In Vitro Evaluation and Mitigation of Niclosamide's Liabilities as a COVID-19 Treatment.
In Vitro Evaluation and Mitigation of Niclosamide's Liabilities as a COVID-19 Treatment.
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DOI：
10.3390/vaccines10081284
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发表时间：
2022-08-09
期刊：
影响因子：
7.8
通讯作者：
Sexton, Jonathan Z.
中科院分区：
文献类型：
--
作者：
Wotring, Jesse W.;McCarty, Sean M.;Shafiq, Khadija;Zhang, Charles J.;Nguyen, Theophilus;Meyer, Sophia R.;Fursmidt, Reid;Mirabelli, Carmen;Clasby, Martin C.;Wobus, Christiane E.;O'Meara, Matthew J.;Sexton, Jonathan Z.
氯硝柳胺是FDA批准的口服驱虫药，具有广泛的生物活性，包括抗癌、抗菌和抗病毒特性。氯硝柳胺在体外也被确定为一种有效的SARS-CoV-2感染抑制剂，引起了人们对其用于治疗或预防新冠肺炎的兴趣。不幸的是，使用氯硝柳胺治疗新冠肺炎有几个潜在的问题，包括低生物利用度，显著的多药理作用，高细胞毒性，以及对新出现的令人担忧的SARS-CoV-2变种的疗效未知。在这项研究中，我们在两个不同的细胞模型中使用基于高含量成像的免疫荧光分析来评估这些局限性，并评估将氯硝柳胺用作新冠肺炎抗病毒药物的潜力。我们发现，尽管初步报道前景看好，但氯硝柳胺的抗病毒效果与其细胞毒性重叠，使其在体外抗SARS-CoV-2抑制方面的选择性指数较差。我们还表明，氯硝柳胺对关注的不同SARS-CoV-2变异体具有显著不同的效力，并且对包括B.1.1.7(α)变异体在内的细胞间传播增强的变异体最有效。最后，我们报道了33个氯硝柳胺类似物的活性，其中一些与氯硝柳胺相比降低了细胞毒性并提高了效力。初步的结构-活性关系分析表明，抗病毒效果依赖于原载体，这意味着非特异的内切酶中和是主要的作用机制。进一步的单细胞形态分析表明，氯硝柳胺也可以抑制病毒进入和合胞体在细胞间的传播。总之，我们的结果表明氯硝柳胺不是治疗新冠肺炎的理想候选药物，但未来有潜力开发具有更高临床翻译潜力的改进类似物。
Niclosamide, an FDA-approved oral anthelmintic drug, has broad biological activity including anticancer, antibacterial, and antiviral properties. Niclosamide has also been identified as a potent inhibitor of SARS-CoV-2 infection in vitro, generating interest in its use for the treatment or prevention of COVID-19. Unfortunately, there are several potential issues with using niclosamide for COVID-19, including low bioavailability, significant polypharmacology, high cellular toxicity, and unknown efficacy against emerging SARS-CoV-2 variants of concern. In this study, we used high-content imaging-based immunofluorescence assays in two different cell models to assess these limitations and evaluate the potential for using niclosamide as a COVID-19 antiviral. We show that despite promising preliminary reports, the antiviral efficacy of niclosamide overlaps with its cytotoxicity giving it a poor in vitro selectivity index for anti-SARS-CoV-2 inhibition. We also show that niclosamide has significantly variable potency against the different SARS-CoV-2 variants of concern and is most potent against variants with enhanced cell-to-cell spread including the B.1.1.7 (alpha) variant. Finally, we report the activity of 33 niclosamide analogs, several of which have reduced cytotoxicity and increased potency relative to niclosamide. A preliminary structure–activity relationship analysis reveals dependence on a protonophore for antiviral efficacy, which implicates nonspecific endolysosomal neutralization as a dominant mechanism of action. Further single-cell morphological profiling suggests niclosamide also inhibits viral entry and cell-to-cell spread by syncytia. Altogether, our results suggest that niclosamide is not an ideal candidate for the treatment of COVID-19, but that there is potential for developing improved analogs with higher clinical translational potential in the future.
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影响因子：
4.8
作者：
Chen W;Mook RA Jr;Premont RT;Wang J
通讯作者：
Wang J
影响因子：
5.6
作者：
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Cheok CF
影响因子：
16.6
作者：
Gassen NC;Papies J;Bajaj T;Emanuel J;Dethloff F;Chua RL;Trimpert J;Heinemann N;Niemeyer C;Weege F;Hönzke K;Aschman T;Heinz DE;Weckmann K;Ebert T;Zellner A;Lennarz M;Wyler E;Schroeder S;Richter A;Niemeyer D;Hoffmann K;Meyer TF;Heppner FL;Corman VM;Landthaler M;Hocke AC;Morkel M;Osterrieder N;Conrad C;Eils R;Radbruch H;Giavalisco P;Drosten C;Müller MA
通讯作者：
Müller MA
DOI：
10.1056/nejmoa2116846
发表时间：
2022-01-27
期刊：
The New England journal of medicine
影响因子：
--
作者：
Gottlieb RL;Vaca CE;Paredes R;Mera J;Webb BJ;Perez G;Oguchi G;Ryan P;Nielsen BU;Brown M;Hidalgo A;Sachdeva Y;Mittal S;Osiyemi O;Skarbinski J;Juneja K;Hyland RH;Osinusi A;Chen S;Camus G;Abdelghany M;Davies S;Behenna-Renton N;Duff F;Marty FM;Katz MJ;Ginde AA;Brown SM;Schiffer JT;Hill JA;GS-US-540-9012 (PINETREE) Investigators
通讯作者：
GS-US-540-9012 (PINETREE) Investigators