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Antimalarial evaluation of copper(II) nanohybrid solids: inhibition of plasmepsin II, a hemoglobin-degrading malarial aspartic protease from Plasmodium falciparum

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Abstract

A new class of copper(II) nanohybrid solids, LCu(CH3COO)2 and LCuCl2, have been synthesized and characterized by transmission electron microscopy, dynamic light scattering, and IR spectroscopy, and have been found to be capped by a bis(benzimidazole) diamide ligand (L). The particle sizes of these nanohybrid solids were found to be in the ranges 5–10 and 60–70 nm, respectively. These nanohybrid solids were evaluated for their in vitro antimalarial activity against a chloroquine-sensitive isolate of Plasmodium falciparum (MRC 2). The interactions between these nanohybrid solids and plasmepsin II (an aspartic protease and a plausible novel target for antimalarial drug development), which is believed to be essential for hemoglobin degradation by the parasite, have been assayed by UV–vis spectroscopy and inhibition kinetics using Lineweaver–Burk plots. Our results suggest that these two compounds have antimalarial activities, and the IC50 values (0.025–0.032 μg/ml) are similar to the IC50 value of the standard drug chloroquine used in the bioassay. Lineweaver–Burk plots for inhibition of plasmepsin II by LCu(CH3COO)2 and LCuCl2 show that the inhibition is competitive with respect to the substrate. The inhibition constants of LCu(CH3COO)2 and LCuCl2 were found to be 10 and 13 μM, respectively. The IC50 values for inhibition of plasmepsin II by LCu(CH3COO)2 and LCuCl2 were found to be 14 and 17 μM, respectively. Copper(II) metal capped by a benzimidazole group, which resembles the histidine group of copper proteins (galactose oxidase, β-hydroxylase), could provide a suitable anchoring site on the nanosurface and thus could be useful for inhibition of target enzymes via binding to the S1/S3 pocket of the enzyme hydrophobically. Both copper(II) nanohybrid solids were found to be nontoxic against human hepatocellular carcinoma cells and were highly selective for plasmepsin II versus human cathepsin D. The pivotal mechanism of antimalarial activity of these compounds via plasmepsin II inhibition in the P. falciparum malaria parasite is demonstrated.

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Acknowledgments

The authors are thankful to Benn M. Dunn (Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA) for helpful discussion and donating the plasmid for proplasmepsin II. We are also thankful to Vineeta Singh and C.R. Pillai, Parasite Bank at NIMR, for help in performing red blood cell parasite inhibition assays. Thanks are also due to Bhanu Arya, Technical Officer, and Poonam Gupta, Technical Assistant, for excellent technical help during the course of this investigation.

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Authors and Affiliations

  1. Department of Chemistry, University of Delhi, Delhi, 110007, India

    Subash Chandra Mohapatra, Manisha Singla, Brijesh Rathi, Kuldeep Mahiya & Mukesh Kumar

  2. Department of Chemistry, N.R.E.C. College, Khurja, 203131, India

    Hemandra Kumar Tiwari

  3. Protein Biochemistry Division, National Institute of Malaria Research (ICMR), 22 Sham Nath Marg, Delhi, 110054, India

    Arun Sharma

  4. Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Delhi, 110029, India

    Saket Sinha & Shyam Singh Chauhan

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  1. Subash Chandra Mohapatra
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  2. Hemandra Kumar Tiwari
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Correspondence to Subash Chandra Mohapatra.

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Mohapatra, S.C., Tiwari, H.K., Singla, M. et al. Antimalarial evaluation of copper(II) nanohybrid solids: inhibition of plasmepsin II, a hemoglobin-degrading malarial aspartic protease from Plasmodium falciparum . J Biol Inorg Chem 15, 373–385 (2010). https://doi.org/10.1007/s00775-009-0610-9

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  • DOI: https://doi.org/10.1007/s00775-009-0610-9

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