生物信息学
化学
三肽
体内
体外
药代动力学
维罗细胞
严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)
合理设计
药物发现
结构-活动关系
计算生物学
2019年冠状病毒病(COVID-19)
药理学
生物化学
纳米技术
氨基酸
生物
生物技术
材料科学
病理
基因
传染病(医学专业)
疾病
医学
作者
Simone Di Micco,Rahila Rahimova,Marina Sala,Maria C. Scala,Giovanni Vivenzio,Simona Musella,Graciela Andrei,Kim Remans,Léa Mammri,Robert Snoeck,Giuseppe Bifulco,Francesca Di Matteo,Vincenzo Vestuto,Pietro Campiglia,José A. Márquez,Alessio Fasano
标识
DOI:10.1016/j.ejmech.2022.114857
摘要
Although vaccines are greatly mitigating the worldwide pandemic diffusion of SARS-Cov-2, therapeutics should provide many distinct advantages as complementary approach to control the viral spreading. Here, we report the development of new tripeptide derivatives of AT1001 against SARS-CoV-2 Mpro. By molecular modeling, a small compound library was rationally designed and filtered for enzymatic inhibition through FRET assay, leading to the identification of compound 4. X-ray crystallography studies provide insights into its binding mode and confirm the formation of a covalent bond with Mpro C145. In vitro antiviral tests indicate the improvement of biological activity of 4 respect to AT1001. In silico and X-ray crystallography analysis led to 58, showing a promising activity against three SARS-CoV-2 variants and a valuable safety in Vero cells and human embryonic lung fibroblasts. The drug tolerance was also confirmed by in vivo studies, along with pharmacokinetics evaluation. In summary, 58 could pave the way to develop a clinical candidate for intranasal administration.
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