Multistage and transmission-blocking tubulin targeting potent antimalarial discovered from the open access MMV pathogen box

The development of resistance to current antimalarial therapies remains a significant source of concern. To address this risk, new drugs with novel targets in distinct developmental stages of Plasmodium parasites are required. In the current study, we have targeted P. falciparum Tubulin (PfTubulin) proteins which represent some of the potential drug targets for malaria chemotherapy. Plasmodial Microtubules (MTs) play a crucial role during parasite proliferation, growth, and transmission, which render them highly desirable targets for the development of next-generation chemotherapeutics. Towards this, we have evaluated the antimalarial activity of Tubulin targeting compounds received from the Medicines for Malaria Venture (MMV) Pathogen Box against the human malaria parasite, P. falciparum including 3D7 (chloroquine and artemisinin sensitive strain), RKL-9 (chloroquine-resistant strain), and R539T (artemisinin-resistant strain). At nanomolar concentrations, the filtered-out compounds exhibited pronounced multistage antimalarial effects across the parasite life cycle, including intra-erythrocytic blood stages, liver stage parasites, gametocytes, and ookinetes. Concomitantly, these compounds were found to impede male gamete ex-flagellation, thus showing their transmission-blocking potential. Target mining of these potent compounds, by combining in silico, biochemical and biophysical assays, implicated PfTubulin as their molecular target, which may possibly act by disrupting MT assembly dynamics by binding at the interface of alpha-beta Tubulin-dimer. Further, the promising ADME profile of the parent scaffold supported its consideration as a lead compound for further development. Thus, our work highlights the potential of targeting PfTubulin proteins in discovering and developing next-generation, multistage antimalarial agents against Multi-Drug Resistant (MDR) malaria parasites.

Automated summary

The development of resistance to current antimalarial therapies is a major concern. In this study, the antimalarial activity of Tubulin targeting compounds against P. falciparum was evaluated. The compounds showed multistage antimalarial effects and potential transmission-blocking activity. Target mining implicated PfTubulin as their molecular target. These compounds have potential for further development as next-generation antimalarial agents.