Abstract
Diospyrin is a plant product that has significant inhibitory effect on the growth of Leishmania donovani promastigotes. This compound inhibits the catalytic activity of DNA topoisomerase I of the parasite. Like camptothecin, it induces topoisomerase I mediated DNA cleavage in vitro. Treatment of DNA with diospyrin before addition of topoisomerase I has no effect. Preincubation of topoisomerase I with diospyrin before the addition of DNA in the relaxation reaction increases this inhibition. Our results suggest that this bis-naphthoquinone compound exerts its inhibitory effect by binding with the enzyme and stabilizing the topoisomerase I-DNA “cleavable complex.” Diospyrin is a specific inhibitor of the parasitic topoisomerase I. It does not inhibit type II topoisomerase ofL. donovani and requires much higher concentrations to inhibit type I topoisomerase of calf thymus. The potent inhibitory effect of diospyrin on type I DNA topoisomerase fromL. donovani can be exploited for rational drug design in human leishmaniasis.
Footnotes
- Received March 2, 1998.
- Accepted August 31, 1998.
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Send reprint requests to: Dr. Hemanta K. Majumder, Molecular Parasitology Laboratory, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Calcutta −700 032. E-mail:iichbio{at}giascl01.vsnl.net.in
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↵1 Current affiliation: Department of Pharmacology, University of Texas South Western Medical Center at Dallas, Dallas, TX 75235.
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This work was supported by grants from Department of Biotechnology, Government of India (BT/R&D/15/26/91 and BT/PRO/493/MED/09/096/96) to H.K.M. and University Grants Commission, India and International Foundation for Science, Sweden (Grant No. 1836/F-2) to B.H.
- The American Society for Pharmacology and Experimental Therapeutics
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