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The neutralization effect of montelukast on SARS-CoV-2 is shown by multiscale in silico simulations and combined in vitro studies
Molecular Therapy ( IF 12.4 ) Pub Date : 2021-10-19 , DOI: 10.1016/j.ymthe.2021.10.014
Serdar Durdagi 1 , Timucin Avsar 2 , Muge Didem Orhan 2 , Muge Serhatli 3 , Bertan Koray Balcioglu 3 , Hasan Umit Ozturk 3 , Alisan Kayabolen 4 , Yuksel Cetin 3 , Seyma Aydinlik 3 , Tugba Bagci-Onder 5 , Saban Tekin 6 , Hasan Demirci 7 , Mustafa Guzel 8 , Atilla Akdemir 9 , Seyma Calis 10 , Lalehan Oktay 1 , Ilayda Tolu 1 , Yasar Enes Butun 8 , Ece Erdemoglu 11 , Alpsu Olkan 1 , Nurettin Tokay 3 , Şeyma Işık 3 , Aysenur Ozcan 12 , Elif Acar 12 , Sehriban Buyukkilic 13 , Yesim Yumak 14
Affiliation  

Small molecule inhibitors have previously been investigated in different studies as possible therapeutics in the treatment of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In the current drug repurposing study, we identified the leukotriene (D4) receptor antagonist montelukast as a novel agent that simultaneously targets two important drug targets of SARS-CoV-2. We initially demonstrated the dual inhibition profile of montelukast through multiscale molecular modeling studies. Next, we characterized its effect on both targets by different in vitro experiments including the enzyme (main protease) inhibition-based assay, surface plasmon resonance (SPR) spectroscopy, pseudovirus neutralization on HEK293T/hACE2+TMPRSS2, and virus neutralization assay using xCELLigence MP real-time cell analyzer. Our integrated in silico and in vitro results confirmed the dual potential effect of montelukast both on the main protease enzyme inhibition and virus entry into the host cell (spike/ACE2). The virus neutralization assay results showed that SARS-CoV-2 virus activity was delayed with montelukast for 20 h on the infected cells. The rapid use of new small molecules in the pandemic is very important today. Montelukast, whose pharmacokinetic and pharmacodynamic properties are very well characterized and has been widely used in the treatment of asthma since 1998, should urgently be completed in clinical phase studies and, if its effect is proved in clinical phase studies, it should be used against coronavirus disease 2019 (COVID-19).



中文翻译:

孟鲁司特对 SARS-CoV-2 的中和作用通过多尺度计算机模拟和联合体外研究显示

小分子抑制剂先前已在不同的研究中作为治疗严重急性呼吸综合征冠状病毒-2 (SARS-CoV-2) 的可能疗法进行了研究。在当前的药物再利用研究中,我们将白三烯 (D4) 受体拮抗剂孟鲁司特确定为一种同时靶向 SARS-CoV-2 的两个重要药物靶点的新型药物。我们最初通过多尺度分子建模研究证明了孟鲁司特的双重抑制作用。接下来,我们通过不同的体外表征了它对两个靶点的影响实验包括基于酶(主要蛋白酶)抑制的测定、表面等离子共振 (SPR) 光谱、HEK293T/hACE2+TMPRSS2 上的假病毒中和以及使用 xCELLigence MP 实时细胞分析仪的病毒中和测定。我们整合了计算机体外结果证实了孟鲁司特对主要蛋白酶抑制和病毒进入宿主细胞(spike/ACE2)的双重潜在影响。病毒中和试验结果表明,孟鲁司特对感染细胞的 SARS-CoV-2 病毒活性延迟 20 小时。今天,在大流行中快速使用新的小分子非常重要。孟鲁司特的药代动力学和药效学特性已得到很好的表征,自1998年以来已广泛用于治疗哮喘,应紧急完成临床阶段研究,如果临床阶段研究证明其效果,则应用于抗冠状病毒2019 年疾病 (COVID-19)。

更新日期:2021-10-19
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