COVID-19 and the potential of Janus family kinase (JAK) pathway inhibition: A novel treatment strategy

Khaledi, Mansoor; Sameni, Fatemeh; Yahyazade, Sheida; Radandish, Maedeh; Owlia, Parviz; Bagheri, Nader; Afkhami, Hamed; Mahjoor, Mohamad; Esmaelpour, Zahra; Kohansal, Maryam; Aghaei, Farzad

doi:10.3389/fmed.2022.961027

Cited by 7 publications

(5 citation statements)

References 196 publications

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“…In COVID-19 patients, viral entry stimulates multiple signaling pathways and produces a broad spectrum of clinical manifestations such as acute respiratory distress syndrome (ARDS), multi-organ failure, and even death ( Rarani et al, 2022 ). The primary etiological factor is a systemic immune activation characterized by elevated levels of pro-inflammatory cytokines (IL-2, IL-4, IL-6, IL-7, IL-10, TNF-alpha, IFN-gamma) and chemokines (CCL2, CCL8), also known as cytokine release syndrome or cytokine storm ( Khaledi et al, 2022 ). One of several signaling pathways is the JAK-STAT signaling pathway in the immunity and immunopathology of COVID-19 disease ( Luo et al, 2020 ).…”

Section: Jakinibs and Covid-19mentioning

confidence: 99%

Therapeutic implications of current Janus kinase inhibitors as anti-COVID agents: A review

et al. 2023

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Severe cases of COVID-19 are characterized by hyperinflammation induced by cytokine storm, ARDS leading to multiorgan failure and death. JAK-STAT signaling has been implicated in immunopathogenesis of COVID-19 infection under different stages such as viral entry, escaping innate immunity, replication, and subsequent inflammatory processes. Prompted by this fact and prior utilization as an immunomodulatory agent for several autoimmune, allergic, and inflammatory conditions, Jakinibs have been recognized as validated small molecules targeting the rapid release of proinflammatory cytokines, primarily IL-6, and GM-CSF. Various clinical trials are under investigation to evaluate Jakinibs as potential candidates for treating COVID-19. Till date, there is only one small molecule Jakinib known as baricitinib has received FDA-approval as a standalone immunomodulatory agent in treating critical COVID-19 patients. Though various meta-analyses have confirmed and validated the safety and efficacy of Jakinibs, further studies are required to understand the elaborated pathogenesis of COVID-19, duration of Jakinib treatment, and assess the combination therapeutic strategies. In this review, we highlighted JAK-STAT signalling in the pathogenesis of COVID-19 and clinically approved Jakinibs. Moreover, this review described substantially the promising use of Jakinibs and discussed their limitations in the context of COVID-19 therapy. Hence, this review article provides a concise, yet significant insight into the therapeutic implications of Jakinibs as potential anti-COVID agents which opens up a new horizon in the treatment of COVID-19, effectively.

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Section: Jakinibs and Covid-19mentioning

confidence: 99%

Therapeutic implications of current Janus kinase inhibitors as anti-COVID agents: A review

et al. 2023

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“…The cytokine storm is the loss of control and the outbreak of systemic in ammatory response to many stressors such as infection, drugs, rheumatoid disorders and malignancy. (35) This situation is characterized by the over activation of immune cells that produce enormous amounts of in ammatory cytokines, chemokines, as well as other chemical mediators which may cause tissue damage. (36) Cytokine storm characterized by increased TNF-α, IFN-γ, IL-1β, IL-18 and IL-6, was veri ed well-corelated with the severity of the coronavirus disease 2019 (COVID-19) in patients.…”

Section: Discussionmentioning

confidence: 99%

The activation of AIM2/Caspase-1/GSDMD pathway contributes to pyroptosis of keratinocytes in Stevens-Johnson syndrome/toxic epidermal necrolysis

Yang

Shou

et al. 2023

Preprint

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Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) are severe cutaneous adverse drug reactions, rare but life-threatening, characterized by massive keratinocyte death and development of a systemic inflammatory response. Pyroptosis is a lytic form of pro-inflammatory programmed necrotic cell death which participates in the pathogenesis of various inflammatory diseases, it depends on activation of inflammasomes such as NLRP3/NALP1/AIM2/NLRC4 and inflammatory caspases (caspase 1/4/5), subsequently it is executed by pore-forming protein of the gasdermin family, resulting in releases of inflammatory cytokines such as IL-1β, IL-18. However, does pyroptotic machinery exist in the SJS/TEN remains open. In our study, we present evidence for the involvement and mechanism of pyroptosis in SJS/TEN keratinocytes. Inflammatory cytokines TNF-α and IFN-γ participating in keratinocyte pyroptosis through strengthening of cytoplasmic dsDNA/AIM2/Caspase-1/GSDMD pathway were identified in vivo and in vitro. Further, we observed that all of the four small molecular pyroptosis inhibitors including Z-YVAD-FMK，dimethyl fumarate (DMF), necrosulfonamide (NSA) and disulfiram caused a significant inhibition of pyroptosis in human primary keratinocytes, and significantly downregulated the release of pyroptosis-related inflammatory cytokines IL-1β and IL-18. These discoveries expand our understanding of the pathogenesis of SJS/TEN and it is hoped that this could facilitate the development of new therapeutics for the treatment of SJS/TEN patients with activated pyroptosis in keratinocytes.

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“…In its anti-inflammatory role, JAK2 also activates pathways promoting tissue repair and regeneration. Thus, drug repurposing candidates with the potential to influence JAK2 signalling, may represent an effective therapeutic strategy for controlling the disease [88]. For instance, IL-6 binds to soluble and transmembrane IL-6R and the resultant complex induces homodimerization of gp130, leading to activation of JAK2 [89].…”

Section: Predicting Candidate Drugs Using Existing Knowledge Graphs D...mentioning

confidence: 99%

Network-based multi-omics-disease-drug associations reveal drug repurposing candidates for COVID-19 disease phases

Agamah,

Ederveen,

Skelton

et al. 2024

Preprint

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Background:The development and roll-out of vaccines, and the use of various drugs have contributed to controlling the COVID-19 pandemic. Nevertheless, challenges such as the inequitable distribution of vaccines, the influence of emerging viral lineages and immune evasive variants on vaccine efficacy, and the inadequate immune defense in subgroups of the population continue to motivate the development of new drugs to combat the disease. Aim:In this study, we sought to identify, prioritize, and characterize drug repurposing candidates appropriate for treating mild, moderate, or severe COVID-19 using a network-based integrative approach that systematically integrates drug-related data and multi-omics datasets. Methods: We leveraged drug data, and multi-omics data, and used a random walk restart algorithm to explore an integrated knowledge graph comprised of three sub-graphs: (i) a COVID-19 knowledge graph, (ii) a drug repurposing knowledge graph, and (iii) a COVID-19 disease-state specific omics graph. Results:We prioritized twenty FDA-approved agents as potential candidate drugs for mild, moderate, and severe COVID-19 disease phases. Specifically, drugs that could stimulate immune cell recruitment and activation including histamine, curcumin, and paclitaxel have potential utility in mild disease states to mitigate disease progression. Drugs like omacetaxine, crizotinib, and vorinostat that exhibit antiviral properties and have the potential to inhibit viral replication can be considered for mild to moderate COVID-19 disease states. Also, given the association between antioxidant deficiency and high inflammatory factors that trigger cytokine storms, antioxidants like glutathione can be considered for moderate disease states. Drugs that exhibit potent anti-inflammatory effects like (i) anti-inflammatory drugs (sarilumab and tocilizumab), (ii) corticosteroids (dexamethasone and hydrocortisone), and (iii) immunosuppressives (sirolimus and cyclosporine) are potential candidates for moderate to severe disease states that trigger a hyperinflammatory cascade of COVID-19. Conclusion:Our study demonstrates that the multi-omics data-driven integrative analysis within the drug data enables prioritizing drug candidates for COVID-19 disease phases, offering a comprehensive basis for therapeutic strategies that can be brought to market quickly given their established safety profiles. Importantly, the multi-omics data-driven integrative analysis within the drug data approach implemented here can be used to prioritize drug repurposing candidates appropriate for other diseases.

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COVID-19 and the potential of Janus family kinase (JAK) pathway inhibition: A novel treatment strategy

Cited by 7 publications

References 196 publications

Therapeutic implications of current Janus kinase inhibitors as anti-COVID agents: A review

Therapeutic implications of current Janus kinase inhibitors as anti-COVID agents: A review

The activation of AIM2/Caspase-1/GSDMD pathway contributes to pyroptosis of keratinocytes in Stevens-Johnson syndrome/toxic epidermal necrolysis

Network-based multi-omics-disease-drug associations reveal drug repurposing candidates for COVID-19 disease phases

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