SARS-CoV-2 3C-樣蛋白酶抑制劑的發現與評估

Abstract

由 SARS-CoV-2 引起的嚴重特殊傳染性肺炎（COVID-19）在全球造成了嚴重的疫情與高致死率，開發有效的抗病毒藥物刻不容緩。SARS-CoV-2 3C 樣蛋白酶（3C-like protease, 3CLpro）在病毒複製過程中扮演關鍵角色，是極具潛力的藥物標的，但使用 Paxlovid 已產生抗藥株。本研究旨在尋找針對 SARS-CoV-2 3CLpro 的新型抑制劑。透過生化活性篩選，我們成功鑑定出具備高度抑制活性的強效化合物。為了進一步探討其分子結合模式，本研究以此強效化合物進行了系統性的蛋白質結晶條件篩選與優化。雖然目前尚未取得可用於繞射的複合物晶體結構，但本研究已成功建立初步的共結晶篩選條件。本研究成果不僅發現了具潛力的候選抑制劑，亦為後續結構解析與合理藥物優化提供了關鍵的基礎。

The global pandemic of COVID-19, caused by SARS-CoV-2, has led to massive mortality, highlighting the urgent need for effective antiviral therapeutics. The SARS-CoV-2 3C-like protease (3CLpro) plays an indispensable role in viral replication and represents an attractive target for drug discovery, but the resistant strains against Paxlovid have emerged. In this study, we successfully identified highly potent compounds demonstrating robust inhibitory activity against SARS-CoV-2 3CLpro through biochemical screening. To further investigate the molecular binding model, systematic protein crystallization screening and optimization were conducted for the protease-inhibitor complexes. Although diffraction-quality crystal structures have yet to be obtained, preliminary co-crystallization conditions have been successfully established. Our findings not only present promising candidate inhibitors but also lay a critical foundation for future structural determination and rational drug optimization.