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Publication Abstract from PubMed

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.

Inhibiting parasite proliferation using a rationally designed anti-tubulin agent.,Gaillard N, Sharma A, Abbaali I, Liu T, Shilliday F, Cook AD, Ehrhard V, Bangera M, Roberts AJ, Moores CA, Morrissette N, Steinmetz MO EMBO Mol Med. 2021 Nov 8;13(11):e13818. doi: 10.15252/emmm.202013818. Epub 2021 , Oct 18. PMID:34661376^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.