Exploration of P1 and P4 modifications of nirmatrelvir: Design, synthesis, biological evaluation, and X-ray structural studies of SARS-CoV-2 Mpro inhibitors,European Journal of Medicinal Chemistry

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Exploration of P1 and P4 modifications of nirmatrelvir: Design, synthesis, biological evaluation, and X-ray structural studies of SARS-CoV-2 Mpro inhibitors
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2024-02-01 , DOI: 10.1016/j.ejmech.2024.116132
Arun K Ghosh ₁ , Monika Yadav ₂ , Satyanarayana Iddum ₂ , Somayeh Ghazi ₂ , Emma K Lendy ₃ , Uttara Jayashankar ₄ , Sydney N Beechboard ₃ , Yuki Takamatsu ₅ , Shin-Ichiro Hattori ₅ , Masayuki Aamano ₆ , Nobuyo Higashi-Kuwata ₅ , Hiroaki Mitsuya ₇ , Andrew D Mesecar ₈

Affiliation

Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN, 47907, USA; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA.
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN, 47907, USA.
Department of Biochemistry, Purdue University, West Lafayette, IN, 47907, USA.
Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA.
Department of Refractory Viral Diseases, National Center for Global Health and Medicine, Shinjuku, Tokyo, 162-8655, Japan.
Department of Clinical Retrovirology, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, 860-0811, Japan.
Department of Refractory Viral Diseases, National Center for Global Health and Medicine, Shinjuku, Tokyo, 162-8655, Japan; Department of Infectious Diseases, Kumamoto University School of Medicine, Kumamoto, 860-8556, Japan; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch National Cancer Institute, Bethesda, MD, 20892, USA.
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN, 47907, USA; Department of Biochemistry, Purdue University, West Lafayette, IN, 47907, USA; Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA.

We report the synthesis, biological evaluation, and X-ray structural studies of a series of SARS-CoV-2 Mpro inhibitors based upon the X-ray crystal structure of nirmatrelvir, an FDA approved drug that targets the main protease of SARS-CoV-2. The studies involved examination of various P4 moieties, P1 five- and six-membered lactam rings to improve potency. In particular, the six-membered P1 lactam ring analogs exhibited high SARS-CoV-2 Mpro inhibitory activity. Several compounds effectively blocked SARS-CoV-2 replication in VeroE6 cells. One of these compounds maintained good antiviral activity against variants of concern including Delta and Omicron variants. A high-resolution X-ray crystal structure of an inhibitor bound to SARS-CoV-2 Mpro was determined to gain insight into the ligand-binding properties in the Mpro active site.

中文翻译：

奈马曲韦 P1 和 P4 修饰的探索：SARS-CoV-2 Mpro 抑制剂的设计、合成、生物学评价和 X 射线结构研究

我们报道了一系列基于 nirmatrelvir 晶体结构的 SARS-CoV-2 Mpro 抑制剂的合成、生物学评价和 X 射线结构研究，nirmatrelvir 是一种 FDA 批准的靶向 SARS-CoV-2 主要蛋白酶的药物。这些研究涉及检查各种 P4 部分、P1 五元和六元内酰胺环以提高效力。特别是，六元 P1 内酰胺环类似物表现出较高的 SARS-CoV-2 Mpro 抑制活性。几种化合物有效阻断了 VeroE6 细胞中的 SARS-CoV-2 复制。其中一种化合物对包括 Delta 和 Omicron 变体在内的令人担忧的变体保持了良好的抗病毒活性。确定了与 SARS-CoV-2 Mpro 结合的抑制剂的高分辨率 X 射线晶体结构，以深入了解 Mpro 活性位点的配体结合特性。

更新日期：2024-02-01

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