1. Voacamine alters Leishmania ultrastructure and kills parasite by poisoning unusual bi-subunit topoisomerase IB.
- Author
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Chowdhury SR, Kumar A, Godinho JLP, De Macedo Silva ST, Zuma AA, Saha S, Kumari N, Rodrigues JCF, Sundar S, Dujardin JC, Roy S, De Souza W, Mukhopadhyay S, and Majumder HK
- Subjects
- Animals, Antiprotozoal Agents administration & dosage, Antiprotozoal Agents isolation & purification, Antiprotozoal Agents therapeutic use, Cell Shape drug effects, DNA Topoisomerases, Type I chemistry, DNA Topoisomerases, Type I genetics, Dose-Response Relationship, Drug, Drug Resistance, Multiple, Enzyme Stability drug effects, Female, Ibogaine administration & dosage, Ibogaine isolation & purification, Ibogaine pharmacology, Ibogaine therapeutic use, Leishmania donovani enzymology, Leishmania donovani growth & development, Leishmania donovani ultrastructure, Leishmania mexicana enzymology, Leishmania mexicana growth & development, Leishmania mexicana ultrastructure, Leishmaniasis, Visceral drug therapy, Leishmaniasis, Visceral parasitology, Lethal Dose 50, Mice, Inbred BALB C, Microscopy, Electron, Scanning, Microscopy, Electron, Transmission, Plant Bark chemistry, Protein Subunits antagonists & inhibitors, Protein Subunits genetics, Protein Subunits metabolism, Recombinant Proteins chemistry, Recombinant Proteins metabolism, Tabernaemontana chemistry, Topoisomerase I Inhibitors administration & dosage, Topoisomerase I Inhibitors isolation & purification, Topoisomerase I Inhibitors therapeutic use, Trypanosoma cruzi enzymology, Trypanosoma cruzi growth & development, Trypanosoma cruzi ultrastructure, Antiprotozoal Agents pharmacology, DNA Topoisomerases, Type I metabolism, Ibogaine analogs & derivatives, Leishmania donovani drug effects, Leishmania mexicana drug effects, Topoisomerase I Inhibitors pharmacology, Trypanosoma cruzi drug effects
- Abstract
Indole alkaloids possess a large spectrum of biological activities including anti-protozoal action. Here we report for the first time that voacamine, isolated from the plant Tabernaemontana coronaria, is an antiprotozoal agent effective against a large array of trypanosomatid parasites including Indian strain of Leishmania donovani and Brazilian strains of Leishmania amazonensis and Trypanosoma cruzi. It inhibits the relaxation activity of topoisomerase IB of L. donovani (LdTop1B) and stabilizes the cleavable complex. Voacamine is probably the first LdTop1B-specific poison to act uncompetitively. It has no impact on human topoisomerase I and II up to 200μM concentrations. The study also provides a thorough insight into ultrastructural alterations induced in three kinetoplastid parasites by a specific inhibitor of LdTop1B. Voacamine is also effective against intracellular amastigotes of different drug unresponsive field isolates of Leishmania donovani obtained from endemic zones of India severely affected with visceral leishmaniasis. Most importantly, this is the first report demonstrating the efficacy of a compound to reduce the burden of drug resistant parasites, unresponsive to SAG, amphotericin B and miltefosine, in experimental BALB/c mice model of visceral leishmaniasis. The findings cumulatively provide a strong evidence that voacamine can be a promising drug candidate against trypanosomatid infections., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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