小柯机器人

近日，美国西奈山伊坎医学院Ivan Marazzi及其研究团队发现，TOP1抑制疗法可预防SARS-CoV-2引起的致死性炎症。这一研究成果于2021年3月30日在线发表在国际学术期刊《细胞》上。

通过使用多维表观遗传学、转录、体外和体内分析，研究人员发现拓扑异构酶1（TOP1）抑制遏制了SARS-CoV-2诱导的致死性炎症。FDA批准的TOP1抑制剂Topotecan（TPT）的两剂治疗性治疗可抑制仓鼠感染引起的炎症。在感染后四天进行TPT治疗可降低转基因小鼠模型中的发病率并降低死亡率。

这些结果表明，TOP1抑制可作为严重SARS-CoV-2感染的有效定向疗法。TPT及其衍生物是在大多数国家/地区可获得的廉价临床级抑制剂。目前需要临床试验来评估TOP1抑制剂重利用对治疗人类严重COVID-19的功效。 

SARS-CoV-2引起的大流行目前影响了全球数百万人的生命。大量的回顾性研究表明，炎性细胞因子和促炎因子水平的升高与疾病严重程度和死亡率的升高有关。

附：英文原文

Title: TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation.

Author: Jessica Sook Yuin Ho, Bobo Wing-Yee Mok, Laura Campisi, Tristan Jordan, Soner Yildiz, Sreeja Parameswaran, Joseph A. Wayman, Natasha N. Gaudreault, David A. Meekins, Sabarish V. Indran, Igor Morozov, Jessie D. Trujillo, Yesai S. Fstkchyan, Raveen Rathnasinghe, Zeyu Zhu, Simin Zheng, Nan Zhao, Kris White, Helen Ray-Jones, Valeriya Malysheva, Michiel J. Thiecke, Siu-Ying Lau, Honglian Liu, Anna Junxia Zhang, Andrew Chak-Yiu Lee, Wen-Chun Liu, Sonia Jangra, Alba Escalera, Teresa Aydillo, Betsaida Salom Melo, Ernesto Guccione, Robert Sebra, Elaine Shum, Jan Bakker, David A. Kaufman, Andre L. Moreira, Mariano Carossino, Udeni B.R. Balasuriya, Minji Byun, Randy A. Albrecht, Michael Schotsaert, Adolfo Garcia-Sastre, Sumit K. Chanda, Emily R. Miraldi, Anand D. Jeyasekharan, Benjamin R. TenOever, Mikhail Spivakov, Matthew T. Weirauch, Sven Heinz, Honglin Chen, Christopher Benner, Juergen A. Richt, Ivan Marazzi

Issue&Volume: 2021-03-30

Abstract: The ongoing pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro and in vivo analyses, we report that Topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of Topotecan (TPT), a FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as four days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of TOP1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing TOP1 inhibitors for severe COVID-19 in humans.

DOI: 10.1016/j.cell.2021.03.051

Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00382-2