Targeting purinergic receptors to suppress the cytokine storm induced by SARS-CoV-2 infection in pulmonary tissue

Abstract

The etiological agent of coronavirus disease (COVID-19) is the new member of the Coronaviridae family, a severe acute respiratory syndrome coronavirus 2 virus (SARS-CoV-2), responsible for the pandemic that is plaguing the world. The single-stranded RNA virus is capable of infecting the respiratory tract, by binding the spike (S) protein on its viral surface to receptors for the angiotensin II-converting enzyme (ACE2), highly expressed in the pulmonary tissue, enabling the interaction of the virus with alveolar epithelial cells promoting endocytosis and replication of viral material. The infection triggers the activation of the immune system, increased purinergic signaling, and the release of cytokines as a defense mechanism, but the response can become exaggerated and prompt the so-called “cytokine storm”, developing cases such as severe acute respiratory syndrome (SARS). This is characterized by fever, cough, and difficulty breathing, which can progress to pneumonia, failure of different organs and death. Thus, the present review aims to compile and correlate the mechanisms involved between the immune and purinergic systems with COVID-19, since the modulation of purinergic receptors, such as A2A, A2B, and P2X7 expressed by immune cells, seems to be effective as a promising therapy, to reduce the severity of the disease, as well as aid in the treatment of acute lung diseases and other cases of generalized inflammation.

The Potential of Purinergic Signaling to Thwart Viruses Including SARS-CoV-2

“…There is growing appreciation that targeting purinergic receptors may bring benefit to treat SARS-CoV-2 induced processes associated with the pathologies of COVID-19 (216)(217)(218)(219)(220)(221)(222). Accumulated clues to the puzzle of SARS-CoV-2 have suggested that when a virus can initiate platelet and neutrophil driven exacerbated macrophage inflammatory circuits, this can spell a pandemic.…”

Immunomodulatory Effects of a M2-Conditioned Medium (PRS®CK STORM): Theory on the Possible Complex Mechanism of Action through Anti-Inflammatory Modulation of the TLR System and the Purinergic System

“…Many published studies have demonstrated the importance of the purinergic system in the inflammation associated with the cytokine storm caused by moderate/ severe infection, including COVID-19, and have shown that using various purinergic system receptors as a therapeutic target can limit the negative effects of the cytokine storm [21,22,[55][56][57]. Extracellular ATP at high concentrations becomes a true alarmin [58], a potent proinflammatory signal capable of overexpressing and stimulating P2X-type purinergic receptors, especially P2X7R, located on various immune cells (neutrophils, eosinophils, monocytes, macrophages, mast cells, and lymphocytes) [59].…”

Irreversible Antagonists for the Adenosine A2B Receptor

“…Column chromatography of the products was performed with a CombiFlash R f Companion System using RediSep packed columns. 1 H-and 13 C-NMR data were collected on a Bruker Avance 500 MHz NMR spectrometer (Bruker Corporation, Billerica, MA, USA)at 500 MHz ( 1 H), and 126 MHz ( 13 C), or on a Bruker Avance 600 MHz NMR spectrometer (Bruker, Karlsruhe, Germany) at 600 MHz ( 1 H), and 151 MHz ( 13 C). DMSO-d 6 was used as solvent.…”

“…Moreover, A2A-and especially A2BARs are often upregulated on canc cells contributing to enhanced proliferation, metastasis, and angiogenesis [10][11][12]. Ther fore, A2A-and A2BAR antagonists, including dual-acting compounds that block both A subtypes, have been developed and are currently evaluated in clinical trials for canc immunotherapy [13]. According to the Protein Data Bank (PDB) [14], 60 X-ray cryst structures of the human A2AAR in complex with 20 different antagonists [15] (and 5 ag nists) have been published up to now, while structural data for the A2BAR are still elusiv However, X-ray co-crystal structures of the A2BAR in complex with antagonists would b highly useful in order to understand their binding and interactions.…”