Improving chemotherapy outcomes with proprietary molecules targeting the human mi

描述(申请人提供)：虽然肠道中的非致病微生物通常为我们提供了许多健康和消化方面的好处，但特定的微生物群落活动也是某些化疗和止痛药产生严重、有时是致命的胃肠道(GI)副作用的原因。这种共生细菌引起的药物毒性最危险、最广为人知的例子是化疗药物伊立替康(也称为CPT-11)，它会引起频繁、剧烈和剂量限制的腹泻。CPT-11的毒性作用发生在较低的GI，这是由于一种微生物酶-细菌β-葡萄糖醛酸苷酶的糖代谢活性所致，该酶将CPT-11的非活性代谢物转化为损害大肠的“重新激活的”细胞毒素形式。细菌介导的毒性机制与使用非类固醇抗炎药(NSAIDs)相关的小肠溃疡的机制相同。该项目旨在开发一种新型的治疗佐剂，选择性地针对细菌β-葡萄糖醛酸苷酶的这种有害活性，在不损害共生和共生肠道菌群的情况下预防或治疗CPT-11引起的腹泻。我们之前曾报道，口服该酶的小分子抑制剂(INH-1)可以缓解CPT-11引起的小鼠胃肠道损伤和血性腹泻。INH-1对微生物和哺乳动物细胞无致死作用，也不阻断哺乳动物β-葡萄糖醛酸酶的活性。为了进一步推进这项技术，我们建议合成和表征新型InH-1类似物，用于标准细菌和哺乳动物蛋白质和细胞检测中的效力、选择性和细胞毒性。我们的目标是设计新的分子，使其具有很少的或没有口服生物利用度，以最大限度地提高肠道的局部治疗效果，并将任何全身副作用的可能性降至最低。该项目的这一阶段旨在确定一种在药学上优于异烟肼-1的分子，该分子可以作为该项目下一阶段进一步优化的主导系列，最终目标是确定一种用于未来临床测试的专利药物。S预计，这项技术的使用将扩展到其他化疗药物和大多数具有相同毒性机制的非甾体抗炎药。

DESCRIPTION (provided by applicant): Although non-pathogenic microbes that reside in our intestines generally provide us with numerous health and digestive benefits, a specific microfloral activity is also responsible for the severe and sometimes deadly gastrointestinal (GI) side effects of certain chemotherapeutic and pain medications. The most dangerous and well-understood example of this commensal bacteria-induced drug toxicity is the chemotherapeutic agent irinotecan (also called CPT-11), which produces frequent, intense, and dose-limiting diarrhea. The toxic effects of CPT-11 occur in the lower GI as a result of the sugar-metabolizing activity of a microbial enzyme, the bacterial ?-glucuronidase, which converts an inactive metabolite of CPT-11 into a "reactivated" cytotoxic form that damages the large intestine. The same mechanism of bacterial-mediated toxicity is responsible for ulcerations of the small intestine associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs). This project aims to develop a new class of therapeutic adjuvants that selectively targets this deleterious activity of bacterial ?-glucuronidases to prevent or treat CPT-11-induced diarrhea without harming the commensal and symbiotic intestinal flora. We previously reported that oral delivery of a small molecule inhibitor (Inh-1) of this enzyme relieved the GI damage and bloody diarrhea caused by CPT-11 in mice. Inh-1 was not lethal to microbial or mammalian cells and did not block the activity of mammalian ?-glucuronidase. To further advance this technology, we propose to synthesize and characterize novel analogues of Inh-1 for potency, selectivity, and cytotoxicity in standard bacterial and mammalian protein and cellular assays. We aim to engineer new molecules to possess little or no oral bioavailability to maximize the local therapeutic effects in the gut and minimize the potential for any systemic side effects. This phase of the project aims to identify a pharmaceutically superior molecule to Inh-1 that could serve as a lead series for further optimization in the next phase of this project, ultimately with the goal of identifying a proprietary drug for future clinical testing. The use of this technology s expected to extend to other chemotherapeutics and most NSAIDs that share this same mechanism of toxicity.