DNA Topoisomerase as Drug Target in unicellular protozoan parasite Leishmania donovani

Abstract

Visceral leishmaniasis or Kala-Azar is a neglected tropical disease caused by the unicellular kinetoplastid parasite Leishmania donovani.The treatments available have various shortcomings like toxicity and high cost. The development of resistance in the strains makes thetreatment less effective. Hence, there is a need for new and better treatments. DNA topoisomerases are a group of enzymes presentubiquitously in all organisms from unicellular protozoan parasites to humans. These enzymes control the cell's topological problemscaused by DNA double helix during nucleic acid metabolism. However, the leishmanial topoisomerase (LdTOPILS) is very differentfrom the human topoisomerase in structure, expression, and function. Therefore, LdTOPILS acts as a potent target for newer drugs. Adiverse range of compounds has been developed to date against Leishmanial topoisomerases. This review article describes Leishmaniatopoisomerase enzyme's structural and catalytic activity and Topo-targeted antileishmanial drug development. Therefore, this reviewarticle would be beneficial for researchers to understand the structure-function relationship of topoisomerases with their targetedinhibitors.

Genomic Insight of Leishmania Parasite: In-Depth Review of Drug Resistance Mechanisms and Genetic Mutations

“…AQP2 is a surface channel protein that aids in the passive movement of liquids and tiny noncharged substances through the plasma membrane. More research is required, but an AQP2 mutation may be the cause of pentamidine resistance in Leishmania parasites. , Verapamil, a Ca 2 + channel and P-glycoprotein inhibitor, has been demonstrated to restrict its efflux, resulting in PMD buildup in resistant parasites . Flavonoid dimers were synthesized to avoid pentamidine resistance in Leishmania parasites, and they demonstrated much stronger reversal activity to pentamidine tolerance in L. enriettii , because of increased drug accumulation in mitochondria.…”