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

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.

Cellular Effects of Curcumin on Plasmodium falciparum Include Disruption of Microtubules

“…To compare these results with those seen for known microtubule destabilizing and stabilizing drugs, we treated cultures with paclitaxel and vinblastine (Figure 6 B, C). Paclitaxel treatment (1 µM for 6 hours) has been shown to result in the appearance of thick rod-like microtubules whereas vinblastine treatment (20 µM for 6 hours) has the converse effect and results in diffuse tubulin staining [35], [44] in P. falciparum . We treated cultures for 24 hours with lower concentrations of paclitaxel and vinblastine (500 nM and 100 nM respectively).…”

“…The primary antibody used for tubulin immunofluorescence (a kind gift from Dr. Angus Bell, Trinity College, Dublin) was raised in rabbit against a P. falciparum specific beta tubulin peptide [35]. Acyl Carrier Protein (ACP) antibody specific for P. falciparum (a kind gift from Prof. Geoff McFadden, The University of Melbourne) was used for apicoplast immunofluorescence.…”

Antimalarial Peptides: The Long and the Short of It

“…The known microtubule inhibitors dolastatin 10 ( Fig. (2)) and auristatin PE were most potent on schizonts, caused growth arrest or delay at the schizont stage, and eliminated normal mitotic structures [92]. Microtubules are considered to have potential as antimalarial drug targets and are already exploited by a number of antiparasitic drugs [93].…”

“…Microtubules are considered to have potential as antimalarial drug targets and are already exploited by a number of antiparasitic drugs [93]. SAR for the dolastatin/auristatin series showed some differences for parasites and human cells but no derivative was clearly parasite-selective [92].…”

Biologically active compounds from natural and marine natural organisms with antituberculosis, antimalarial, leishmaniasis, trypanosomiasis, anthelmintic, antibacterial, antifungal, antiprotozoal, and antiviral activities

“…The antimalarial activity of dolastatin 10, a peptide microtubule inhibitor isolated from the sea hare D. auricularia which is a potent anticancer drug. Although study was described and dolastatin 10 showed potent inhibition of P. falciparum (IC 50 = 0.1 nM) by affecting the schizont stage of intraerythrocytic development, which has the highest concentration of tubulin, the investigators concluded that dolastatin 10 was an "unpromising basis for further antimalarial evaluation" because of the lack of marked selectivity for parasite over mammalian cells (Fennell et al, 2003). The manzamine alkaloids as potential antimalarial agents, Manzamine A was observed to be particularly active against P. falciparum (D6 clone, IC 50 = 4.5 ng/ml) and P. falciparum (chloroquineresistant W2 clone, IC 50 = 8.0 ng/ml), which compared well with artemisinin used as a control (IC 50 = 10 and 6.3 ng/ml, respectively) .…”