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Protein Pept Lett. 2019 Feb 28. doi: 10.2174/0929866526666190301114012. [Epub ahead of print]

Repurposing glyburide as antileishmanial agent to fight against leishmaniasis.

Author information

1
Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al Majmaah, 11952. Saudi Arabia.
2
Infection and Immunity Lab, Department of Biotechnology, Jamia Millia Islamia (A Central University), New Delhi. India.
3
Department of Basic Medical Sciences, College of Medicine, Majmaah University, Al Majmaah, 11952. Saudi Arabia.

Abstract

BACKGROUND:

Leishmaniasis is caused by a protozoan parasite, Leishmania. It is common in more than 98 countries throughout the world. Due to insufficient availability of antileishmanial chemotherapeutics, it is an urgent need to search for new molecules which have better efficacy, low toxicity, and low cost.

OBJECTIVES:

There is a high rate of diabetes cases throughout the world that is why we planned to test the antileishmanial activity of glyburide, an effective sugar lowing drug used for the treatment of diabetes. In this study, glyburide showed a significant decrease in the parasite growth and survival in vitro in a dose-dependent manner.

METHODS:

Anti-leishmanial activity of glyburide was checked by culturing Leishmania donovani promastigotes in the presence of glyburide in a dose and time dependent manner. Docking study against Leishmania donovani-Trypanothione synthetase (LdTrySyn) protein was performed using Autodock Vina tool.

RESULTS:

Growth reversibility assay shows that growth of treated parasite was not reversed when transferred to fresh culture media after 7 days. Moreover, docking studies show efficient interactions of glyburide with key residues in the catalytic site of Leishmania donovani-Trypanothione synthetase (LdTrySyn), a very important leishmanial enzyme involved in parasites survival by detoxification of nitric oxide (NO) species, generated by the mammalian host as a defense mechanism. Thus this study proves that the drug-repurposing is a state of art strategy for identification of new and potent antileishmanial molecules.

CONCLUSION:

The results suggest that glyburide binds to LdTrySyn and inhibits its activity that further leads to altered parasite morphology and inhibition of parasite growth. Glyburide may also be used in combination with other anti-leishmanial drugs to potentiate the response of the chemotherapy. Overall this study provides information about combination therapy as well as a single drug treatment for the infected patients suffering from diabetes. This study also provides raw information for further in vivo disease model studies to confirm the hypothesis.

KEYWORDS:

Leishmania; Leishmaniasis; Trypanothione synthetase; docking; drug repurposing; glyburide; protozoan

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