JAK Inhibition as a New Treatment Strategy for Patients with COVID-19

Abstract

After the advent of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the outbreak of coronavirus disease 2019 (COVID-19) commenced across the world. Understanding the Immunopathogenesis of COVID-19 is essential for interrupting viral infectivity and preventing aberrant immune responses before a vaccine can be developed. In this review, we provide the latest insights into the roles of angiotensin-converting enzyme II (ACE2) and Ang II receptor-1 (AT1-R) in this disease. Novel therapeutic strategies, including recombinant ACE2, ACE inhibitors, AT1-R blockers, and Ang 1-7 peptides, may prevent or reduce viruses-induced pulmonary, cardiac, and renal injuries. However, more studies are needed to clarify the efficacy of these therapeutics. Furthermore, considering the common role of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway in AT1-R expressed on peripheral tissues and cytokine receptors on the surface of immune cells, potential targeting of this pathway using JAK inhibitors (JAKinibs) is suggested as a promising approach in patients with COVID-19 who are admitted to hospitals. In addition to antiviral therapy, potential ACE2- and AT1-R-inhibiting strategies, and other supportive care, we suggest other potential JAKinibs and novel anti-inflammatory combination therapies that affect the JAK-STAT pathway in patients with COVID-19. Since the combination of MTX and baricitinib leads to outstanding clinical outcomes, the addition of baricitinib to MTX might be a potential strategy.

Keywords: Angiotensin receptor blocker; Angiotensin-converting enzyme inhibitor; Bricitinib; Cytokine; JAK inhibitors; JAK-STAT pathway; Methotrexate.

Fig. 1

The renin-angiotensin system is a pivotal regulator of hypertension, which controls the homeostasis of main electrolytes and body fluids. It starts with liver synthesis of the angiotensin (Ang) peptide precursor, named angiotensinogen. Subsequently, the potent vasoconstrictive peptide Ang II is cleaved by ACE, which increases blood pressure through the activation of Ang II type 1 (AT1R). In contrast, ACE2 inactivates Ang II by removing the C-terminal phenyl alanine residue to yield heptapeptide Ang (1–7), which exerts its opposing effects through the Mas receptor. Ang I is also cleaved to Ang (1–7) and Ang (1–9) by the action of neprilysin and ACE2, respectively. Then, Ang-1–9 is cleaved with the help of either NEP or ACE to produce Ang-1–7 in a minor pathway. Higher levels of Ang (1–7) originate from Ang II rather than Ang I and Ang (1–9).

Fig. 2

Target cells potentially infected with SARS-CoV-2 in COVID-19.

Fig. 3

Cytokines and cytokine receptors participating in the COVID-19 immunopathogenesis. G-CSF, granulocyte colony stimulating factor.