Effect of Berenil on Growth, Mitochondrial DNA and Respiration of <i>Leishmania tarentolae</i> Promastigotes*

Leon, Wilson; Brun, R; Krassner, Stuart M.

doi:10.1111/j.1550-7408.1977.tb04773.x

Cited by 13 publications

(9 citation statements)

References 16 publications

(2 reference statements)

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“…Experimental studies shows that the ligands (Table 2) used in this study are good antileishmanials (4–15), but docking of these compounds revealed a great variation in their binding energy. Initially, totally five poses were saved from which best pose with lowest energy was chosen for each compound.…”

Section: Resultsmentioning

confidence: 93%

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Comparative Analysis of Different DNA‐Binding Drugs for Leishmaniasis Cure: A Pharmacoinformatics Approach

Chauhan

Vidyarthi

Poddar³

2012

Chem Biol Drug Des

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Several experiments have been performed to test DNA-binding drugs to cure Leishmania infection. However, there are no details of pharmacoinformatics study. Herein, we have selected a good number of compounds from experimentally verified studies and performed a comparative analysis based on pharmacoinformatics techniques. In silico docking study was performed to observe the molecular level interactions of these known ligands with the DNA receptor by automated computational docking using Glide. A comparison between the calculated interaction energies and in silico ADME ⁄ T study was made. In agreement with drug likeness rules, our study suggests that secohydroxy-aza-CBI-TMI (compound 4b; GScore, ) 12.058) is a potential molecule for targeting the DNA to cure leishmaniasis.

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Section: Resultsmentioning

confidence: 93%

“…Berenil (diminazene aceturate), a minor groove binder in AT‐rich domain (24), has been proven a good antileishmanial previously (5,8). Our in silico docking calculation with a GScore of −10.93398 and ADME/T study with no violence of any parameters is in agreement with previous studies (Table 4).…”

Section: Resultsmentioning

confidence: 99%

Comparative Analysis of Different DNA‐Binding Drugs for Leishmaniasis Cure: A Pharmacoinformatics Approach

Chauhan

Vidyarthi

Poddar³

2012

Chem Biol Drug Des

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“…Southern blot analysis of SacI-cut DNA and probing with the ADOMETDC 5Ј-and 3Ј-flanking regions, 5ЈF and 3ЈF, respectively, revealed the precise nature of the rearrangements observed after the homologous recombination events that gave rise to the heterozygous and (44). ADOMETDC sequences shown include L. donovani (LdADOMETDC), T. cruzi (TcADOMETDC) (13,17), T. brucei (TbADOMETDC) (accession number AAA61969), human (hsADOMETDC) (16), O. volvulus (ovADOEMTDC) (11), and S. cerevisiae (scADOMETDC) (12). Identical residues are highlighted in dark boxes, and similar residues are shown in shaded boxes.…”

Section: Resultsmentioning

confidence: 99%

S-Adenosylmethionine Decarboxylase fromLeishmania donovani

Roberts¹,

Scott²,

Gasteier³

et al. 2002

Journal of Biological Chemistry

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The polyamine biosynthetic enzyme, S-adenosylmethionine decarboxylase (ADOMETDC) has been advanced as a potential target for antiparasitic chemotherapy. To investigate the importance of this protein in a model parasite, the gene encoding ADOMETDC has been cloned and sequenced from Leishmania donovani. The ⌬adometdc null mutants were created in the insect vector form of the parasite by double targeted gene replacement. The ⌬adometdc strains were incapable of growth in medium without polyamines; however, auxotrophy could be rescued by spermidine but not by putrescine, spermine, or methylthioadenosine. Incubation of ⌬adometdc parasites in medium lacking polyamines resulted in a drastic increase of putrescine and glutathione levels with a concomitant decrease in the amounts of spermidine and the spermidine-containing thiol trypanothione. Parasites transfected with an episomal ADOMETDC construct were created in both wild type and ⌬adometdc parasites. ADOMETDC overexpression abrogated polyamine auxotrophy in the ⌬adometdc L. donovani. In addition, ADOMETDC overproduction in wild type parasites alleviated the toxic effects of 5-(((Z)-4-amino-2-butenyl)methylamino)-5-deoxyadenosine (MDL 73811), but not pentamidine, berenil, or methylglyoxyl bis(guanylhydrazone), all inhibitors of ADOMETDC activities in vitro. The molecular, biochemical, and genetic characterization of ADOMETDC establishes that it is essential in L. donovani promastigotes and a potential target for therapeutic validation.The protozoan parasite Leishmania donovani is the causative agent of visceral leishmaniasis, a devastating and often fatal disease in humans. The parasite exhibits a digenetic life cycle with the extracellular promastigote residing in the phlebotomine sandfly vector and the intracellular amastigote propagating within the phagolysosome of mammalian macrophages. Because no effective vaccine for leishmaniasis is available, chemotherapy offers the only means of disease treatment. However, the current arsenal of drugs for treating leishmaniasis is far from ideal because these compounds are moderately to highly toxic, the result of their lack of target specificity. Recently, the emergence of drug-resistant strains has exacerbated the need for more selective and efficacious drugs to treat or prevent leishmaniasis or, for that matter, many other parasitic diseases.One pathway that has been exploited successfully in antiparasitic drug regimens is that for the synthesis of polyamines, organic cations that play indispensable roles in key cellular processes such as growth, differentiation, and macromolecular biosynthesis (1, 2). D,L-␣-Difluoromethylornithine (DFMO), 1 an irreversible inhibitor of ornithine decarboxylase (ODC), the first enzyme in the polyamine biosynthetic pathway, can eradicate Trypanosoma brucei infections in both mice (3) and patients with late stage African sleeping sickness (4, 5). The selective window for drug efficacy is not achieved, however, by dissimilar DFMO binding affinities for the T. brucei and human ODC enzymes but r...

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“…and Leishmania spp. were reported to be inhibition of DNA replication and mitochondrial respiratory activity [3,16,17,21]. On the other hand, pentamidine inhibits the DNA replication and mitochondrial respiratory activity of Pneumocystis carinii [28], breaks the double-stranded DNA of Lewis lung carcinoma in a mouse tumor model in vivo [7], inhibits protein biosynthesis in a cell-free rat liver system in vitro [2] and alters lipidic metabolism in Leishmania donovani and L. amazonesis [1].…”

Section: Discussionmentioning

confidence: 99%

“…However, there is no report proving DA resistance of B. gibsoni and B. canis. In trypanosomiasis and leishmaniasis, it has been reported that DA can inhibit the DNA replication and mitochondrial respiratory activity of these pathogens [3,16]. The loss of P2 nucleoside transporter function in Trypanosoma brucei brucei has been implicated in resistance to DA [6].…”

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confidence: 99%

Development and Characterization of a Strain of Babesia gibsoni Resistant to Diminazene Aceturate In Vitro

Hwang

Yamasaki

Nakamura

et al. 2010

The Journal of Veterinary Medical Science

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ABSTRACT. We attempted to develop a strain of Babesia gibsoni resistant to diminazene aceturate (DA), an anti-babesial drug, in vitro. Since the DA-sensitive B. gibsoni strain could survive and proliferate in culture medium containing 1 ng/ml DA, the concentration of DA was gradually increased from 1 to 200 ng/ml. The results showed that the parasites could survive and proliferate in the medium containing 200 ng/ml DA, which was much higher than the 50% inhibitory concentration (IC 50 ) of DA for B. gibsoni. Subsequently, these parasites were removed from erythrocytes and exposed directly to 200 ng/ml DA. They were able to survive and invade fresh erythrocytes, though the DA-sensitive B. gibsoni strain did not survive. Based on these results, the parasites cultured within 200 ng/ml DA were determined to be a DA-resistant B. gibsoni strain. In addition, the IC 50 levels of clindamycin, doxycycline and pentamidine for the DA-resistant B. gibsoni strain were determined. The IC 50 levels of clindamycin, doxycycline and pentamidine for the DA-resistant strain were higher than those for the DA-sensitive strain. The IC 50 of pentamidine for the resistant strain was much greater than that for the DA-sensitive strain. These results indicated that the DA-resistant B. gibsoni strain could have resistance not only to DA, but also to other anti-babesial drugs. In conclusion, we successfully developed a DA-resistant B. gibsoni strain in vitro. Canine babesiosis, a tick-borne hematozoan disease, is caused by Babesia gibsoni and B. canis. This disease is characterized by fever, lethargy, anemia and, in severe cases, death [9,11]. Diminazene aceturate (DA), an antibabesial drug, is an aromatic diamidine derivative. Currently, the mechanism of action of DA on B. gibsoni and B. canis is unknown. DA can temporarily improve the clinical signs of canine babesiosis [4,13]. However, this drug is unable to eliminate the parasites from infected dogs, and relapses often occur [11]. We believe that this is due to the development of drug resistance of B. gibsoni against DA. Collett [8] considered that B. canis surviving DA treatment could develop drug resistance against DA clinically. However, there is no report proving DA resistance of B. gibsoni and B. canis. In trypanosomiasis and leishmaniasis, it has been reported that DA can inhibit the DNA replication and mitochondrial respiratory activity of these pathogens [3,16]. The loss of P2 nucleoside transporter function in Trypanosoma brucei brucei has been implicated in resistance to DA [6]. Likewise, it is possible that B. gibsoni could develop drug resistance against DA.In reports about other anti-babesial drugs, including atovaquone, clindamycin, metronidazole, doxycycline and pentamidine, almost no single drug treatment or combined treatment could eliminate the parasites from the peripheral blood at the dosages used, and the possibility of relapse and development of resistant variants remained [11,13,24,27,32]. From those previous reports, it seems to be difficult to eliminate B. gibson...

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Effect of Berenil on Growth, Mitochondrial DNA and Respiration of Leishmania tarentolae Promastigotes*

Cited by 13 publications

References 16 publications

Comparative Analysis of Different DNA‐Binding Drugs for Leishmaniasis Cure: A Pharmacoinformatics Approach

Comparative Analysis of Different DNA‐Binding Drugs for Leishmaniasis Cure: A Pharmacoinformatics Approach

S-Adenosylmethionine Decarboxylase fromLeishmania donovani

Development and Characterization of a Strain of Babesia gibsoni Resistant to Diminazene Aceturate In Vitro

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