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: 10543633
• 负责人: Jun Wang
• 金额: $ 39.27万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-04 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543633
• 关键词: Development; dual; inhibitors; targeting; viral

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.

项目摘要 严重的急性呼吸综合征冠状病毒2（SARS-COV-2），也称为新型冠状病毒2019 （NCOV-19），2019年12月左右开始在人类中圈出圈子，现在已成为全球范围 大流行。 SARS-COV-2没有疫苗或抗病毒。在这笔赠款中，我们建议开发双重 靶向病毒主蛋白酶和组织蛋白酶L作为SARS-COV-2抗病毒药的抑制剂。使用基于FRET的 酶测定，我们最近确定了包括Boceprevir，GC-376和Calpain抑制剂II在内的几种抑制剂II 和XII，具有潜在活性，具有单位对酶测定中的粒度IC50值。 值得注意的是，所有四种化合物都抑制EC50值的细胞培养中的感染性SARS-COV-2复制 范围为0.5至3.4 µm。总体而言，确定的化合物为进一步提供了承诺起点 SARS-COV-2疗法的发展。我们发现Calpain抑制剂II是一种潜在的抑制剂 SARS-COV-2具有创新性，因为它表明可以通过 同样，靶向病毒MPRO和宿主组织蛋白酶L，这对于病毒复制都是必不可少的。 与最近报道的MPRO抑制剂相比，从我们的研究中鉴定出的命中是最有效的， 具有新型作用机理的选择性候选药物，因此警告进一步发展。 鉴于我们令人鼓舞的初步数据，我们建议将双重抑制剂优化为SARS-COV-2抗病人。 该提案的目的是开发双重抑制剂作为具有高效力的潜在SARS-COV-2抗病人， 选择性，有利的药代动力学特性以及宽光谱抗病毒活性 相关的冠状病毒，例如SARS和中东呼吸道综合征（MERS）冠状病毒。 我们的这笔赠款的目标是通过高通量筛查和 基于结构的铅优化我们最近确定的双重抑制剂。通过靶向SARS-COV-2 MPRO， 拟议的研究的预期结果是广泛的冠状病毒抗病毒药，并确认 作用机理，高选择性指数和准备就绪的体外药代动力学特性 用于相关动物模型中的体内抗病毒效率测试。总体而言，这笔赠款基于强大的初步 数据和我们在开发靶向半胱氨酸蛋白酶的抗病毒药方面的专业知识。