Effects of the antimitotic natural product dolastatin 10, and related peptides, on the human malarial parasite Plasmodium falciparum

B. J. Fennell, S. Carolan, George Pettit, A. Bell

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Microtubule inhibitors from several chemical classes can block the growth and development of malarial parasites, reflecting the importance of microtubules in various essential parasite functions. With the spread of antimalarial drug resistance, there is an urgent need for new approaches to the chemotherapy of this devastating disease. We investigated the effects of two naturally occurring marine peptides, dolastatin 10 and dolastatin 15, and 10 synthetic dolastatin 10-based compounds (auristatins), on cultured malarial parasites of the species most lethal to humans, Plasmodium falciparum. Dolastatin 10 was a more potent inhibitor of P. falciparum than any other previously described microtubule inhibitor, with a median inhibitory concentration (IC50) of 10-10 M. Dolastatin 15 was less active, and compounds of the auristatin series had various potencies. Comparison of the concentrations required to inhibit P. falciparum and mammalian cell proliferation showed that the orders of potency were not the same. Dolastatin 10 and auristatin PE caused arrested nuclear division and apparent disassembly of mitotic microtubular structures in the parasite. The effects of these agents were, superficially at least, similar to those of vinblastine but different from those of paclitaxel. These studies indicate that compounds binding in the 'Vinca domain' of tubulin can be highly potent antimalarial agents.

Original languageEnglish (US)
Pages (from-to)833-841
Number of pages9
JournalJournal of Antimicrobial Chemotherapy
Volume51
Issue number4
DOIs
StatePublished - Apr 1 2003

Fingerprint

dolastatin 10
Antimitotic Agents
Plasmodium falciparum
Biological Products
Parasites
Peptides
Microtubules
Antimalarials
Vinca
Cell Nucleus Division
Vinblastine
Tubulin
Paclitaxel
Growth and Development
Drug Resistance
Inhibitory Concentration 50
Cell Proliferation
Drug Therapy

ASJC Scopus subject areas

  • Pharmacology
  • Microbiology

Cite this

Effects of the antimitotic natural product dolastatin 10, and related peptides, on the human malarial parasite Plasmodium falciparum. / Fennell, B. J.; Carolan, S.; Pettit, George; Bell, A.

In: Journal of Antimicrobial Chemotherapy, Vol. 51, No. 4, 01.04.2003, p. 833-841.

Research output: Contribution to journalArticle

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