We present a near-term treatment strategy to tackle pandemic outbreaks of coronaviruses with no specific drugs/vaccines by combining evolutionary and physical principles to identify conserved viral domains containing druggable Zn-sites that can be targeted by clinically safe Zn-ejecting compounds. By applying this strategy to SARS-CoV-2 polyprotein-1ab, we predicted multiple labile Zn-sites in papain-like cysteine protease (PL^pro), nsp10 transcription factor, and nsp13 helicase. These are attractive drug targets because they are highly conserved among coronaviruses and play vital structural/catalytic roles in viral proteins indispensable for virus replication. We show that five Zn-ejectors can release Zn²⁺ from PL^pro and nsp10, and clinically-safe disulfiram and ebselen can not only covalently bind to the Zn-bound cysteines in both proteins, but also inhibit PL^pro protease. We propose combining disulfiram/ebselen with broad-spectrum antivirals/drugs to target different conserved domains acting at various stages of the virus life cycle to synergistically inhibit SARS-CoV-2 replication and reduce the emergence of drug resistance.

中文翻译：

---

通过临床安全的锌喷射器对多个保守的 SARS-CoV-2 结构域中的功能性半胱氨酸进行多靶向

我们提出了一种近期治疗策略，通过结合进化和物理原理来识别包含可药物锌位点的保守病毒结构域，无需特定药物/疫苗即可应对冠状病毒的大流行爆发，这些病毒结构域可以被临床安全的锌喷射化合物靶向。通过将此策略应用于 SARS-CoV-2 多蛋白-1ab，我们预测了木瓜蛋白酶样半胱氨酸蛋白酶 (PL ^pro )、nsp10 转录因子和 nsp13 解旋酶中的多个不稳定 Zn 位点。这些是有吸引力的药物靶点，因为它们在冠状病毒中高度保守，并且在病毒复制不可或缺的病毒蛋白中发挥重要的结构/催化作用。我们发现五个Zn-喷射器可以从PL ^{pro和nsp10 中释放Zn 2+}，临床安全的双硫仑和依布硒啉不仅可以与两种蛋白中Zn 结合的半胱氨酸共价结合，而且可以抑制PL ^pro蛋白酶。我们建议将双硫仑/依布硒啉与广谱抗病毒药物/药物相结合，针对作用于病毒生命周期不同阶段的不同保守域，协同抑制 SARS-CoV-2 复制并减少耐药性的出现。