A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants.
A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants.
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DOI：
10.1080/22221751.2023.2246594
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发表时间：
2023-12
影响因子：
13.2
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中科院分区：
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具有广泛冠状病毒活性的抗病毒药物对于治疗暴露于不断演变的SARS-CoV-2变异体（VOC）以及新出现的耐药变异体的高风险个体非常重要。我们开发并表征了一类新的活性位点定向的3-胰凝乳蛋白酶样蛋白酶（3CLpro）抑制剂（C2-C5 a）。我们的主要直接作用抗病毒药物（DAA）C5 a是一种非共价非肽，对重组SARS-CoV-2 3CLpro的解离常数为170 nM。化合物C2-C5 a表现出针对人细胞中的Omicron亚变体（BA.5、BQ.1.1和XBB.1.5）和季节性人冠状病毒-229E感染的广谱活性。值得注意的是，在两种不同的人细胞系中，C5 a对BQ.1.1和XBB.1.5的中位有效浓度为30-50 nM。 X射线晶体学已经证实了C2-C5 a与3CLpro的独特结合模式，这可以限制病毒对新出现的帕昔洛韦抗性变体的交叉抗性。我们用我们新发现的两种宿主定向抗病毒药物（HDAs）测试了C5 a的作用：N-0385，一种TMPRSS 2抑制剂，和巴弗洛霉素D（BafD），一种人空泡H+-ATP酶[V-ATP酶]抑制剂。我们证明了C5 a与N-0385和BafD组合对人Calu-3肺细胞中Omicron BA.5感染的协同作用。我们的研究结果强调，基于DAA（C5 a）和HDA（N-0385或BafD）的SARS-CoV-2多靶向治疗循环Omicron亚变体可以通过增强治疗效果产生治疗益处。此外，SARS-CoV-2 3CLpro与C2-C5 a复合的高分辨率结构将有助于我们的新型广谱活性位点定向3C样蛋白酶抑制剂的未来合理优化。
Antivirals with broad coronavirus activity are important for treating high-risk individuals exposed to the constantly evolving SARS-CoV-2 variants of concern (VOCs) as well as emerging drug-resistant variants. We developed and characterized a novel class of active-site-directed 3-chymotrypsin-like protease (3CLpro) inhibitors (C2–C5a). Our lead direct-acting antiviral (DAA), C5a, is a non-covalent, non-peptide with a dissociation constant of 170 nM against recombinant SARS-CoV-2 3CLpro. The compounds C2–C5a exhibit broad-spectrum activity against Omicron subvariants (BA.5, BQ.1.1, and XBB.1.5) and seasonal human coronavirus-229E infection in human cells. Notably, C5a has median effective concentrations of 30–50 nM against BQ.1.1 and XBB.1.5 in two different human cell lines. X-ray crystallography has confirmed the unique binding modes of C2–C5a to the 3CLpro, which can limit virus cross-resistance to emerging Paxlovid-resistant variants. We tested the effect of C5a with two of our newly discovered host-directed antivirals (HDAs): N-0385, a TMPRSS2 inhibitor, and bafilomycin D (BafD), a human vacuolar H+-ATPase [V-ATPase] inhibitor. We demonstrated a synergistic action of C5a in combination with N-0385 and BafD against Omicron BA.5 infection in human Calu-3 lung cells. Our findings underscore that a SARS-CoV-2 multi-targeted treatment for circulating Omicron subvariants based on DAAs (C5a) and HDAs (N-0385 or BafD) can lead to therapeutic benefits by enhancing treatment efficacy. Furthermore, the high-resolution structures of SARS-CoV-2 3CLpro in complex with C2–C5a will facilitate future rational optimization of our novel broad-spectrum active-site-directed 3C-like protease inhibitors.