National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China; The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China.
National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China; The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China.
Antiviral Res. 2024 Nov;231:106019. doi: 10.1016/j.antiviral.2024.106019. Epub 2024 Oct 10.
Porcine deltacoronavirus (PDCoV) is an emerging swine enteric coronavirus with zoonotic potential. PDCoV spillovers were recently detected in Haitian children with acute undifferentiated febrile illness, underscoring the urgent need to develop anti-PDCoV therapeutics. Coronavirus 3C-like protease (CoV 3CL) is essential for viral replication, and therefore provides an attractive target for drugs directed against CoV. Here, we initially evaluated the anti-PDCoV effect of Nirmatrelvir (PF-07321332), an FDA-approved anti-SARS-CoV-2 drug targeting viral 3CL. Regrettably, a very limited anti-PDCoV effect was achieved. By analyzing the binding modes of Nirmatrelvir with PDCoV 3CL and SARS-CoV-2 3CL, we demonstrated that the S2 pocket of 3CL is the primary factor underlying the differential inhibitory potency of Nirmatrelvir against different CoV 3CLs. Based on the specific characteristics of the S2 pocket of PDCoV 3CL, four derivatives of Nirmatrelvir (compounds T1-T4) with substituted P2 moieties were synthesized. Compound T1, with an isobutyl at the P2 site, displayed improved anti-PDCoV activity invitro (cell infection model) and invivo (embryonated chicken egg infection model), and therefore is a potential candidate drug to combat PDCoV. Together, our results identify the substrate-binding mode and substrate specificity of PDCoV 3CL, providing insight into the optimization of Nirmatrelvir as an antiviral therapeutic agent against PDCoV.
猪德尔塔冠状病毒（PDCoV）是一种具有人畜共患潜力的新兴猪肠道冠状病毒。最近在海地患有急性未分化发热病的儿童中检测到 PDCoV 溢出，这突显出迫切需要开发抗 PDCoV 的疗法。冠状病毒 3C 样蛋白酶（CoV 3CL）是病毒复制所必需的，因此为针对 CoV 的药物提供了有吸引力的靶标。在这里，我们最初评估了 Nirmatrelvir（PF-07321332），一种针对 SARS-CoV-2 的 FDA 批准的抗病毒药物，对 PDCoV 的抗病毒作用。令人遗憾的是，只取得了非常有限的抗 PDCoV 效果。通过分析 Nirmatrelvir 与 PDCoV 3CL 和 SARS-CoV-2 3CL 的结合模式，我们证明 3CL 的 S2 口袋是 Nirmatrelvir 对不同 CoV 3CL 抑制效力差异的主要因素。基于 PDCoV 3CL 的 S2 口袋的特定特征，我们合成了四种 Nirmatrelvir 的衍生物（化合物 T1-T4），它们的 P2 取代基不同。化合物 T1 在 P2 位上有一个异丁基，在体外（细胞感染模型）和体内（鸡胚感染模型）显示出改善的抗 PDCoV 活性，因此是一种有潜力的对抗 PDCoV 的候选药物。总之，我们的结果确定了 PDCoV 3CL 的底物结合模式和底物特异性，为 Nirmatrelvir 作为抗 PDCoV 的抗病毒治疗药物的优化提供了思路。
