噻唑类化合物PTC-209HBr靶向受体hSCARB2和衣壳蛋白VP1的抗肠道病毒71机制研究

肠道病毒引起的重大传染病严重危害公众健康，每年可以感染数百万婴幼儿。临床上尚无特异性的抗肠道病毒药物，因此寻找和研制特异性药物在肠道病毒防控中至关重要。肠道病毒衣壳蛋白与宿主细胞受体结合是病毒成功感染宿主的第一步，也是该病毒的致病性和病毒嗜性的决定性因素之一。而该病毒衣壳蛋白VP1和受体hSCARB2抑制剂报道甚少。我们发现PTC-209HBr通过靶向VP1和hSCARB2，从而抑制多种肠道病毒感染。但是PTC-209HBr抗肠道病毒机制和病毒逃逸进化机制还不清楚。我们拟通过肠道病毒的耐药性和适应性研究，探索该病毒对PTC-209HBr耐药性和适应性的逃逸进化途径；通过深入的抗肠道病毒的分子机制研究，揭示PTC-209HBr与VP1和hSCARB2的作用位点，解析PTC-209HBr与受体hSCARB2作用结构。我们的工作为进一步研发广谱抗肠道病毒药物奠定重要基础并提供理论依据。

Enteroviruses can infect millions of infants and young children every year, which are a major threat to the public health. Currently there are no specific anti-enterovirus drugs in clinic. Thus specific enterovirus inhibitors with high efficacy are urgently needed. The first step in successful enteroviral infection and one of the key determinants of viral tropism and pathogenesis is the binding between host cell receptor and capsid protein involved in the recognition of receptors on the surface of host cells. However, there are few reports on enterovirus capsid protein VP1 and receptor hSCARB2 inhibitors. We have preliminarily confirmed that PTC-209HBr exhibited broad-spectrum antiviral activity by targeting enterovirus capsid protein VP1 and receptor hSCARB2. However, the roles of mutants in resistance viruses as well as the binding sites between PTC-209HBr and proteins are unclear. Studies on the mechanism of action, drug resistance and fitness studies will be carried out to elucidate the molecular mechanism of antivirals, and evolutionary pathways to fit and resistant enterovirus inhibitor escape variants which will provide new insights for antiviral research system.