Interaction of trivalent antimony with a CCHC zinc finger domain: potential relevance to the mechanism of action of antimonial drugs

Demicheli, Cynthia; Frézard, Frédéric; Mangrum, John B.; Farrell, Nicholas

doi:10.1039/b809186b

Cited by 47 publications

(36 citation statements)

References 29 publications

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“…It is well documented that the potential molecular targets of Sb III are associated with DNA replication, structure, and repair (35,36). Previously, Sb III had been reported to induce DNA fragmentation in Leishmania, which prevents further replication and cell proliferation and ultimately causes cell death.…”

Section: Figmentioning

confidence: 99%

Characterization of the Proliferating Cell Nuclear Antigen of Leishmania donovani Clinical Isolates and Its Association with Antimony Resistance

Tandon

Chandra

Baharia

et al. 2014

Antimicrob Agents Chemother

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Previously, through a proteomic analysis, proliferating cell nuclear antigen (PCNA) was found to be overexpressed in the sodium antimony gluconate (SAG)-resistant clinical isolate compared to that in the SAG-sensitive clinical isolate of Leishmania donovani. The present study was designed to explore the potential role of the PCNA protein in SAG resistance in L. donovani. For this purpose, the protein was cloned, overexpressed, purified, and modeled. Western blot (WB) and real-time PCR (RT-PCR) analyses confirmed that PCNA was overexpressed by >3-fold in the log phase, stationary phase, and peanut agglutinin isolated procyclic and metacyclic stages of the promastigote form and by ϳ5-fold in the amastigote form of the SAG-resistant isolate compared to that in the SAG-sensitive isolate. L. donovani PCNA (LdPCNA) was overexpressed as a green fluorescent protein (GFP) fusion protein in a SAG-sensitive clinical isolate of L. donovani, and modulation of the sensitivities of the transfectants to pentavalent antimonial (Sb V ) and trivalent antimonial (Sb III ) drugs was assessed in vitro against promastigotes and intracellular (J774A.1 cell line) amastigotes, respectively. Overexpression of LdPCNA in the SAG-sensitive isolate resulted in an increase in the 50% inhibitory concentrations (IC 50 ) of Sb V (from 41.2 ؎ 0.6 g/ml to 66.5 ؎ 3.9 g/ml) and Sb III (from 24.0 ؎ 0.3 g/ml to 43.4 ؎ 1.8 g/ml). Moreover, PCNA-overexpressing promastigote transfectants exhibited less DNA fragmentation compared to that of wild-type SAG-sensitive parasites upon Sb III treatment. In addition, SAG-induced nitric oxide (NO) production was found to be significantly inhibited in the macrophages infected with the transfectants compared with that in wild-type SAG-sensitive parasites. Consequently, we infer that LdPCNA has a significant role in SAG resistance in L. donovani clinical isolates, which warrants detailed investigations regarding its mechanism.

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Section: Figmentioning

confidence: 99%

Characterization of the Proliferating Cell Nuclear Antigen of Leishmania donovani Clinical Isolates and Its Association with Antimony Resistance

Tandon

Chandra

Baharia

et al. 2014

Antimicrob Agents Chemother

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“…Regarding the interactions of inorganic Sb with biomolecules, other groups have determined the existence of Sb-S complexes with zinc finger peptides (Demicheli et al, 2008;Frézard et al, 2012), glutathione (Burford et al, 2005;Sun et al, 2000), guanine and adenosine nucleosides (Demicheli et al, 2002), but the direct interaction of Sb with proteins has not been described.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms underlying the toxic effects of antimony species in human embryonic kidney cells (HEK-293) and their comparison with arsenic species

2016

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-Antimony cytotoxicity was assessed in human embryonic kidney cells . Uptake, mitochondrial respiratory activity, ROS generation and diffusional kinetics were measured using fluorescence recovery after photobleaching (FRAP). Furthermore, the toxic effect induced by Sb was compared with As toxicity in regard to ROS generation and diffusional kinetics, which provides information on the protein aggregation process. Our results show a favored uptake of Sb(III) and a more severe effect, decreasing the mitochondrial activity more than in the presence of Sb(V). In comparison with As, the Sb species did not generate a significant increase in ROS generation, which was observed with As(III) and As(V). FRAP analysis yielded important information on the diffusion and binding dynamics of live cells in presence of these metalloids. The mobile fraction showed a strong decrease with the As species and Sb(III). The diffusion rate and the k off-rate were significantly decreased for the As and Sb species but were more strong in the presence of As(III).

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“…The mechanism of pentavalent antimony compounds action is the inhibition of glycolytic pathway and -oxidation enzymes of the parasites (Baiocco et al, 2009), but being a heavy metal it is non-selective and it is believed to interfere with other metabolic pathways of parasites and hosts. Furthermore, these drugs can interact with the zinc finger domain of proteins, and many proteins have this motif in their tridimensional structures (Demicheli et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Immunocytochemistry of Proteases in the Study of Leishmania Physiology and Host-Parasite Interaction

Silva-López¹

2012

Applications of Immunocytochemistry

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Interaction of trivalent antimony with a CCHC zinc finger domain: potential relevance to the mechanism of action of antimonial drugs

Abstract: Sb(III) competes with Zn(II) for its binding to the CCHC zinc finger domain of the NCp7 protein of HIV-1, indicating that zinc finger proteins may be targets for antimony-based drugs and thus responsible for their important pharmacological actions.

Cited by 47 publications

References 29 publications

Characterization of the Proliferating Cell Nuclear Antigen of Leishmania donovani Clinical Isolates and Its Association with Antimony Resistance

Characterization of the Proliferating Cell Nuclear Antigen of Leishmania donovani Clinical Isolates and Its Association with Antimony Resistance

Mechanisms underlying the toxic effects of antimony species in human embryonic kidney cells (HEK-293) and their comparison with arsenic species

Immunocytochemistry of Proteases in the Study of Leishmania Physiology and Host-Parasite Interaction

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