Macrofilaricidal Aminoacyl-tRNA Synthetase Inhibitors

描述（由申请人提供）：治疗最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，当一个学术寄生虫学研究团队和一个制药公司研究小组共享传染病治疗的新分子靶点时，这为合作抗寄生虫药物发现伙伴关系的形成提供了一个独特的机会。本研究计划的长期目标是临床前开发治疗性阿尔斯酶抑制剂，以根除引起人类丝虫病的线虫寄生虫。 丝虫病是世界卫生组织（WHO）排名前十位的热带寄生虫病之一，但治疗这种疾病的药物并不能杀死蠕虫，而且由于在社区人类控制计划和兽医学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中表达的独特阿尔斯，以及对蠕虫生存力至关重要的沃尔巴克氏体内共生细菌中的酶。 我们的方法使用1）重组丝虫和沃尔巴克氏体MRS和2）基于蛋白质结构的药物设计技术，对专有化学品和天然产物文库进行高通量筛选。 通过使用MSU开发的基于蛋白质结构的设计软件SLIDE（筛选具有诱导拟合对接的配体），使筛选成本最小化。 抑制剂的原子结构：酶复合物的晶体学解决，作为模板的配体搜索，铅化合物优化，并在体外寄生虫杀灭试验的验证。 选择具有最佳药理特性的新型酶抑制剂用于大规模有机合成和未来的临床阶段研究。 阿尔斯是一个非常重要的结构异质性酶家族，可以使用分子和生物信息学技术的组合来鉴定。该计划建立的跨学科伙伴关系为未来的传染病治疗研究提供了基础设施和模型，以对抗人类细菌，真菌，单细胞和多细胞寄生虫的全谱，以及人类疾病的昆虫媒介。

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.