Sphingosine Kinase 2 associates with the nsP3 of chikungunya virus and is required for replication

Oyewole, Opeoluwa O.; Reid, St Patrick

doi:10.1101/2020.09.10.291682

Cited by 1 publication

(1 citation statement)

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“… 36 Conversely, overexpression of SK2 in response to opaganib may further suppress viral replication by competing with G3BP binding to the RTC. 112 Nsp3 plays a parallel membrane anchoring role for SARS-CoV-2 replication, 113 and therefore, disruption of the viral RTC may be involved in the ability of opaganib to suppress replication by SARS-CoV-2.…”

Section: Mechanism For the Antiviral Efficacy Of Opaganibmentioning

confidence: 99%

Recent Progress in the Development of Opaganib for the Treatment of Covid-19

Smith¹,

Maines²,

Keller³

et al. 2022

DDDT

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The Covid-19 pandemic driven by the SARS-CoV-2 virus continues to exert extensive humanitarian and economic stress across the world. Although antivirals active against mild disease have been identified recently, new drugs to treat moderate and severe Covid-19 patients are needed. Sphingolipids regulate key pathologic processes, including viral proliferation and pathologic host inflammation. Opaganib (aka ABC294640) is a first-in-class clinical drug targeting sphingolipid metabolism for the treatment of cancer and inflammatory diseases. Recent work demonstrates that opaganib also has antiviral activity against several viruses including SARS-CoV-2. A recently completed multinational Phase 2/3 clinical trial of opaganib in patients hospitalized with Covid-19 demonstrated that opaganib can be safely administered to these patients, and more importantly, resulted in a 62% decrease in mortality in a large subpopulation of patients with moderately severe Covid-19. Furthermore, acceleration of the clearance of the virus was observed in opaganib-treated patients. Understanding the biochemical mechanism for the anti-SARS-CoV-2 activity of opaganib is essential for optimizing Covid-19 treatment protocols. Opaganib inhibits three key enzymes in sphingolipid metabolism: sphingosine kinase-2 (SK2); dihydroceramide desaturase (DES1); and glucosylceramide synthase (GCS). Herein, we describe a tripartite model by which opaganib suppresses infection and replication of SARS-CoV-2 by inhibiting SK2, DES1 and GCS. The potential impact of modulation of sphingolipid signaling on multi-organ dysfunction in Covid-19 patients is also discussed.

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Section: Mechanism For the Antiviral Efficacy Of Opaganibmentioning

confidence: 99%