针对人畜共患猪三角花叶病毒(PDCoV)的候选药物的设计和生物学评价

IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY
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引用次数: 0

摘要

猪三角冠状病毒(PDCoV)是一种新出现的猪肠道冠状病毒,具有人畜共患病的潜能。最近在海地急性未分化发热性疾病患儿中发现了 PDCoV 外溢,这突出表明迫切需要开发抗 PDCoV 治疗药物。冠状病毒 3C 样蛋白酶(CoV 3CLpro)对病毒复制至关重要,因此为针对 CoV 的药物提供了一个有吸引力的靶点。在这里,我们初步评估了Nirmatrelvir(PF-07321332)的抗PDCoV效果,Nirmatrelvir是FDA批准的一种以病毒3CLpro为靶点的抗SARS-CoV-2药物。遗憾的是,该药物的抗 PDCoV 效果非常有限。通过分析 Nirmatrelvir 与 PDCoV 3CLpro 和 SARS-CoV-2 3CLpro 的结合模式,我们证明 3CLpro 的 S2 口袋是 Nirmatrelvir 对不同 CoV 3CLpro 产生不同抑制效力的主要因素。根据 PDCoV 3CLpro S2 口袋的具体特征,我们合成了四种具有取代 P2 分子的 Nirmatrelvir 衍生物(化合物 T1-T4)。化合物 T1 的 P2 位点上有一个异丁基,在体外(细胞感染模型)和体内(胚胎鸡卵感染模型)显示出更好的抗 PDCoV 活性,因此是抗 PDCoV 的潜在候选药物。综上所述,我们的研究结果确定了 PDCoV 3CLpro 的底物结合模式和底物特异性,为优化 Nirmatrelvir 作为 PDCoV 抗病毒治疗药物提供了启示。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Design and biological evaluation of candidate drugs against zoonotic porcine deltacoronavirus (PDCoV)

Design and biological evaluation of candidate drugs against zoonotic porcine deltacoronavirus (PDCoV)
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 3CLpro) 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 3CLpro. Regrettably, a very limited anti-PDCoV effect was achieved. By analyzing the binding modes of Nirmatrelvir with PDCoV 3CLpro and SARS-CoV-2 3CLpro, we demonstrated that the S2 pocket of 3CLpro is the primary factor underlying the differential inhibitory potency of Nirmatrelvir against different CoV 3CLpros. Based on the specific characteristics of the S2 pocket of PDCoV 3CLpro, 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 in vitro (cell infection model) and in vivo (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 3CLpro, providing insight into the optimization of Nirmatrelvir as an antiviral therapeutic agent against PDCoV.
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来源期刊
Antiviral research
Antiviral research 医学-病毒学
CiteScore
17.10
自引率
3.90%
发文量
157
审稿时长
34 days
期刊介绍: Antiviral Research is a journal that focuses on various aspects of controlling viral infections in both humans and animals. It is a platform for publishing research reports, short communications, review articles, and commentaries. The journal covers a wide range of topics including antiviral drugs, antibodies, and host-response modifiers. These topics encompass their synthesis, in vitro and in vivo testing, as well as mechanisms of action. Additionally, the journal also publishes studies on the development of new or improved vaccines against viral infections in humans. It delves into assessing the safety of drugs and vaccines, tracking the evolution of drug or vaccine-resistant viruses, and developing effective countermeasures. Another area of interest includes the identification and validation of new drug targets. The journal further explores laboratory animal models of viral diseases, investigates the pathogenesis of viral diseases, and examines the mechanisms by which viruses avoid host immune responses.
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