Authors

I Hallyburton⁴; S N Hewitt²; D M Dranow²; B Forte⁴; C Jansen⁴; B Baragaña⁴; C Walpole³; W C Van Voorhis¹;  ¹ Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington, United States;  ² Seattle Structural Genomics Center for Infectious Disease (SSGCID), United States;  ³ Structure-guided Drug Discovery Coalition (SDDC), Canada;  ⁴ University of Dundee, UK

Discussion

Plasmodium falciparum (Pf) prolyl-tRNA synthetase (ProRS) is one of the few chemical-genetically validated drug targets for malaria, yet highly selective inhibitors have not been described. In this poster we describe the screening of approximately 40,000 compounds to identify compounds that selectively inhibit Pf ProRS enzyme activity. X-ray crystallography structures were solved for apo, as well as substrate- and inhibitor-bound forms of Pf ProRS. Two new inhibitors of Pf ProRS that bind outside the active site were identified. These two allosteric inhibitors showed >100 times specificity for Pf ProRS compared to HsProRS, demonstrating that this class of compounds could overcome the toxicity related to HsProRS inhibition by halofuginone and its analogues. Initial medicinal chemistry was performed on one of the two compounds, guided by the co-crystallography of the compound with Pf ProRS, and the results can instruct future medicinal chemistry work to optimize these promising new leads for drug development against malaria.