Gil-Moles Maria, O'Beirne Cillian, Esarev Igor V, Lippmann Petra, Tacke Matthias, Cinatl Jindrich, Bojkova Denisa, Ott Ingo
Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig Beethovenstr. 55 38106 Braunschweig Germany
Departamento de Química, Universidad de La Rioja, Centro de Investigación de Síntesis Química (CISQ), Complejo Científico Tecnológico 26004 Logroño Spain.
RSC Med Chem. 2023 May 16;14(7):1260-1271. doi: 10.1039/d3md00067b. eCollection 2023 Jul 20.
The ongoing SARS-CoV-2 pandemic has caused a high demand for novel innovative antiviral drug candidates. Despite promising results, metal complexes have been relatively unexplored as antiviral agents in general and in particular against SARS-CoV-2. Here we report on silver NHC complexes with chloride or iodide counter ligands that are potent inhibitors of the SARS-CoV-2 papain-like protease (PL) but inactive against 3C-like protease (3CL) as another SARS-CoV-2 protease. Mechanistic studies on a selected complex confirmed zinc removal from a zinc binding domain of PL as relevant factor of their activity. In addition, enzyme kinetic experiments revealed that the complex is an uncompetitive inhibitor and with this rare type of inhibition it offers great pharmacological advantages in terms selectivity. The silver NHC complexes with iodide ligands showed very low or absent host cell toxicity and triggered strong effects on viral replication in cells infected with SARS-CoV-2, making them promising future antiviral drug candidates.
持续的新型冠状病毒肺炎大流行引发了对新型创新抗病毒候选药物的高需求。尽管取得了有前景的结果，但金属配合物作为抗病毒剂总体上相对未被充分探索，尤其是针对新型冠状病毒。在此，我们报道了具有氯离子或碘离子抗衡配体的银氮杂环卡宾配合物，它们是新型冠状病毒木瓜样蛋白酶（PL）的有效抑制剂，但对作为新型冠状病毒另一种蛋白酶的3C样蛋白酶（3CL）无活性。对一种选定配合物的机制研究证实，从PL的锌结合结构域去除锌是其活性的相关因素。此外，酶动力学实验表明该配合物是一种非竞争性抑制剂，这种罕见的抑制类型在选择性方面具有很大的药理学优势。具有碘离子配体的银氮杂环卡宾配合物显示出非常低的或不存在宿主细胞毒性，并对感染新型冠状病毒的细胞中的病毒复制产生强烈影响，使其成为未来有前景的抗病毒候选药物。
