Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M^pro) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing the severity of COVID-19, but the presence of resistance-conferring mutations in sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants are thus urgently needed. We hypothesized that the covalent hepatitis C virus protease inhibitor boceprevir (BPV) could serve as the basis for orally bioavailable drugs that inhibit SARS-CoV-2 M^pro more efficiently than existing drugs. Performing structure-guided modifications of BPV, we developed a picomolar-affinity inhibitor, ML2006a4, with antiviral activity, oral pharmacokinetics, and therapeutic efficacy similar or superior to those of NTV. A crucial feature of ML2006a4 is a derivatization of the ketoamide reactive group that improves cell permeability and oral bioavailability. Last, ML2006a4 was found to be less sensitive to several mutations that cause resistance to NTV or ETV and occur in the natural SARS-CoV-2 population. Thus, anticipatory design can preemptively address potential resistance mechanisms to expand future treatment options against coronavirus variants.

中文翻译：

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口服生物可利用的 SARS-CoV-2 主要蛋白酶抑制剂表现出更高的亲和力并降低对突变的敏感性

严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 主要蛋白酶 (M ^pro ) 的抑制剂，如 nirmatrelvir (NTV) 和 enitrelvir (ETV) 已被证明可有效减轻 COVID-19 的严重程度，但存在耐药性-在已测序的病毒基因组中赋予突变引起了对未来耐药性的担忧。因此，迫切需要保留针对这些突变体的功能的第二代口服药物。我们假设共价丙型肝炎病毒蛋白酶抑制剂 boceprevir (BPV) 可以作为口服生物药物的基础，比现有药物更有效地抑制 SARS-CoV-2 M ^pro。通过对 BPV 进行结构指导修饰，我们开发了一种皮摩尔亲和力抑制剂 ML2006a4，其抗病毒活性、口服药代动力学和治疗效果与 NTV 相似或优于 NTV。ML2006a4 的一个重要特征是酮酰胺反应基团的衍生化，可提高细胞通透性和口服生物利用度。最后，发现 ML2006a4 对几种导致 NTV 或 ETV 耐药的突变不太敏感，这些突变发生在自然 SARS-CoV-2 群体中。因此，预期设计可以先发制人地解决潜在的耐药机制，以扩大未来针对冠状病毒变体的治疗选择。