当前位置: X-MOL 学术Science › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2
Science ( IF 56.9 ) Pub Date : 2021-07-30 , DOI: 10.1126/science.abi4708
Tia A Tummino 1, 2, 3, 4 , Veronica V Rezelj 5 , Benoit Fischer 6 , Audrey Fischer 6 , Matthew J O'Meara 7 , Blandine Monel 8 , Thomas Vallet 5 , Kris M White 9, 10 , Ziyang Zhang 3, 4, 11, 12 , Assaf Alon 13 , Heiko Schadt 6 , Henry R O'Donnell 1 , Jiankun Lyu 1, 3, 4 , Romel Rosales 9, 10 , Briana L McGovern 9, 10 , Raveen Rathnasinghe 9, 10, 14 , Sonia Jangra 9, 10 , Michael Schotsaert 9, 10 , Jean-René Galarneau 15 , Nevan J Krogan 3, 4, 11, 16 , Laszlo Urban 15 , Kevan M Shokat 3, 4, 11, 12 , Andrew C Kruse 13 , Adolfo García-Sastre 9, 10, 17, 18 , Olivier Schwartz 8 , Francesca Moretti 6 , Marco Vignuzzi 5 , Francois Pognan 6 , Brian K Shoichet 1, 3, 4
Affiliation  

Repurposing drugs as treatments for COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has drawn much attention. Beginning with sigma receptor ligands and expanding to other drugs from screening in the field, we became concerned that phospholipidosis was a shared mechanism underlying the antiviral activity of many repurposed drugs. For all of the 23 cationic amphiphilic drugs we tested, including hydroxychloroquine, azithromycin, amiodarone, and four others already in clinical trials, phospholipidosis was monotonically correlated with antiviral efficacy. Conversely, drugs active against the same targets that did not induce phospholipidosis were not antiviral. Phospholipidosis depends on the physicochemical properties of drugs and does not reflect specific target-based activities—rather, it may be considered a toxic confound in early drug discovery. Early detection of phospholipidosis could eliminate these artifacts, enabling a focus on molecules with therapeutic potential.



中文翻译:

药物诱导的磷脂沉积混淆了 SARS-CoV-2 的药物再利用

将药物重新用于治疗由严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 引起的 COVID-19 引起了广泛关注。从西格玛受体配体开始,并通过现场筛选扩展到其他药物,我们开始担心磷脂沉积是许多重新利用药物的抗病毒活性的共同机制。对于我们测试的所有 23 种阳离子两亲性药物,包括羟氯喹、阿奇霉素、胺碘酮和其他四种已进入临床试验的药物,磷脂沉积与抗病毒功效单调相关。相反,针对相同靶标但不诱发磷脂沉积的药物则不具有抗病毒作用。磷脂沉积取决于药物的理化性质,并不反映特定的基于靶点的活性,相反,它可能被认为是早期药物发现中的毒性混淆。磷脂沉积的早期检测可以消除这些伪影,从而使人们能够关注具有治疗潜力的分子。

更新日期:2021-07-30
down
wechat
bug