Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA, USA.
Department of Neurobiology, Stanford University, Stanford, CA, USA.
Antiviral Res. 2024 Nov;231:106022. doi: 10.1016/j.antiviral.2024.106022. Epub 2024 Oct 17.
There is an ongoing need to expand the anti-SARS-CoV-2 armamentarium to include agents capable of suppressing replication of drug-resistant mutants emerging during monotherapy with approved direct-acting antivirals. Using a subgenomic SARS-CoV-2 replicon system, we studied the RNA replication capacity of nirmatrelvir (NTV)-resistant mutants and their susceptibility to next-generation Mpro inhibitors, including ibuzatrelvir (ITV), ensitrelvir (ETV), and ML2006a4. Our findings revealed that E166V Mpro mutants reduced viral RNA replication, whereas other Mpro mutations retained or increased the replication capacity, suggesting the potential of the latter to dominate under NTV selective pressure. Except for having an advantage against E166A mutants, ITV largely showed the same mutational sensitivity as NTV. ETV was more effective than NTV against E166V mutants but less effective against S144A, E166A, and L167F mutants. ML2006a4 demonstrated the most effective suppression across most mutants (S144A, E166V, S144A + L50F, E166 A/V + L50F, L167F + L50F, and E166A + L167F + L50F). Thus, ML2006a4 represents an attractive investigational candidate against clinically relevant NTV-resistant SARS-CoV-2 mutants.
目前仍需要扩大针对 SARS-CoV-2 的武器库，纳入能够抑制批准的直接作用抗病毒药物单药治疗期间出现的耐药突变体复制的药物。我们使用亚基因组 SARS-CoV-2 复制子系统研究了 nirmatrelvir（NTV）耐药突变体的 RNA 复制能力及其对下一代 Mpro 抑制剂（包括 ibuzatrelvir（ITV）、ensitrelvir（ETV）和 ML2006a4）的敏感性。我们的研究结果表明，E166V Mpro 突变体降低了病毒 RNA 复制，而其他 Mpro 突变保留或增加了复制能力，这表明后者在 NTV 选择压力下可能具有优势。除了对 E166A 突变体具有优势外，ITV 在很大程度上与 NTV 具有相同的突变敏感性。与 NTV 相比，ETV 对 E166V 突变体更有效，但对 S144A、E166A 和 L167F 突变体的效果较差。ML2006a4 对大多数突变体（S144A、E166V、S144A+L50F、E166A+L50F、L167F+L50F 和 E166A+L167F+L50F）的抑制作用最为有效。因此，ML2006a4 是一种有吸引力的针对临床相关 NTV 耐药 SARS-CoV-2 突变体的研究候选药物。
