Open AccessArticle
Specific Targeting of Plant and Apicomplexa Parasite Tubulin through Differential Screening Using In Silico and Assay-Based Approaches
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Emmanuelle Soleilhac, Loraine Brillet-Guéguen, Véronique Roussel, Renaud Prudent, Bastien Touquet, Sheena Dass, Samia Aci-Sèche, Vinod Kasam, Caroline Barette, Anne Imberty, Vincent Breton, Marylin Vantard, Dragos Horvath, Cyrille Botté, Isabelle Tardieux, Sylvaine Roy, Eric Maréchal and Laurence Lafanechère
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Abstract
Dinitroanilines are chemical compounds with high selectivity for plant cell α-tubulin in which they promote microtubule depolymerization. They target α-tubulin regions that have diverged over evolution and show no effect on non-photosynthetic eukaryotes. Hence, they have been used as herbicides over decades. Interestingly,
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Dinitroanilines are chemical compounds with high selectivity for plant cell α-tubulin in which they promote microtubule depolymerization. They target α-tubulin regions that have diverged over evolution and show no effect on non-photosynthetic eukaryotes. Hence, they have been used as herbicides over decades. Interestingly, dinitroanilines proved active on microtubules of eukaryotes deriving from photosynthetic ancestors such as
Toxoplasma gondii and
Plasmodium falciparum, which are responsible for toxoplasmosis and malaria, respectively. By combining differential in silico screening of virtual chemical libraries on
Arabidopsis thaliana and mammal tubulin structural models together with cell-based screening of chemical libraries, we have identified dinitroaniline related and non-related compounds. They inhibit plant, but not mammalian tubulin assembly in vitro, and accordingly arrest
A. thaliana development. In addition, these compounds exhibit a moderate cytotoxic activity towards
T. gondii and
P. falciparum. These results highlight the potential of novel herbicidal scaffolds in the design of urgently needed anti-parasitic drugs.
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