Ipglycermides Novel potent and selective inhibitors of parasitic phosphoglycerate mutase

Ipglycermides 新型有效且选择性的寄生磷酸甘油酸变位酶抑制剂

• 批准号: 10011390
• 负责人: James Inglese
• 金额: $ 24.9万
• 依托单位: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10011390
• 关键词: Affinity; Animal Model; Binding Sites; Biological Assay; Boston; Caenorhabditis elegans; Categories; Cell Membrane Permeability; Cell model; Chemicals; Coenzymes; Collaborations; Crystallization; Cyclic Peptides; Development; Enzymes; Filarial Elephantiases; Infectious Agent; Kansas; Laboratories; Lead; Metabolic; Molecular; Mutate; Nematoda; Onchocerciasis; Organism; Orthologous Gene; Parasites; Pathogenicity; Peptide Library; Peptides; Phase; Phosphoglycerate Mutase; Publishing; Structure; System; Testing; Therapeutic; Tokyo; Work; analog; base; college; design; inhibitor/antagonist; insight; membrane activity; novel; phosphoglycerate; screening

This project has advanced from our Target-based Assays and Screening Strategies for Chemical Probe and Therapeutic Lead Discovery category In continued and expanded collaboration with Prof. H. Suga (U. Tokyo), Prof. C. Hoffman (Boston College) and Scott Lovell (U. Kansas) the ADST laboratory has developed peptide macrocycles targeting this essential metabolic enzyme of the pathogenic nematode using novel cyclic peptide libraries and affinity selection and enrichment approaches. The work describing the initial phase of this project was published in 2017. This project has resulted in the discovery and characterization of Ipglycermides, the first inhibitor class that potently and selectively inhibits iPGM from all nematodes species thus far tested. A model organism C. elegans systems is being developed to test the activity of membrane permeable analogs on the viability of the organism. The binding site interaction revealed from a co-crystal structure have provided general molecular insights for the design of analogs now being evaluated in across a panel of iPGM orthologs with the eventual aim to evaluate in the secondary cell and model organism assays now under development.

该项目是从我们的化学探针和治疗性先导化合物发现类别的基于目标的测定和筛选策略发展而来的 通过与 H. Suga 教授（东京大学）、C. Hoffman 教授（波士顿学院）和 Scott Lovell（堪萨斯大学）的持续和扩大合作，ADST 实验室开发了针对致病线虫的这种重要代谢酶的肽大环化合物使用新型环肽库以及亲和力选择和富集方法。描述该项目初始阶段的著作于 2017 年发表。 该项目导致了 Ipglycermides 的发现和表征，这是第一个能够有效、选择性地抑制迄今为止测试的所有线虫物种的 iPGM 的抑制剂。 正在开发一种模型生物体线虫系统，以测试膜渗透类似物对生物体活力的活性。 共晶结构揭示的结合位点相互作用为类似物的设计提供了一般分子见解，目前正在一系列 iPGM 直系同源物中进行评估，最终目标是在目前正在开发的次级细胞和模型生物测定中进行评估。