论文
论文标题：Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2
作者：Tia A. Tummino , Veronica V. Rezelj , Benoit Fischer , Audrey Fischer , Matthew J. O’Meara , Blandine Monel , Thomas Vallet , Kris M. White , Ziyang Zhang , Assaf Alon , Heiko Schadt , Henry R. O’Donnell , Jiankun Lyu , Romel Rosales , Briana L. McGovern , Raveen Rathnasinghe , Sonia Jangra , Michael Schotsaert , Jean-René Galarneau , Nevan J. Krogan , Laszlo Urban , Kevan M. Shokat , Andrew C. Kruse , Adolfo García-Sastre , Olivier Schwartz , Francesca Moretti , Marco Vignuzzi , Francois Pognan , Brian K. Shoichet
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期刊：Science
发表时间：2021/07/30
数字识别码：10.1126/science.abi4708
摘要：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.
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所属学科：
药学
医学
（导读 郭怿暄）本研究发现在针对COVID-19的“老药新用”筛选中，许多药物在体外拥有抗病毒活性的原因是，它们能够引发磷脂沉积，例如，在本研究测试的23种阳离子两亲性药物中，磷脂沉积与抗病毒效力单调正相关。但是，此类以磷脂沉积为机制的药物通常没有体内抗病毒活性。因此，应当努力在早期发现此类药物，这有助于去除假象，筛选出真正有治疗潜能的分子。
