Inhibiting parasite proliferation using a rationally designed anti‐tubulin agent
Natacha Gaillard, Ashwani Sharma, Izra Abbaali, Tianyang Liu, Fiona Shilliday, Alexander D. Cook, Valentin A. Ehrhard, Mamata Bangera, A. J. Roberts, Carolyn A. Moores, Naomi S. Morrissette, Michel O. Steinmetz
Abstract
Infectious diseases caused by apicomplexan parasites remain a global public health threat. The presence of multiple ligand-binding sites in tubulin makes this protein an attractive target for anti-parasite drug discovery. However, despite remarkable successes as anti-cancer agents, the rational development of protozoan parasite-specific tubulin drugs has been hindered by a lack of structural and biochemical information on protozoan tubulins. Here, we present atomic structures for a protozoan tubulin and microtubule and delineate the architectures of apicomplexan tubulin drug-binding sites. Based on this information, we rationally designed the parasite-specific tubulin inhibitor parabulin and show that it inhibits growth of parasites while displaying no effects on human cells. Our work presents for the first time the rational design of a species-specific tubulin drug providing a framework to exploit structural differences between human and protozoa tubulin variants enabling the development of much-needed, novel parasite inhibitors.