Can Resveratrol-Inhaled Formulations Be Considered Potential Adjunct Treatments for COVID-19?

Abstract

The pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has led to an extraordinary threat to the global healthcare system. This infection disease, named COVID-19, is characterized by a wide clinical spectrum, ranging from asymptomatic or mild upper respiratory tract illness to severe viral pneumonia with fulminant cytokine storm, which leads to respiratory failure. To improve patient outcomes, both the inhibition of viral replication and of the unwarranted excessive inflammatory response are crucial. Since no specific antiviral drug has been proven effective for the treatment of patients and the only upcoming promising agents are monoclonal antibodies, inexpensive, safe, and widely available treatments are urgently needed. A potential anti-inflammatory molecule to be evaluated, which possesses antiviral activities in several experimental models, is the polyphenol resveratrol. This compound has been shown to inhibit SARS-CoV-2 replication in human primary bronchial epithelial cell cultures and to downregulate several pathogenetic mechanisms involved in COVID-19 severity. The use of resveratrol in clinical practice is limited by the low bioavailability following oral administration, due to the pharmacokinetic and metabolic characteristics of the molecule. Therefore, topical administration through inhaled formulations could allow us to achieve sufficiently high concentrations of the compound in the airways, the entry route of SARS-CoV-2.

Keywords: COVID-19; anti-inflammatory; antiviral; inhaled formulations; resveratrol.

Figure 1

Activities of resveratrol against the most common respiratory viruses. Mode of action and inhibitory effects on Influenza virus, (A); Respiratory Syncytial virus, (B); Human Rhinovirus, (C); MERS-CoV, (D).

Figure 2

Direct antiviral activity against SARS-CoV-2 and other inhibitory functions displayed by resveratrol through Sirt1-ACE2 activation on the pathogenetic mechanism involved in COVID-19 severity.

Figure 3

SARS-CoV-2 and aberrant NLRP3 inflammasome activation (A) Physiological activation of NLRP3 inflammasome by microorganisms and stressors induce the secretion of proinflammatory products with induction of adaptive immune response against pathogens. (B) Aberrant dysregulated activation of NLRP3 inflammasome by the SARS-CoV-2 viroporin protein 3a and excessive IL-1β release promotes cytokine storm and acute lung injury, leading to the most severe Covid-19 complications. (C) Through Sirt1 activation, resveratrol induces autophagy, a cellular function that facilitating self-digestion of misfolded or unused protein and cellular debris, facilitates infected cell apoptosis and dendritic cell maturation, downregulating the aberrant dysregulated NLRP3 activation.

Figure 4

SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) expression and dysregulation of the renin-angiotensin system. (A) Infection of the host cell by SARS-COV-2 is associated with a down-regulation of ACE2 protein expression and function. (B) The downregulation of ACE2 protein function inhibits the conversion of angiotensin II (Ang II) into Ang 1-9 and then to Ang 1-7, leading to dysfunction of the renin angiotensin system with excessive production of pro-inflammatory and pro-oxidant agents. (C) Inhibiting SARS-CoV-2 replication, resveratrol reduces lung inflammation and lung injury.