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

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

doi:10.1016/j.cell.2021.03.051

Cited by 93 publications

(78 citation statements)

References 81 publications

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“…A recent study showed that the drug plitidepsin (Aplidin), which targets the host protein eEF1A, exhibits potent anti-SARS-CoV-2 activity in cell cultures and mouse models 25 . Another US FDA-approved inhibitor topotecan (TPT) targeting topoisomerase 1 has been reported to suppress the lethal inflammation induced by SARS-CoV-2 and reduce morbidity and mortality in a preclinical mouse model 26 . Thus, identification of additional host biological pathways and corresponding drugs is urgently needed to facilitate new drug development for the treatment of the COVID-19 disease and prevent viral spread.…”

Section: Mainmentioning

confidence: 99%

Pharmacological inhibition of fatty acid synthesis blocks SARS-CoV-2 replication

Chu

Xing

et al. 2021

Nat Metab

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Caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19 is a virus-induced inflammatory disease of the airways and lungs that leads to severe multi-organ damage and death. Here we show that cellular lipid synthesis is required for SARS-CoV-2 replication and offers an opportunity for pharmacological intervention. Screening a short-hairpin RNA sublibrary that targets metabolic genes, we identified genes that either inhibit or promote SARS-CoV-2 viral infection, including two key candidate genes, ACACA and FASN , which operate in the same lipid synthesis pathway. We further screened and identified several potent inhibitors of fatty acid synthase (encoded by FASN ), including the US Food and Drug Administration-approved anti-obesity drug orlistat, and found that it inhibits in vitro replication of SARS-CoV-2 variants, including more contagious new variants, such as Delta. In a mouse model of SARS-CoV-2 infection (K18-hACE2 transgenic mice), injections of orlistat resulted in lower SARS-CoV-2 viral levels in the lung, reduced lung pathology and increased mouse survival. Our findings identify fatty acid synthase inhibitors as drug candidates for the prevention and treatment of COVID-19 by inhibiting SARS-CoV-2 replication. Clinical trials are needed to evaluate the efficacy of repurposing fatty acid synthase inhibitors for severe COVID-19 in humans.

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Section: Mainmentioning

confidence: 99%

Pharmacological inhibition of fatty acid synthesis blocks SARS-CoV-2 replication

Chu

Xing

et al. 2021

Nat Metab

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“…The copyright holder for this preprint (which this version posted May 26, 2021. ; https://doi.org/10.1101/2021.05. 26.445787 doi: bioRxiv preprint (IL)-6 and IL-8 (5,7,8). In certain cases, massive inflammatory responses occur due to hyper-activation of the immune system, resulting in a widespread and uncontrolled cytokine storm, leading to acute respiratory distress syndrome (ARDS), life-threatening lung damage, and increased mortality of COVID-19 patients.…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Nsp14 activates NF-κB signaling and induces IL-8 upregulation

Kenney

Liu

et al. 2021

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to NF-κB activation and induction of pro-inflammatory cytokines, though the underlying mechanism for this activation is not fully understood. Our results reveal that the SARS-CoV-2 Nsp14 protein contributes to the viral activation of NF-κB signaling. Nsp14 caused the nuclear translocation of NF-κB p65. Nsp14 induced the upregulation of IL-6 and IL-8, which also occurred in SARS-CoV-2 infected cells. IL-8 upregulation was further confirmed in lung tissue samples from COVID-19 patients. A previous proteomic screen identified the putative interaction of Nsp14 with host Inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) protein, which is known to regulate NF-κB signaling. We confirmed the Nsp14-IMPDH2 protein interaction and found that IMPDH2 knockdown or chemical inhibition using ribavirin (RIB) and mycophenolic acid (MPA) abolishes Nsp14-mediated NF-κB activation and cytokine induction. Furthermore, IMDPH2 inhibitors (RIB, MPA) efficiently blocked SARS-CoV-2 infection, indicating that IMDPH2, and possibly NF-κB signaling, is beneficial to viral replication. Overall, our results identify a novel role of SARS-CoV-2 Nsp14 in causing the activation of NF-κB.

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“…Combined with remdesivir, clofazimine exhibited antiviral synergy in cell culture and animal models [ 2 ]. Topotecan suppresses infection-induced inflammation, thus reducing morbidity and rescuing mortality in a transgenic animal model [ 3 ]. However, the efficacies of these drugs on patients await further clinical investigation.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide analysis of protein–protein interactions and involvement of viral proteins in SARS-CoV-2 replication

et al. 2021

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Background Analysis of viral protein–protein interactions is an essential step to uncover the viral protein functions and the molecular mechanism for the assembly of a viral protein complex. We employed a mammalian two-hybrid system to screen all the viral proteins of SARS-CoV-2 for the protein–protein interactions. Results Our study detected 48 interactions, 14 of which were firstly reported here. Unlike Nsp1 of SARS-CoV, Nsp1 of SARS-CoV-2 has the most interacting partners among all the viral proteins and likely functions as a hub for the viral proteins. Five self-interactions were confirmed, and five interactions, Nsp1/Nsp3.1, Nsp3.1/N, Nsp3.2/Nsp12, Nsp10/Nsp14, and Nsp10/Nsp16, were determined to be positive bidirectionally. Using the replicon reporter system of SARS-CoV-2, we screened all viral Nsps for their impacts on the viral replication and revealed Nsp3.1, the N-terminus of Nsp3, significantly inhibited the replicon reporter gene expression. We found Nsp3 interacted with N through its acidic region at N-terminus, while N interacted with Nsp3 through its NTD, which is rich in the basic amino acids. Furthermore, using purified truncated N and Nsp3 proteins, we determined the direct interactions between Nsp3 and N protein. Conclusions Our findings provided a basis for understanding the functions of coronavirus proteins and supported the potential of interactions as the target for antiviral drug development.

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

Cited by 93 publications

References 81 publications

Pharmacological inhibition of fatty acid synthesis blocks SARS-CoV-2 replication

Pharmacological inhibition of fatty acid synthesis blocks SARS-CoV-2 replication

SARS-CoV-2 Nsp14 activates NF-κB signaling and induces IL-8 upregulation

Genome-wide analysis of protein–protein interactions and involvement of viral proteins in SARS-CoV-2 replication

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