【作者】 张帆；

【导师】 童贻刚； 王洪权；

【作者基本信息】 北京化工大学 ， 制药工程（专业学位）， 2022， 硕士

【摘要】 冠状病毒在自然界中普遍存在,对人、畜、禽类等均有不同程度的危害。迄今已发现7种对人类致病的冠状病毒。其中2003年发现的“SARS-Co V”和2012年发现的“MERS-Co V”曾经给人类造成巨大影响。自2019年末至今,由“SARS-Co V-2”引发的新型冠状病毒肺炎疫情仍在全世界范围内不断蔓延。为应对此次疫情,“老药新用”成为了初始阶段快速有效的应对方式,但面对反复爆发、不断变异的新冠病毒,新药的快速研发工作仍迫在眉睫。本研究从两种不同的抗病毒机制入手,一方面延续目前主流靶向病毒自身的核苷类抗病毒药物的研究,另一方面着眼于靶向宿主寡糖基转移酶的抗病毒机制,共合成38个目标化合物。EIDD-1931(NHC)是目前已经获批上市治疗新型冠状病毒肺炎药物莫诺拉韦的体内代谢产物,它是发挥抗病毒作用的核心结构。由于NHC的极性较强,生物利用度较差,本研究以引入碳链的方式共合成目标化合物14个,旨在降低其极性,提升其细胞通透性。经体外抗HCo V-OC43和HCo V-229E活性评价,全部化合物均具有抗病毒活性。其中有3个化合物的活性优于NHC,可继续深入研究。NGI-1是已报道的由高通量筛选出的寡糖基转移酶抑制剂,在体外研究中已经证实其对登革热、寨卡、新冠病毒等多种病毒具有活性。但其活性有待增强,因此,本研究在NGI-1化合物的5-甲基-噻唑位置进行活性基团的衍生化,共合成目标化合物24个,旨在提升其抗病毒活性。经体外抗HCo V-OC43和HCo V-229E活性评价,其中3个化合物的活性较好,具有继续研究的价值。更多还原

【Abstract】 Coronaviruses are ubiquitous in nature and it does harm to humans,livestock,and poultry in different degrees.Up to now,Seven coronaviruses that are pathogenic to humans have been found.Among them,"SARS-Co V" and "MERS-Co V" have had a great impact on human being,which appeared in2003 and 2012,respectively.Since the end of 2019,the novel coronavirus epidemic caused by "SARS-Co V-2" is still spreading all over the world.To deal with this epidemic,"reuse of old drugs" has become a fast and effective response method in the initial stage.However,in the face of repeated outbreaks and constant mutations of the new coronavirus,the rapid research and development of new drugs is still imminent.In this study,we started with two different antiviral mechanisms.On the one hand,we continued the research of nucleoside antiviral drugs targeting the virus itself,and on the other hand,we focused on the antiviral mechanism targeting host oligosaccharide transferases,and synthesized 38 target compounds.EIDD-1931(NHC)is the in vivo metabolite of molnupiravir,a new drug for the treatment of coronavirus pneumonia.It is the core structure that plays an antiviral role.Due to the strong polarity and poor bioavailability of NHC,14 target compounds were synthesized by introducing carbon chains in this study,aiming to reduce its polarity and improve its cell permeability.All compounds showed antiviral activity to HCo V-OC43 and HCo V-229 E in vitro.Among them,there are three compounds whose activity is better than that of NHC,which can be further studied.NGI-1 is a reported oligosaccharide transferase inhibitor found by high-throughput screening,which has been confirmed to be active against dengue fever,Zika,new coronavirus and other viruses in vitro studies,however its activity needs to be enhanced.Therefore,in this study,the active group of NGI-1 compound was derivatized at the 5-methyl-thiazole position,and a total of 24 target compounds were synthesized to enhance the antiviral activity.In vitro evaluation of anti-HCo V-OC43 and HCo V-229 E showed that three of them had good activity which was worthy of further study.更多还原