Macrofilaricidal Aminoacyl-tRNA Synthetase Inhibitors

描述（由申请人提供）：大多数重要的热带寄生虫病（如淋巴丝虫病）的药物开发由于没有足够的利润潜力而被制药公司遗弃。然而，当寄生虫学学术研究团队和制药公司研究团队共享传染病治疗新分子靶点的选择时，这为合作抗寄生虫药物发现伙伴关系的形成提供了独特的机会。该研究项目的长期目标是临床前开发治疗性AARS酶抑制剂，以根除导致人类丝虫病的线虫寄生虫。丝虫病是世界卫生组织（世卫组织）列出的十大热带寄生虫病之一，但治疗这种疾病的首选药物并不能杀死成虫，而且由于在社区人类控制规划和兽医中广泛使用相同的药物，对耐药性的担忧正在上升。这项新研究计划的目标酶包括丝虫寄生虫和沃尔巴克氏体内共生细菌中表达的独特AARS，这些酶对蠕虫的生存至关重要。

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.