PDF(Pubmed)
Abstract：
Protein seldom performs biological activities in isolation. Understanding the protein-protein interactions\' physical rewiring in response to pathological conditions or pathogen infection can help advance our comprehension of disease etiology, progression, and pathogenesis, which allow us to explore the alternate route to control the regulation of key target interactions, timely and effectively. Nonalcoholic steatohepatitis (NASH) is now a global public health problem exacerbated due to the lack of appropriate treatments. The most advanced anti-NASH lead compound (selonsertib) is withdrawn, though it is able to inhibit its target Apoptosis signal-regulating kinase 1 (ASK1) completely, indicating the necessity to explore alternate routes rather than complete inhibition. Understanding the interaction fingerprints of endogenous regulators at the molecular level that underpin disease formation and progression may spur the rationale of designing therapeutic strategies. Based on our analysis and thorough literature survey of the various key regulators and PTMs, the current review emphasizes PPI-based drug discovery\'s relevance for NASH conditions. The lack of structural detail (interface sites) of ASK1 and its regulators makes it challenging to characterize the PPI interfaces. This review summarizes key regulators interaction fingerprinting of ASK1, which can be explored further to restore the homeostasis from its hyperactive states for therapeutics intervention against NASH.
摘要：
蛋白质很少单独进行生物活性。了解蛋白质-蛋白质相互作用对病理状况或病原体感染的物理重新连接有助于提高我们对疾病病因的理解。programming,和发病机制，这使我们能够探索控制关键目标相互作用调节的替代途径，及时有效。由于缺乏适当的治疗方法，非酒精性脂肪性肝炎（NASH）现在是一个全球性的公共卫生问题。最先进的抗NASH先导化合物（selonsertib）被撤回，尽管它能够完全抑制其靶标凋亡信号调节激酶1（ASK1），表明有必要探索替代路线，而不是完全抑制。在分子水平上了解内源性调节因子的相互作用指纹，这些指纹是疾病形成和进展的基础，可能会激发设计治疗策略的理论基础。根据我们对各种关键监管机构和PTM的分析和深入的文献调查，当前的审查强调了基于PPI的药物发现与NASH条件的相关性。缺乏ASK1及其调节器的结构细节(接口位点)使得表征PPI接口具有挑战性。这篇综述总结了ASK1的关键调节因子相互作用指纹图谱，可以进一步探索从其过度活跃状态恢复体内平衡，以治疗NASH。
