Macrofilaricidal Aminoacyl-tRNA Synthetase Inhibitors

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DESCRIPTION (provided by applicant): Drug development for most important tropical parasitic diseases, such as lymphatic filariasis, has been orphaned by pharmaceutical companies as not having enough profit potential. However, when the choice of a novel molecular target for infectious diseases therapeutics is shared between an academic parasitology research team and a pharmaceutical company research group, this provides a unique opportunity for nucleation of a collaborative anti-parasite drug discovery partnership. The long-term goal of this research program is the pre-clinical development of therapeutic AARS enzyme inhibitors to eradicate the nematode parasites that cause human filariasis. Filariasis is one of the top ten tropical parasitic diseases ranked by the World Health Organization (WHO), yet the drug of choice to treat this disease does not kill adult worms, and concerns for drug resistance are rising because of wide spread use of the same drugs in community-based human control programs and veterinary medicine. The enzymes targeted by this new research program include both the unique AARS expressed in filarial parasites and those within the Wolbachia endosymbiotic bacteria that are essential for worm viability. Our approach couples high throughput screening of proprietary chemical and natural product libraries using 1) recombinant filarial and Wolbachia MRS and 2) protein structure-based drug design techniques. Screening costs are minimized by the use of SLIDE (Screening for Ligands with Induced Fit Docking) protein structure based design software developed at MSU. Atomic structures of inhibitor:enzyme complexes are solved crystallographically, serving as templates for ligand searches, lead compound optimization, and validation by in vitro parasite killing assays. Novel enzyme inhibitors with the best pharmacological properties are selected for large-scale organic synthesis and future clinical phase studies. AARS are a critically important family of structurally heterogeneous enzymes that can be identified using a combination of molecular and bioinformatic techniques. The interdisciplinary partnership established by this program provides an infrastructure and model for future infectious disease therapeutics research to combat the full spectrum of bacterial, fungal, unicellular, and multicellular parasites of man, as well as insect vectors of human disease.