Researchers succeeded in the purification of Plasmodium "tubulin", the molecular building block of cytoskeletal filaments - an important step in the search for novel anti-malarials Despite all efforts, malaria remains one of the deadliest diseases with an estimated 240.000.000 cases and more than 600.000 fatalities in 2020 alone. Sadly, most malaria deaths (60-75 per cent) still occur in children aged under 5 years (World Malaria Report 2021). Thus, reducing the burden of malaria cases and deaths remains a global aim and medical challenge.
Like most eukaryotic cells, Plasmodium falciparum, the causative agent of malaria, relies on its cytoskeletal filaments, including microtubules, for proliferation, growth, and transmission. Indeed, microtubules and their molecular building block tubulin have gained outstanding importance as targets for drug development, in particular for a variety of cancers. Despite the remarkable successes in chemotherapies, the development of parasite-specific tubulin drugs has been neglected. Although P. falciparum and human tubulin are very similar, molecular biologist and first author of the study William Hirst and colleagues reasoned that the tubulins were sufficiently divergent to identify compounds that would selectively disrupt parasite microtubules but would keep the human cytoskeleton intact.
Researchers can now screen for parasite-specific inhibitorsSo far, the limitation for testing this idea was the availability of P. falciparum tubulin. In this study, Hirst and colleagues from Humboldt-Universität zu Berlin, Freie Universität Berlin and the Australian National University in Canberra, succeeded for the first time in the purification and characterization of functional Plasmodium tubulin from infected human red blood cells. Now that functional parasite and human tubulin were available, the researchers could pursue their idea and screen for parasite-specific inhibitors. They tested compounds that had already been suspected to specifically target Plasmodium microtubules, but for which the exact molecular mechanism of parasite growth inhibition remained unknown.
Among the various compounds tested, two compounds exhibited selective toxicity towards parasite microtubules but - importantly - did not inhibit human microtubule growth. Simone Reber, head of the research group, is very enthusiastic about this success. "Our ability to now specifically screen for compounds that disrupt protozoan microtubule growth without affecting human microtubules provides an exciting opportunity for the development of novel, much-needed anti-malarials." she says.
It supported William Hirst and Dominik Fachet and enabled their stay in the lab of Kevin Saliba at the ANU, Canberra.