A metabolic modeling approach reveals promising therapeutic targets and antiviral drugs to combat COVID-19

Santos-Beneit, Fernando; Raškevičius, Vytautas; Skeberdis, Vytenis Arvydas; Bordel, Sergio

doi:10.1038/s41598-021-91526-3

Cited by 33 publications

(23 citation statements)

References 66 publications

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“…Based on the results above, we suspected that targeting ACSL1 may help eliminate MHV-A59 infection. Two individual compound screening studies have found that Triacsin C inhibited SARS-CoV-2 replication [59,60], supporting our hypothesis. We first determined the effects of ACSL1 inhibitor Triacsin C on MHV-A59 infection in murine macrophages.…”

Section: Inhibiting Acsl1 Suppressed Mhv-a59 Infectionsupporting

confidence: 86%

Inhibiting ACSL1-Related Ferroptosis Restrains Murine Coronavirus Infection

Xia

Zhang

You

2021

Viruses

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Murine hepatitis virus strain A59 (MHV-A59) was shown to induce pyroptosis, apoptosis, and necroptosis of infected cells, especially in the murine macrophages. However, whether ferroptosis, a recently identified form of lytic cell death, was involved in the pathogenicity of MHV-A59 is unknown. We utilized murine macrophages and a C57BL/6 mice intranasal infection model to address this. In primary macrophages, the ferroptosis inhibitor inhibited viral propagation, inflammatory cytokines released, and cell syncytia formed after MHV-A59 infection. In the mouse model, we found that in vivo administration of liproxstatin-1 ameliorated lung inflammation and tissue injuries caused by MHV-A59 infection. To find how MHV-A59 infection influenced the expression of ferroptosis-related genes, we performed RNA-seq in primary macrophages and found that MHV-A59 infection upregulates the expression of the acyl-CoA synthetase long-chain family member 1 (ACSL1), a novel ferroptosis inducer. Using ferroptosis inhibitors and a TLR4 inhibitor, we showed that MHV-A59 resulted in the NF-kB-dependent, TLR4-independent ACSL1 upregulation. Accordingly, ACSL1 inhibitor Triacsin C suppressed MHV-A59-infection-induced syncytia formation and viral propagation in primary macrophages. Collectively, our study indicates that ferroptosis inhibition protects hosts from MHV-A59 infection. Targeting ferroptosis may serve as a potential treatment approach for dealing with hyper-inflammation induced by coronavirus infection.

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Section: Inhibiting Acsl1 Suppressed Mhv-a59 Infectionsupporting

confidence: 86%

Inhibiting ACSL1-Related Ferroptosis Restrains Murine Coronavirus Infection

Xia

Zhang

You

2021

Viruses

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“…On the other hand, S-palmitoylation is a unique protein lipidation process essential for viral invasion. Spalmitoylation of SARS-CoV-2 S protein has been reported to facilitate its anchor and fusion with the host cellular membrane receptor (Santos-Beneit et al, 2020). Thirdly, coronaviruses hijack the host cells for the formation of the replication and transcription complex, the double membrane vesicles (DMVs).…”

Section: Discussionmentioning

confidence: 99%

Altered Lipid Profile Is a Risk Factor for the Poor Progression of COVID-19: From Two Retrospective Cohorts

Jin

Dong

et al. 2021

Front. Cell. Infect. Microbiol.

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BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has spread worldwide. However, the impact of baseline lipid profile on clinical endpoints in COVID-19 and the potential effect of COVID-19 on lipid profile remain unclear.MethodsIn this retrospective cohort study, we consecutively enrolled 430 adult COVID-19 patients from two Chinese hospitals (one each in Chengdu and Wuhan). The lipid profile before admission and during the disease course and the clinical endpoint including in-hospital death or oropharyngeal swab test positive again (OSTPA) after discharge were collected. We used Kaplan–Meier and Cox regression to explore the lipid risk factors before admission associated with endpoints. Then, we assessed the lipid level change along with the disease course to determine the relationship between pathology alteration and the lipid change.ResultsIn the Chengdu cohort, multivariable Cox regression showed that low-density lipoprotein cholesterol (LDL-C) dyslipidemia before admission was associated with OSTPA after discharge for COVID-19 patients (RR: 2.51, 95% CI: 1.19, 5.29, p = 0.006). In the Wuhan cohort, the patients with triglyceride (TG) dyslipidemia had an increased risk of in-hospital death (RR: 1.92, 95% CI: 1.08, 3.60, p = 0.016). In addition, in both cohorts, the lipid levels gradually decreased in the in-hospital death or OSTPA subgroups since admission. On admission, we also noticed the relationship between the biomarkers of inflammation and the organ function measures and this lipid level in both cohorts. For example, after adjusting for age, sex, comorbidities, smoking, and drinking status, the C-reactive protein level was negatively associated with the TC lipid level [β (SE) = -0.646 (0.219), p = 0.005]. However, an increased level of alanine aminotransferase, which indicates impaired hepatic function, was positively associated with total cholesterol (TC) lipid levels in the Chengdu cohort [β (SE) = 0.633 (0.229), p = 0.007].ConclusionsThe baseline dyslipidemia should be considered as a risk factor for poor prognosis of COVID-19. However, lipid levels may be altered during the COVID-19 course, since lipidology may be distinctly affected by both inflammation and organic damage for SARS-CoV-2.

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“…In this context the SARS-CoV-2 pandemic boosted research on metabolic antiviral host targets, which resulted in a multitude of potential candidates. While interference with many of these candidate targets already showed promising results in vitro and/or in vivo, there are even more potential targets that have been proposed, but not yet experimentally tested [ 121 ].…”

Section: Coronavirusesmentioning

confidence: 99%

Metabolic Modifications by Common Respiratory Viruses and Their Potential as New Antiviral Targets

Kleinehr

Wilden

Boergeling

et al. 2021

Viruses

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Respiratory viruses are known to be the most frequent causative mediators of lung infections in humans, bearing significant impact on the host cell signaling machinery due to their host-dependency for efficient replication. Certain cellular functions are actively induced by respiratory viruses for their own benefit. This includes metabolic pathways such as glycolysis, fatty acid synthesis (FAS) and the tricarboxylic acid (TCA) cycle, among others, which are modified during viral infections. Here, we summarize the current knowledge of metabolic pathway modifications mediated by the acute respiratory viruses respiratory syncytial virus (RSV), rhinovirus (RV), influenza virus (IV), parainfluenza virus (PIV), coronavirus (CoV) and adenovirus (AdV), and highlight potential targets and compounds for therapeutic approaches.

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A metabolic modeling approach reveals promising therapeutic targets and antiviral drugs to combat COVID-19

Cited by 33 publications

References 66 publications

Inhibiting ACSL1-Related Ferroptosis Restrains Murine Coronavirus Infection

Inhibiting ACSL1-Related Ferroptosis Restrains Murine Coronavirus Infection

Altered Lipid Profile Is a Risk Factor for the Poor Progression of COVID-19: From Two Retrospective Cohorts

Metabolic Modifications by Common Respiratory Viruses and Their Potential as New Antiviral Targets

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