Battling COVID-19 Pandemic: Sphingosine-1-Phosphate Analogs as an Adjunctive Therapy?

Naz, Farha; Arish, Mohd

doi:10.3389/fimmu.2020.01102

Cited by 28 publications

(31 citation statements)

References 27 publications

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“…Thus, selectively targeting S1P 1 receptors, as central orchestrators of cytokine storm suppression, may prove to be promising in alleviating the severity of diseases where amplification of the cytokine storm is a significant pathological manifestation [ 230 ], such as demonstrated in acute and chronic COVID-19 patients. As such, S1P analogues have been successful in reducing lung tissue inflammation and injury in response to viral diseases in preclinical mouse models [ 231 ]. Conversely, as briefly mentioned in Section 5.3 , intracellular SphK-S1P signalling has been demonstrated to regulate LPS-induced inflammation in lung endothelium, whereby LPSs have been very effective in the activation of signals to induce an antiviral response [ 129 ].…”

Section: Targeting Sphk/s1p/s1pr In Viral Infection and Alleviatiomentioning

confidence: 99%

Targeting the SphK-S1P-SIPR Pathway as a Potential Therapeutic Approach for COVID-19

McGowan

Haddadi

Nassif

et al. 2020

IJMS

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The world is currently experiencing the worst health pandemic since the Spanish flu in 1918—the COVID-19 pandemic—caused by the coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This pandemic is the world’s third wake-up call this century. In 2003 and 2012, the world experienced two major coronavirus outbreaks, SARS-CoV-1 and Middle East Respiratory syndrome coronavirus (MERS-CoV), causing major respiratory tract infections. At present, there is neither a vaccine nor a cure for COVID-19. The severe COVID-19 symptoms of hyperinflammation, catastrophic damage to the vascular endothelium, thrombotic complications, septic shock, brain damage, acute disseminated encephalomyelitis (ADEM), and acute neurological and psychiatric complications are unprecedented. Many COVID-19 deaths result from the aftermath of hyperinflammatory complications, also referred to as the “cytokine storm syndrome”, endotheliitus and blood clotting, all with the potential to cause multiorgan dysfunction. The sphingolipid rheostat plays integral roles in viral replication, activation/modulation of the immune response, and importantly in maintaining vasculature integrity, with sphingosine 1 phosphate (S1P) and its cognate receptors (SIPRs: G-protein-coupled receptors) being key factors in vascular protection against endotheliitus. Hence, modulation of sphingosine kinase (SphK), S1P, and the S1P receptor pathway may provide significant beneficial effects towards counteracting the life-threatening, acute, and chronic complications associated with SARS-CoV-2 infection. This review provides a comprehensive overview of SARS-CoV-2 infection and disease, prospective vaccines, and current treatments. We then discuss the evidence supporting the targeting of SphK/S1P and S1P receptors in the repertoire of COVID-19 therapies to control viral replication and alleviate the known and emerging acute and chronic symptoms of COVID-19. Three clinical trials using FDA-approved sphingolipid-based drugs being repurposed and evaluated to help in alleviating COVID-19 symptoms are discussed.

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Section: Targeting Sphk/s1p/s1pr In Viral Infection and Alleviatiomentioning

confidence: 99%

Targeting the SphK-S1P-SIPR Pathway as a Potential Therapeutic Approach for COVID-19

McGowan

Haddadi

Nassif

et al. 2020

IJMS

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“…Agonist of S1P1R, S1P3R, S1P4R and S1P5R receptors. Approved [176] JAK Clarithromycin inhibits bacterial protein synthesis and neutrophil activity Approved [195,196] Immune Supplements…”

Section: Fingolimodmentioning

confidence: 99%

“…Sphingosine-1-phosphate receptors, a group of G-protein-coupled receptors (GPCRs) to which the biologically active lipid called sphingosine 1-phosphate (S1P) have strong affinity, are sub-divided into: S1PR1, S1PR2, S1PR3, S1PR4 and S1PR5 [175]. SIP acts as signaling molecules for specific targets and their upregulation could serve as potential targets in combating hyperinflammation associated with SARS-CoV-2 infection [176,177]. Specifically, S1PR1 abundantly found on endothelial cells plays two important roles: (a) modulation of immune responses through the regulation of the maturation, migration, and trafficking of lymphocytes [178,179] (b) protection of the vascular endothelium against infection by regulating the vascular maturation, migration, cytoskeletal structure, and capillary-like network formation of endothelial cells [180,181].…”

Section: Tnf Blockermentioning

confidence: 99%

“…Fingolimod is an approved agonist of S1P1, S1P3, S1P4 and S1P5 receptors. The oral administration of Fingolimod in COVID-19 patients stabilized the pulmonary endothelial barrier, decreased the inflammatory infiltrate, and reduced histopathologies associated with ARDS [176,184]. Also, CYM5442, a S1P1R analog significantly reduced hyperinflammation in H1N1 induced mice and improved survival.…”

Section: Tnf Blockermentioning

confidence: 99%

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Preparing for the Storm: Mitigating the Effect of SARS-CoV-2 Induced Hypercytokinemia

Rowaiye¹,

Okpalefe²,

Onuh³

et al. 2020

Preprint

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With increasing fatalities, the COVID-19 pandemic constitutes a formidable global health challenge. The causative agent, SARS-CoV-2 constantly tests the efficacy of the immune system of its victims. The protective ability of the innate immune system as the first responder largely determines the progression of disease and its clinical prognosis. Evidence suggests that mortalities associated with COVID-19 are largely due to hyperinflammation and a dysregulated immune response. Consequently, the degree of the release of pro-inflammatory cytokines such as IL1, IL-6, and TNF alpha remarkably distinguishes between mild and severe cases of COVID-19. The early prediction of a cytokine storm is made possible by several serum chemistry and hematological markers. The prompt use of these markers for laboratory tests, and the aggressive prevention and management of a cytokine release syndrome is critical in determining the level of morbidity and fatality associated with COVID-19. With respect to the SARS-CoV-2 and the host cell, this literature review focuses on the dynamics of the COVID-19 disease highlighting on the pathogenesis, and the markers of Cytokine Storm. It also proffers solutions by critically looking at the current and potential pharmacological agents that are or can be used to mitigate and manage cytokine storms.

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“…Antagonism of interferon response negative regulators has been proposed as a mechanism to enhance host antiviral responses to clear infection, both alone and in conjunction with IFN treatment (14)(15)(16), and most recently during the COVID-19 pandemic (17). However, regulators working upstream of transcription impact ISGs indiscriminately, including suppression of the pro-inflammatory effectors, that when overabundant, can induce a cytokine storm; for example, agonists of an IFNAR-downregulating protein, S1PR1 (18), are proposed for use against pandemic influenza viruses (19) and SARS-CoV-2 (20) to instead limit excessive immune responses associated with interferon signaling. An ideal negative regulator of the IFN response for antiviral therapeutic targeting would enhance virus restricting ISGs specifically, without affecting pro-immune cytokines.…”

Section: Introductionmentioning

confidence: 99%

ETV7 limits antiviral gene expression and control of SARS-CoV-2 and influenza viruses

Froggatt

Harding

Heaton

et al. 2019

Preprint

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42The type I interferon (IFN) response is an important component of the innate immune 43 response to viral infection. Precise control of interferon responses is critical, as insufficient 44 levels of interferon-stimulated genes (ISGs) can lead to a failure to restrict viral spread, 45 while excessive ISG activation results in interferon-related pathologies. While both 46 positive and negative regulatory factors can control the magnitude and duration of IFN 47Significance 60Interferons (IFNs) were first described in 1957 and are now known to be critical for 61 restriction of viruses. Still, our understanding of the complex web of interactions that 62 underlie IFN responses remains incomplete. In particular, negative regulation of interferon 63 responses has received disproportionately less study. In this work, we performed a 64 genome-wide overexpression screen for factors capable of suppressing IFN response 65 signaling. We identified a DNA binding transcription factor (ETV7) that, after induction by 66 interferon, acts to suppress a subset of IFN-stimulated genes required for control of 67 influenza viruses. Our work highlights the importance of understanding negative IFN 68 signaling not only with respect to the magnitude and duration of the response, but also 69 the specificity of its antiviral effects. 70

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Battling COVID-19 Pandemic: Sphingosine-1-Phosphate Analogs as an Adjunctive Therapy?

Cited by 28 publications

References 27 publications

Targeting the SphK-S1P-SIPR Pathway as a Potential Therapeutic Approach for COVID-19

Targeting the SphK-S1P-SIPR Pathway as a Potential Therapeutic Approach for COVID-19

Preparing for the Storm: Mitigating the Effect of SARS-CoV-2 Induced Hypercytokinemia

ETV7 limits antiviral gene expression and control of SARS-CoV-2 and influenza viruses

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