Plasmodium falciparum UvrD activities are downregulated by DNA-interacting compounds and its dsRNA inhibits malaria parasite growth

Mohammed Tarique,Renu Tuteja,Moaz Ahmad,Farha Tabassum

doi:10.1186/1471-2091-15-9

Mohammed Tarique, Renu Tuteja + Show 2 more

Open Access

https://doi.org/10.1186/1471-2091-15-9

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Abstract

BackgroundHuman malaria parasite infection and its control is a global challenge which is responsible for ~0.65 million deaths every year globally. The emergence of drug resistant malaria parasite is another challenge to fight with malaria. Enormous efforts are being made to identify suitable drug targets in order to develop newer classes of drug. Helicases play crucial roles in DNA metabolism and have been proposed as therapeutic targets for cancer therapy as well as viral and parasitic infections. Genome wide analysis revealed that Plasmodium falciparum possesses UvrD helicase, which is absent in the human host.ResultsRecently the biochemical characterization of P. falciparum UvrD helicase revealed that N-terminal UvrD (PfUDN) hydrolyses ATP, translocates in 3’ to 5’ direction and interacts with MLH to modulate each other’s activity. In this follow up study, further characterization of P. falciparum UvrD helicase is presented. Here, we screened the effect of various DNA interacting compounds on the ATPase and helicase activity of PfUDN. This study resulted into the identification of daunorubicin (daunomycin), netropsin, nogalamycin, and ethidium bromide as the potential inhibitor molecules for the biochemical activities of PfUDN with IC50 values ranging from ~3.0 to ~5.0 μM. Interestingly etoposide did not inhibit the ATPase activity but considerable inhibition of unwinding activity was observed at 20 μM. Further study for analyzing the importance of PfUvrD enzyme in parasite growth revealed that PfUvrD is crucial/important for its growth ex-vivo.ConclusionsAs PfUvrD is absent in human hence on the basis of this study we propose PfUvrD as suitable drug target to control malaria. Some of the PfUvrD inhibitors identified in the present study can be utilized to further design novel and specific inhibitor molecules.

Highlights

Human malaria parasite infection and its control is a global challenge which is responsible for ~0.65 million deaths every year globally
The results clearly show that ciprofloxacin, morin, nogalamycin, netropsin, daunobrubicin, ethidium bromide and DAPI, (Figure 1A, lanes 3, 9-14 respectively) inhibit the ssDNA dependent ATPase activity of PfUDN under these conditions
Increasing concentration of inhibitors (0.2 to 5.0 μM) was used in the ATPase reaction (Figure 2A-2D, lanes 1-8 in each panel) and the results show that the effective inhibitors are netropsin, daunorubicin, nogalamycin and ethidium bromide with IC50 value ranging from ~3.0 to ~4.5 μM, respectively (Figure 2A-2D) (Table 1)

Summary

Introduction

Human malaria parasite infection and its control is a global challenge which is responsible for ~0.65 million deaths every year globally. Helicases play crucial roles in DNA metabolism and have been proposed as therapeutic targets for cancer therapy as well as viral and parasitic infections. Genome wide analysis revealed that Plasmodium falciparum possesses UvrD helicase, which is absent in the human host. The efforts to identify suitable drug targets to fight with malaria parasite infections are a global concern [1,4] as many previous attempts further studies are required in order to get the insight for the successful development of suitable drugs. The genome wide analysis of P. falciparum helicases revealed that the parasite contains a UvrD helicase while this enzyme is absent in human host [34,35]. The biochemical characterization of this P. falciparum specific UvrD helicase revealed its characteristic biochemical activities [32]

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