Macrofilaricidal Aminoacyl-tRNA Synthetase Inhibitors

描述(申请人提供)：针对最重要的热带寄生虫病的药物开发，如淋巴丝虫病，一直被制药公司孤立，因为没有足够的盈利潜力。然而，当学术寄生虫学研究小组和制药公司研究小组共享传染病治疗的新分子靶标的选择时，这为合作的抗寄生虫药物发现伙伴关系的形成提供了独特的机会。这项研究计划的长期目标是在临床前开发治疗性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(WHO)排名前十的热带寄生虫病之一，但治疗这种疾病的首选药物并不能杀死成虫，而且由于相同药物在社区人类控制项目和兽医中的广泛使用，人们对耐药性的担忧日益加剧。这项新的研究计划针对的酶包括丝虫寄生虫中表达的独特的AARs和沃尔巴克氏菌内共生菌中对蠕虫生存至关重要的那些AARs。 我们的方法结合了使用1)重组丝虫和沃尔巴克氏菌MRS和2)基于蛋白质结构的药物设计技术对专有化学和天然产物库进行高通量筛选。通过使用密歇根州立大学开发的基于蛋白质结构的设计软件SLICE(筛选具有诱导匹配对接的配体)，将筛选成本降至最低。抑制剂的原子结构：酶复合体是结晶学解析的，用作配基搜索、先导化合物优化和体外寄生虫杀灭试验验证的模板。具有最佳药理性能的新型酶抑制剂被用于大规模有机合成和未来的临床阶段研究。AARs是一个重要的结构异质性酶家族，可以利用分子和生物信息学技术相结合的方法进行鉴定。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，以对抗人类的细菌、真菌、单细胞和多细胞寄生虫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.