Wang Ming-Shu, Gong Yi, Zhuo Lin-Sheng, Shi Xing-Xing, Tian Yan-Guang, Huang Chang-Kang, Huang Wei, Yang Guang-Fu
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, China.
Nanjing Shuohui Pharmatechnology Co., Ltd., Nanjing 210046, China.
Research (Wash D C). 2022 Jul 22;2022:9852518. doi: 10.34133/2022/9852518. eCollection 2022.
Conventional methods of drug design require compromise in the form of side effects to achieve sufficient efficacy because targeting drugs to specific organs remains challenging. Thus, new strategies to design organ-specific drugs that induce little toxicity are needed. Based on characteristic tissue niche-mediated drug distribution (TNMDD) and patterns of drug metabolism into specific intermediates, we propose a strategy of distribution- and metabolism-based drug design (DMBDD); through a physicochemical property-driven distribution optimization cooperated with a well-designed metabolism pathway, SH-337, a candidate potassium-competitive acid blocker (P-CAB), was designed. SH-337 showed specific distribution in the stomach in the long term and was rapidly cleared from the systemic compartment. Therefore, SH-337 exerted a comparable pharmacological effect but a 3.3-fold higher no observed adverse effect level (NOAEL) compared with FDA-approved vonoprazan. This study contributes a proof-of-concept demonstration of DMBDD and provides a new perspective for the development of highly efficient, organ-specific drugs with low toxicity.
传统的药物设计方法需要以副作用为代价进行权衡，以实现足够的疗效，因为将药物靶向特定器官仍然具有挑战性。因此，需要设计低毒性的器官特异性药物的新策略。基于特征性组织微环境介导的药物分布（TNMDD）和药物代谢为特定中间体的模式，我们提出了一种基于分布和代谢的药物设计策略（DMBDD）；通过物理化学性质驱动的分布优化与精心设计的代谢途径相结合，设计了一种候选钾竞争性酸阻滞剂（P-CAB）SH-337。SH-337长期在胃中显示出特异性分布，并迅速从全身循环中清除。因此，与FDA批准的沃克帕唑相比，SH-337发挥了相当的药理作用，但未观察到不良反应水平（NOAEL）高出3.3倍。本研究为DMBDD提供了概念验证，并为开发高效、低毒的器官特异性药物提供了新的视角。
