold-based compounds have shown promising activity against a wide range of clinical conditions and microorganism infections including HIV-1. A typical example is auranofin which resulted in an elevated CD4? T-cell count in an HIV patient being treated for psoriatic arthritis. In addition, reports exist on gold-based inhibitors of reverse transcriptase (RT), protease (PR) and viral entry of host cells. These and other characteristics of goldbased HIV drugs are reviewed here.

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Section: Gold(iii) Compoundssupporting

confidence: 72%

HIV therapeutic possibilities of gold compounds

2010

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“…Despite these observations, neither ZnPP nor SnPP incubation altered Egr1 or Sp1 protein levels (Fig. 3C) (10). Because ZnPP preferentially enhanced Egr1 but decreased Sp1 binding at the S/E site, we speculated that ZnPP inhibits cyclin D1 gene expression through direct interaction with transcription factor complexes, specifically those containing Egr1 and/or Sp1.…”

Section: Znpp Facilitates the Competition Of Egr1 With Sp1 In Targetimentioning

confidence: 62%

“…In kinetic assays, ZnPP inhibited the soluble guanylyl cyclase activity independent of HO-1 (9). In vitro studies showed that ZnPP directly interacts with human immunodeficiency virus type 1 reverse transcriptase and modulates its activity (10). We showed that ZnPP induces the expression of HMOX1 and TP53 genes and localizes to the nucleus (11).…”

Section: Zinc Protoporphyrin IX (Znpp)mentioning

confidence: 86%

Zinc Protoporphyrin Regulates Cyclin D1 Expression Independent of Heme Oxygenase Inhibition

Fernando

Wang

et al. 2009

Journal of Biological Chemistry

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Zinc protoporphyrin IX (ZnPP), an endogenous heme analogue that inhibits heme oxygenase (HO) activity, represses tumor growth. It can also translocate into the nucleus and upregulate heme oxygenase 1 (HMOX1) gene expression. Here, we demonstrate that tumor cell proliferation was inhibited by ZnPP, whereas tin protoporphyrin (SnPP), another equally potent HO-1 inhibitor, had no effect. Microarray analysis on 128 tumorigenesis related genes showed that ZnPP suppressed genes involved in cell proliferation and angiogenesis. Among these genes, CYCLIN D1 (CCND1) was specifically inhibited as were its mRNA and protein levels. Additionally, ZnPP inhibited CCND1 promoter activity through an Sp1 and Egr1 overlapping binding site (S/E). We confirmed that ZnPP modulated the S/E site, at least partially by associating with Sp1 and Egr1 proteins rather than direct binding to DNA targets. Furthermore, administration of ZnPP significantly inhibited cyclin D1 expression and progression of a B-cell leukemia/lymphoma 1 tumor in mice by preferentially targeting tumor cells. These observations show HO independent effects of ZnPP on cyclin D1 expression and tumorigenesis. Zinc protoporphyrin IX (ZnPP)2 is a metabolite formed in trace amounts during heme biosynthesis. In this process, the final reaction is the chelation of zinc in the protoporphyrin ring, whereas heme is formed by chelation of iron in the ring. During periods of iron insufficiency or impaired iron utilization, ZnPP formation is enhanced. Clinically, ZnPP quantification is a sensitive and specific tool for measuring iron mineral status and metabolism (1). In addition, ZnPP regulates heme catabolism through competitively inhibiting the activity of heme oxygenase (HO), the rate-limiting enzyme in the heme degradation pathway that produces carbon monoxide and biliverdin. The latter is rapidly reduced to bilirubin by biliverdin reductase. Thus, ZnPP has potential therapeutic applications in controlling exaggerated bilirubin formation leading to neonatal jaundice (2). Moreover, because the by-products of the HO reaction, carbon monoxide and bilirubin, are antioxidants, the potential effects of ZnPP have been studied in numerous diseases, including cancer, such as chronic myelogenous leukemia (3-6).Whereas ZnPP has been largely studied in relation to its inhibition of HO activity, reports show that ZnPP could exert cellular effects independent of HO activity (7,8). In kinetic assays, ZnPP inhibited the soluble guanylyl cyclase activity independent of HO-1 (9). In vitro studies showed that ZnPP directly interacts with human immunodeficiency virus type 1 reverse transcriptase and modulates its activity (10). We showed that ZnPP induces the expression of HMOX1 and TP53 genes and localizes to the nucleus (11). Although the underling mechanism is unknown, zinc mesoporphyrin, another analogue of heme, has been shown to induce HMOX1 expression by accelerating Bach1 protein degradation (12). Heme itself can affect gene expression by associating with transcription factors (13,14). Th...

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“…Interestingly, it has been shown that free extracellular heme has a potent inhibitory effect on HIV-1 replication (69 -71). The inhibitory effect of heme was proposed to be either due to direct interaction with the reverse transcriptase (72,73) or through indirect effects of heme on host cells (such as up-regulation of heme oxygenase-1) (69 -71). Importantly, a recent analysis that includes more than 400,000 patients with sickle cell anemia, a condition accompanied by high levels of intravascular hemolysis and heme release, demonstrated a 70% lower incidence of HIV-1 infection as compared with the normal population (74).…”

Section: F425mentioning

confidence: 99%

A Cryptic Polyreactive Antibody Recognizes Distinct Clades of HIV-1 Glycoprotein 120 by an Identical Binding Mechanism

Dimitrov

Planchais

Scheel

et al. 2014

Journal of Biological Chemistry

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Background: Polyreactive antibodies can efficiently neutralize HIV. Results: Heme induces polyreactivity of a human antibody, which recognizes distinct gp120 clades by an identical binding mechanism. Conclusion: Antigen-binding promiscuity of a polyreactive antibody allows recognition of antigen with high molecular heterogeneity. Significance: Characterization of the interaction of polyreactive antibodies with envelope proteins of HIV reveals novel strategies for control of the virus.

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The Connection Domain Is Implicated in Metalloporphyrin Binding and Inhibition of HIV Reverse Transcriptase

Cited by 26 publications

References 46 publications

HIV therapeutic possibilities of gold compounds

HIV therapeutic possibilities of gold compounds

Zinc Protoporphyrin Regulates Cyclin D1 Expression Independent of Heme Oxygenase Inhibition

A Cryptic Polyreactive Antibody Recognizes Distinct Clades of HIV-1 Glycoprotein 120 by an Identical Binding Mechanism

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