Antimitotic herbicides bind to an unidentified site on malarial parasite tubulin and block development of liver-stage Plasmodium parasites.

摘要: Malarial parasites are exquisitely susceptible to a number of microtubule inhibitors but most these compounds also affect human microtubules. Herbicides the dinitroaniline and phosphorothioamidate classes however some plant protozoal cells not mammalian ones. We have previously shown that herbicides block schizogony in erythrocytic lethal malaria, Plasmodium falciparum, disrupt their mitotic spindles, bind selectively parasite tubulin. Here we show for first time antimitotic development malarial liver stage. Structure-based design novel antimalarial agents binding tubulin at herbicide site, which presumably exists on (some) tubulins ones, can therefore constitute an important transmission blocking approach. The nature this site is controversial, with three overlapping non-identical locations α-tubulin proposed literature. tested validity sites by (i) using site-directed mutagenesis introduce six amino acid changes designed occlude them, (ii) producing resulting recombinantly Escherichia coli (iii) measuring affinity amiprophosmethyl oryzalin proteins comparison wild-type fluorescence quenching. had little or no effect, dissociation constants (Kd) more than 1.3-fold (amiprophosmethyl) 1.6-fold (oryzalin) higher wild-type. conclude impair stage as well blood location remains be proven.