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Review
. 2021 May 22;22(11):5460.
doi: 10.3390/ijms22115460.

Possible Beneficial Actions of Caffeine in SARS-CoV-2

Bianca S Romero-Martínez  1 , Luis M Montaño  1 , Héctor Solís-Chagoyán  2 , Bettina Sommer  3 , Gemma Lizbeth Ramírez-Salinas  4 , Gloria E Pérez-Figueroa  5 , Edgar Flores-Soto  1
Affiliations
Review

Possible Beneficial Actions of Caffeine in SARS-CoV-2

Bianca S Romero-Martínez et al. Int J Mol Sci. .

Abstract

The COVID-19 pandemic has established an unparalleled necessity to rapidly find effective treatments for the illness; unfortunately, no specific treatment has been found yet. As this is a new emerging chaotic situation, already existing drugs have been suggested to ameliorate the infection of SARS-CoV-2. The consumption of caffeine has been suggested primarily because it improves exercise performance, reduces fatigue, and increases wakefulness and awareness. Caffeine has been proven to be an effective anti-inflammatory and immunomodulator. In airway smooth muscle, it has bronchodilator effects mainly due to its activity as a phosphodiesterase inhibitor and adenosine receptor antagonist. In addition, a recent published document has suggested the potential antiviral activity of this drug using in silico molecular dynamics and molecular docking; in this regard, caffeine might block the viral entrance into host cells by inhibiting the formation of a receptor-binding domain and the angiotensin-converting enzyme complex and, additionally, might reduce viral replication by the inhibition of the activity of 3-chymotrypsin-like proteases. Here, we discuss how caffeine through certain mechanisms of action could be beneficial in SARS-CoV-2. Nevertheless, further studies are required for validation through in vitro and in vivo models.

Keywords: COVID-19; SARS-CoV-2; airway smooth muscle; antiviral activity; caffeine; immunomodulatory effects.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Schematic diagram of the immunomodulatory and bronchodilatory effects of caffeine. Various cells of the immune system express adenosine receptors (ARs) and TAS2R receptors that can modulate their activity; caffeine is a known antagonist of the AR receptor and an agonist of TAS2R receptors. Antagonism of A1 and A2B on immune cells will decrease pro-inflammatory activity. Caffeine activation of TAS2R in epithelial cells will increase the secretion of antimicrobial peptides (AMPs), NO, and H2O2, all of which have direct effects on the virus. In macrophages it inhibits pro-inflammatory cytokine production, and in mast cells it inhibits histamine and prostaglandin D2 release. In ASM, caffeine can activate various pathways that promote bronchodilation: it activates TAS2R and A2 receptors and inhibits PDE4 to induce relaxation. At high concentrations, it can also increase the open probability of RyR; this last mechanism has no therapeutic use. ASM, airway smooth muscle; AR, adenosine receptor; DC, dendritic cell; GPCRs, G-protein-coupled receptors; TAS2R, type 2 taste receptor; NC, natural killer cell; CD, lymphocyte CD 8+; His, histamine; PD2, prostaglandin D2; PDE4: phosphodiesterase 4; AMPs, antimicrobial peptides; IP3, inositol 1,4,5-triphosphate; PLC-β2, phospholipase C-β2; SR, sarcoplasmic reticulum; PKA, protein kinase A; cAMP, cyclic adenosine monophosphate; GPCR, G-protein-coupled receptor; IP3R, IP3 receptor.
Figure 2
Figure 2
Schematic diagram of the proposed antiviral mechanisms of caffeine against SARS-CoV-2. Caffeine can inhibit the production of TNF-α and the expression of the inflammasome NLRP3 and its activity by the MAPK/NF-κβ pathway, decreasing the production of IL-1β and IL-18. Caffeine also inhibits viral entrance by blocking the RBD and ACE2 complex formation. Caffeine also inhibits 3CLpro, a protease required to release two polypeptides that are necessary for viral transcription and replication. TNF-α, tumor necrosis factor alpha; NF-κβ, nuclear factor kappa beta; ACE2, angiotensin-converting enzyme 2; NLRP3, inflammasome NOD-like receptor 3; IL-6, interleukin 6; IL-1β, interleukin 1 beta; IL-18, interleukin 18; MAPK, mitogen-activated protein kinase; 3CLpro, 3-chymotrypsin-like protease.
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