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

Abstract

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.

Cyclooxygenase-2/prostaglandin E2 pathway regulates infectious bronchitis virus replication in avian macrophages

“…An effect was noticed in both IBV strains, though such an effect was not observed in the case of treatment with JAK-I inhibitor 420 092, and this is difficult to explain. Overall, our data indicated that inhibition of JAK-II decreases the IBV loads in macrophages, and our observation in this regard agrees with the observations made on other host viral models involving SARS-CoV-2, and Middle East respiratory syndrome coronavirus (MERS-CoV) [53,54].…”

Whole transcriptome profiling of placental pathobiology in SARS-CoV-2 pregnancies identifies placental dysfunction signatures

“…Despite the SARS-CoV-2 samples showing undetectable SARS-CoV-2 by RNA-scope, transcriptional profiling showed positive enrichment of SARS-CoV-2 related pathways in the SARS-CoV-2 samples, such as “SARS_COV_2_INFECTION”, and “SARS_COV_2_HOST_INTERACTIONS” from the Reactome database, as well as the Interferon Alpha Response pathway from the Hallmark database, which is a first-line immune response pathway that has been associated with SARS-CoV-2 infection (Figure 2d-f) 15 . These pathways were supported by increased expression of genes that have been associated with SARS-CoV-2, such as the inflammatory marker IFI16 16 , disease progression marker IFI27 17 , disease prognosticator B2M 18 , activation of Janus Kinases (i.e., JAK1 ), and expression of STAT3 19 (Figure 2 g-j). Notably, gene expression for these markers was elevated predominantly in the villous core stroma cell compartment, presumably stemming from the immune subpopulation within the stroma.…”

Whole transcriptome profiling of placental pathobiology in SARS‐CoV‐2 pregnancies identifies placental dysfunction signatures

“… 15 These pathways were supported by increased expression of genes that have been associated with SARS‐CoV‐2, such as the inflammatory marker IFI16 , 16 disease progression marker IFI27 , 17 disease prognosticator B2M , 18 activation of Janus Kinases (i.e. JAK1 ), and expression of STAT3 19 (Figure 2g–j ). Notably, gene expression for these markers was elevated predominantly in the villous core stromal cell compartment, presumably stemming from the immune subpopulation within the stroma.…”