Molecular target of the antileishmanial action of sinefungin

Nolan, Linda L.

doi:10.1128/aac.31.10.1542

Cited by 34 publications

(31 citation statements)

References 24 publications

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“…It was suggested to have the potential to serve as a lead compound for a novel antiparasitic drug (59). However, some Leishmania strains were found to be intrinsically resistant to SNF (60), a finding supported here with the intrinsic SNF resistance observed in L. major Friedlin or L. infantum JPCM5 (Table 1).…”

Section: Discussionsupporting

confidence: 77%

High Affinity S-Adenosylmethionine Plasma Membrane Transporter of Leishmania Is a Member of the Folate Biopterin Transporter (FBT) Family

Dridi¹,

Ouameur²,

Ouellette

2010

Journal of Biological Chemistry

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S-Adenosylmethionine (AdoMet) is an important methyl group donor that plays a central role in many essential biochemical processes. The parasite Leishmania can both synthesize and transport AdoMet. Leishmania cells resistant to the antifolate methotrexate due to a rearrangement in folate biopterin transporter (FBT) genes were cross-resistant to sinefungin, an AdoMet analogue. FBT gene rearrangements were also observed in Leishmania major cells selected for sinefungin resistance. One of the rearranged FBT genes corresponded to the main AdoMet transporter (AdoMetT1) of Leishmania as determined by gene transfection and gene inactivation experiments. AdoMetT1 was determined to be a high affinity plasma membrane transporter expressed constitutively throughout the growth phases of the parasite. Leishmania cells selected for resistance or naturally insensitive to sinefungin had lower expression of AdoMetT1. A new function in one carbon metabolism, also a pathway of interest for chemotherapeutic interventions, is described for a novel class of membrane proteins found in diverse organisms.The parasite Leishmania is distributed globally and causes a variety of clinical symptoms ranging from self-healing cutaneous lesions to visceral infections that are usually fatal if left untreated (1, 2). Current first-line chemotherapy against leishmaniasis relies on a rather limited arsenal of drugs, including pentavalent antimonials, liposomal amphotericin B, or miltefosine (2). These drugs are associated with side effects, high costs, and drug resistance, and therefore, the search for new drugs and targets to control this parasite is warranted (3, 4).S-Adenosylmethionine (AdoMet or SAM) 5 is an important biological sulfonium compound recognized as the universal methyl donor for methylation of lipids, proteins, nucleic acids, and xenobiotics in living cells (5). AdoMet is also a donor of propylamine groups for the synthesis of polyamines and participates in the reverse trans-sulfuration pathway where AdoMet is converted into cysteine and glutathione and in Leishmania in the spermidine-glutathione conjugate trypanothione (6, 7). AdoMet is also used as a source of methylene groups, amino groups, and ribosyl groups in the synthesis of fatty acids, biotin, and the modified nucleoside epoxyqueusine of tRNAs (reviewed in Ref. 8).Most cells are capable of synthesizing AdoMet from L-methionine and ATP, in a process requiring the enzyme methionine adenosyltransferase (MAT). The gene coding for this enzyme is present in most sequenced organisms (reviewed in Ref. 9). However, in some Rickettsia strains, the MAT gene is inactivated by a mutation (10), and in the fungus Pneumocystis carinii, no MAT activity has been detected (11). These organisms have the rare distinction of meeting their AdoMet needs by importing it (12). The Rickettsia transporter is part of the drug/ metabolite transporter superfamily (10), and the identity of the Pneumocystis transporter is not known. Transport of AdoMet across the plasma membrane does not occur to a signifi...

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Section: Discussionsupporting

confidence: 77%

High Affinity S-Adenosylmethionine Plasma Membrane Transporter of Leishmania Is a Member of the Folate Biopterin Transporter (FBT) Family

Dridi¹,

Ouameur²,

Ouellette

2010

Journal of Biological Chemistry

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“…28,29 In this study, we administrated sinefungin at a dose of 10 mg/kg/day, which resulted in the suppression of renal fibrosis as well as H4K4me1. Taken together, SET7/9 upregulation is involved in the progression of renal fibrosis, and sinefungin suppresses renal fibrosis through SET7/9 inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…We selected the dose of sinefungin based on described studies. 28,29 immunohistochemical staining. (n=5 for each group).…”

Section: Drug and Sirna Administration In Vivomentioning

confidence: 99%

Inhibition of SET Domain–Containing Lysine Methyltransferase 7/9 Ameliorates Renal Fibrosis

Sasaki

Doi

Nakashima

et al. 2016

Journal of the American Society of Nephrology

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TGF-b1 activity results in methylation of lysine 4 of histone H3 (H3K4) through SET domain-containing lysine methyltransferase 7/9 (SET7/9) induction, which is important for the transcriptional activation of fibrotic genes in vitro. However, in vivo studies utilizing an experimental model of renal fibrosis are required to develop therapeutic interventions that target SET7/9. In this study, we investigated the signaling pathway of TGF-b1-induced SET7/9 expression and whether inhibition of SET7/9 suppresses renal fibrosis in unilateral ureteral obstruction (UUO) mice and kidney cell lines. Among the SET family, SET7/9 was upregulated on days 3 and 7 in UUO mice, and the upregulation was suppressed by TGF-b1 neutralizing antibody. TGF-b1 induced SET7/9 expression via Smad3 in normal rat kidney (NRK)-52E cells. In human kidney biopsy specimens from patients diagnosed with IgA nephropathy and membranous nephropathy, SET7/9 expression was positively correlated with the degree of interstitial fibrosis (r=0.59, P=0.001 in patients with IgA nephropathy; and r=0.58, P,0.05 in patients with membranous nephropathy). In addition, small interfering RNA-mediated knockdown of SET7/9 expression significantly attenuated renal fibrosis in UUO mice. Sinefungin, an inhibitor of SET7/9, also suppressed the expression of mesenchymal markers and extracellular matrix proteins and inhibited H3K4 mono-methylation (H3K4me1) in kidneys of UUO mice. Moreover, sinefungin had an inhibitory effect on TGF-b1-induced a-smooth muscle actin expression and H3K4me1 in both NRK-52E and NRK-49F cells. In conclusion, sinefungin, a SET7/9 inhibitor, ameliorates renal fibrosis by inhibiting H3K4me1 and may be a candidate therapeutic agent.

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“…(7, 17), Leishmania spp. (13,18), and Entamoeba histolytica (12). Nolan (13) reported on selective inhibition of leishmanial and mammalian DNA polymerases.…”

mentioning

confidence: 99%

Antileishmanial Activities of Aphidicolin and Its Semisynthetic Derivatives

Kayser

Kiderlen

Bertels³

et al. 2001

Antimicrob Agents Chemother

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Diseases caused by protozoan parasites are responsible for considerable morbidity and mortality, especially in developing countries. The most prevalent parasitic disease is malaria, but leishmaniasis is also considered to be a genuine emerging disease, afflicting worldwide over 12 million people in 88 countries with an annual incidence of about 2 million (2). Lately, leishmaniasis has become better known to the industrialized countries after eight Americans were infected during Operation Desert Storm (11) and especially because of the highly problematic coincidence of visceral leishmaniasis and AIDS in southern Europe (1).The advancement of antileishmanial chemotherapy has been widely neglected in the past decades, leaving pentavalent antimonials, sodium stibogluconate, and meglumine antimonate as the first-line drugs for visceral and cutaneous leishmaniasis despite their variable efficacies and severe side effects (1). There is an obvious need for new drugs with structures and mechanisms of action different from those of drugs in use to date. Nature has been a source for important antiparasitic drugs in the past. Most of these are plant derived (e.g., quinine and artemisinin) (5, 19), but an increasing number have been isolated from microorganisms (amphotericin B and ivermectins) (20).The fungal metabolite aphidicolin (compound 1, Fig. 1 and Table 1) was isolated from Nigrospora sphaerica and was first described as a highly active drug for inhibiting cell division and synchronizing cell cycles in experimental medicine (10,14). Aphidicolin (compound 1) is a tetracyclic diterpene antibiotic with a bridged ring system rarely found among diterpenes. As reported in recent publications, aphidicolin has been tested for antiparasitic potential against Trypanosoma spp. (7, 17), Leishmania spp. (13, 18), and Entamoeba histolytica (12). Nolan (13) reported on selective inhibition of leishmanial and mammalian DNA polymerases. Furthermore, aphidicolin also possesses antineoplastic activity (3, 15). Aphidicolin is cytotoxic for neuroblastoma cells, while not significantly affecting the viability of normal cells (3). Its toxic dose in mice is quite high (60 mg/kg of body weight), indicating a wide pharmacological window.Despite the caveats, the antiparasitic efficacy and in vivo tolerance prompted us to further investigate the antileishmanial potential of aphidicolin and 17 of its semisynthetic derivatives. The parent aphidicolin structure was chemically modified at specific regions to allow a rational structure-activity analysis among this group of tetracyclic diterpenes derived from microbiological sources. MATERIALS AND METHODSCompounds. All compounds (Fig. 1) were produced by AnalytiCon AG, Potsdam, Germany. Purity was determined by high-performance liquid chromatography and nuclear magnetic resonance spectroscopy. Amphotericin B and miltefosin (Sigma, Munich, Germany) were used as standard drugs for positive controls. All compounds were first dissolved in dimethyl sulfoxide at 20 mg/ml and stored frozen before being dilu...

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Molecular target of the antileishmanial action of sinefungin

Cited by 34 publications

References 24 publications

High Affinity S-Adenosylmethionine Plasma Membrane Transporter of Leishmania Is a Member of the Folate Biopterin Transporter (FBT) Family

High Affinity S-Adenosylmethionine Plasma Membrane Transporter of Leishmania Is a Member of the Folate Biopterin Transporter (FBT) Family

Inhibition of SET Domain–Containing Lysine Methyltransferase 7/9 Ameliorates Renal Fibrosis

Antileishmanial Activities of Aphidicolin and Its Semisynthetic Derivatives

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