Štefek Milan, Chalupská Dominika, Chalupský Karel, Zgarbová Michala, Dvořáková Alexandra, Krafčíková Petra, Li Alice Shi Ming, Šála Michal, Dejmek Milan, Otava Tomáš, Chaloupecká Ema, Kozák Jaroslav, Kozic Ján, Vedadi Masoud, Weber Jan, Mertlíková-Kaiserová Helena, Nencka Radim
Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Náměstí 2, Prague 6 166 10, Czech Republic.
Department of Organic Chemistry, Faculty of Science, Charles University, Prague 128 00, Czech Republic.
ACS Omega. 2023 Jul 21;8(30):27410-27418. doi: 10.1021/acsomega.3c02815. eCollection 2023 Aug 1.
The search for new drugs against COVID-19 and its causative agent, SARS-CoV-2, is one of the major trends in the current medicinal chemistry. Targeting capping machinery could be one of the therapeutic concepts based on a unique mechanism of action. Viral RNA cap synthesis involves two methylation steps, the first of which is mediated by the nsp14 protein. Here, we rationally designed and synthesized a series of compounds capable of binding to both the -adenosyl-l-methionine and the RNA-binding site of SARS-CoV-2 nsp14 -methyltransferase. These hybrid molecules showed excellent potency, high selectivity toward various human methyltransferases, nontoxicity, and high cell permeability. Despite the outstanding activity against the enzyme, our compounds showed poor antiviral performance in vitro. This suggests that the activity of this viral methyltransferase has no significant effect on virus transcription and replication at the cellular level. Therefore, our compounds represent unique tools to further explore the role of the SARS-CoV-2 nsp14 methyltransferase in the viral life cycle and the pathogenesis of COVID-19.
寻找针对新型冠状病毒肺炎（COVID-19）及其病原体严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的新药是当前药物化学的主要趋势之一。基于独特的作用机制，靶向封端机制可能是一种治疗理念。病毒RNA帽合成涉及两个甲基化步骤，其中第一步由nsp14蛋白介导。在此，我们合理设计并合成了一系列能够与SARS-CoV-2 nsp14 N7-甲基转移酶的S-腺苷-L-甲硫氨酸和RNA结合位点结合的化合物。这些杂合分子表现出优异的效力、对各种人类甲基转移酶的高选择性、无毒性和高细胞渗透性。尽管对该酶具有出色的活性，但我们的化合物在体外显示出较差的抗病毒性能。这表明这种病毒甲基转移酶的活性在细胞水平上对病毒转录和复制没有显著影响。因此，我们的化合物是进一步探索SARS-CoV-2 nsp14甲基转移酶在病毒生命周期和COVID-19发病机制中作用的独特工具。
