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Development of dual inhibitors targeting the viral main protease and the host cathepsin L as SARS-CoV-2 antivirals

Development of dual inhibitors targeting the viral main protease and the host cathepsin L as SARS-CoV-2 antivirals
开发针对病毒主要蛋白酶和宿主组织蛋白酶 L 的双重抑制剂作为 SARS-CoV-2 抗病毒药物
批准号:
10693823
负责人:
Jun Wang
金额:
$73.01万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-01-04 至 2026-07-31

项目摘要

项目成果

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中文摘要
翻译
项目摘要 严重急性呼吸综合征冠状病毒2(SARS-CoV-2),也称为2019年新型冠状病毒 (nCoV-19)于2019年12月左右开始在人类中传播,目前已成为全球性的流行病。 流行病目前还没有针对SARS-CoV-2的疫苗或抗病毒药物。在这项拨款中,我们建议发展双 靶向病毒主要蛋白酶和组织蛋白酶L的抑制剂作为SARS-CoV-2抗病毒药物。使用基于FRET的 酶分析,我们最近确定了几种抑制剂,包括boceprevir,GC-376和钙蛋白酶抑制剂II 和XII,其在酶测定中具有有效活性,IC 50值为个位数至亚微摩尔。 值得注意的是,所有四种化合物均抑制细胞培养物中的感染性SARS-CoV-2复制,EC 50值 范围为0.5至3.4 µM。总的来说,所鉴定的化合物为进一步研究提供了有希望的起点。 开发SARS-CoV-2治疗药物。我们发现钙蛋白酶抑制剂II作为一种有效的抑制剂, SARS-CoV-2是创新的,因为它表明通过以下方法开发SARS-CoV-2抗病毒药物可能是可行的: 同时靶向病毒Mpro和宿主组织蛋白酶L两者,这两者对于病毒复制是必需的。 与最近报道的Mpro抑制剂相比,从我们的研究中鉴定的命中代表了最有效的, 具有新的作用机制的选择性候选药物,因此阻碍了进一步的开发。 鉴于我们令人鼓舞的初步数据,我们建议优化双重抑制剂作为SARS-CoV-2抗病毒药物。 该提案的目的是开发双重抑制剂作为具有高效力的有效SARS-CoV-2抗病毒药物, 选择性,良好的药代动力学特性,以及广谱抗病毒活性, 相关冠状病毒,如SARS和中东呼吸综合征(MERS)冠状病毒。 我们这项资助的目标是通过高通量筛选, 基于结构的铅优化我们最近确定的双重抑制剂。通过瞄准SARS-CoV-2 Mpro, 拟议研究的预期成果是广泛有效的冠状病毒抗病毒药物, 作用机制,高选择性指数和良好的体外药代动力学特性, 用于在相关动物模型中进行体内抗病毒功效测试。总的来说,这笔赠款是基于强大的初步 数据和我们在开发针对半胱氨酸蛋白酶的抗病毒药物方面的专业知识。
英文摘要
Project Summary The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also called novel coronavirus 2019 (nCoV-19), started to circulate among humans around December 2019, and it is now widespread as a global pandemic. There is no vaccine or antiviral available for SARS-CoV-2. In this grant, we propose to develop dual inhibitors targeting viral main protease and cathepsin L as SARS-CoV-2 antivirals. Using the FRET-based enzymatic assay, we recently identified several inhibitors including boceprevir, GC-376, and calpain inhibitors II and XII, that have potent activity with single-digit to submicromolar IC50 values in the enzymatic assay. Significantly, all four compounds inhibit infectious SARS-CoV-2 replication in cell culture with EC50 values ranging from 0.5 to 3.4 µM. Overall, the compounds identified provide promising starting points for the further development of SARS-CoV-2 therapeutics. Our discovery of calpain inhibitor II as a potent inhibitor against SARS-CoV-2 is innovative as it suggests it might be feasible to develop SARS-CoV-2 antivirals by simultaneously targeting both viral Mpro and host cathepsin L, both of which are essential for viral replication. Compared to recently reported Mpro inhibitors, the hits identified from our study represent the most potent and selective drug candidates with a novel mechanism of action, therefore warranting further development. Given our encouraging preliminary data, we propose to optimize dual inhibitors as SARS-CoV-2 antivirals. The objective of this proposal is to develop dual inhibitors as potent SARS-CoV-2 antivirals with high potency, selectivity, favorable pharmacokinetic properties, as well as broad-spectrum antiviral activity against closely related coronaviruses such as SARS and Middle East respiratory syndrome (MERS) coronaviruses. Our goals of this grant are to identify additional dual inhibitors through both high-throughput screening and structure-based lead optimization of our recently identified dual inhibitors. By targeting the SARS-CoV-2 Mpro, the expected outcomes of the proposed research are broad-acting coronavirus antivirals with a confirmed mechanism of action, a high selectivity index, and favorable in vitro pharmacokinetic properties that are ready for in vivo antiviral efficacy testing in relevant animal models. Overall, this grant is based on strong preliminary data and our expertise in developing antivirals targeting cysteine proteases.
期刊论文(6)
专著(0)
科研奖励(0)
会议论文
DOI: 10.1016/j.ejmech.2023.115667
发表时间: 2023-07
期刊: European journal of medicinal chemistry
影响因子: 6.7
作者: [Bin Tan;M. Sacco;Hao Tan;Kan Li;Ryan Joyce;Xiujun Zhang;Yu Chen;Jun Wang]
通讯作者: Bin Tan;M. Sacco;Hao Tan;Kan Li;Ryan Joyce;Xiujun Zhang;Yu Chen;Jun Wang
A yeast-based system to study SARS-CoV-2 M pro structure and to identify nirmatrelvir resistant mutations.
基于酵母的系统,用于研究 SARS-CoV-2 M 原结构并识别 nirmatrelvir 耐药突变。
DOI: 10.1101/2022.08.06.503039
发表时间: 2022
期刊: bioRxiv : the preprint server for biology
影响因子: --
作者: [Ou,Jin, Lewandowski,EricM, Hu,Yanmei, Lipinski,AustinA, Morgan,RyanT, Jacobs,LianMC, Zhang,Xiujun, Bikowitz,MelissaJ, Langlais,Paul, Tan,Haozhou, Wang,Jun, Chen,Yu, Choy,JohnS]
通讯作者: Choy,JohnS
A yeast-based system to study SARS-CoV-2 Mpro structure and to identify nirmatrelvir resistant mutations.
基于酵母的系统,用于研究 SARS-CoV-2 Mpro 结构并识别 nirmatrelvir 耐药突变。
DOI: 10.21203/rs.3.rs-1942964/v1
发表时间: 2022
期刊: Research square
影响因子: --
作者: [Ou,Jin, Lewandowski,EricM, Hu,Yanmei, Lipinski,AustinA, Morgan,RyanT, Jacobs,LianMC, Zhang,Xiujun, Bikowitz,MelissaJ, Langlais,Paul, Tan,Haozhou, Wang,Jun, Chen,Yu, Choy,JohnS]
通讯作者: Choy,JohnS
Striatal ensemble plasticity in alcohol use disorder
Development of dual inhibitors targeting the viral main protease and the host cathepsin L as SARS-CoV-2 antivirals
High-Resolution Spatial MIST Technology for Functional Proteomic Study of Neuroinflammation in Alzheimer's Disease
Repurposing of Maraviroc for the treatment of neuropathic pain
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