Propolis and its potential against SARS-CoV-2 infection mechanisms and COVID-19 disease: Running title: Propolis against SARS-CoV-2 infection and COVID-19

Abstract

Propolis, a resinous material produced by honey bees from plant exudates, has long been used in traditional herbal medicine and is widely consumed as a health aid and immune system booster. The COVID-19 pandemic has renewed interest in propolis products worldwide; fortunately, various aspects of the SARS-CoV-2 infection mechanism are potential targets for propolis compounds. SARS-CoV-2 entry into host cells is characterized by viral spike protein interaction with cellular angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2. This mechanism involves PAK1 overexpression, which is a kinase that mediates coronavirus-induced lung inflammation, fibrosis, and immune system suppression. Propolis components have inhibitory effects on the ACE2, TMPRSS2 and PAK1 signaling pathways; in addition, antiviral activity has been proven in vitro and in vivo. In pre-clinical studies, propolis promoted immunoregulation of pro-inflammatory cytokines, including reduction in IL-6, IL-1 beta and TNF-α. This immunoregulation involves monocytes and macrophages, as well as Jak2/STAT3, NF-kB, and inflammasome pathways, reducing the risk of cytokine storm syndrome, a major mortality factor in advanced COVID-19 disease. Propolis has also shown promise as an aid in the treatment of various of the comorbidities that are particularly dangerous in COVID-19 patients, including respiratory diseases, hypertension, diabetes, and cancer. Standardized propolis products with consistent bioactive properties are now available. Given the current emergency caused by the COVID-19 pandemic and limited therapeutic options, propolis is presented as a promising and relevant therapeutic option that is safe, easy to administrate orally and is readily available as a natural supplement and functional food.

Keywords: Anti-inflammatory; Antiviral; COVID-19; PAK1 blocker; Propolis; SARS-CoV-2.

Graphical abstract

Fig. 1

Major pathways through which propolis can interfere with SARS-CoV-2 attachment to the host cell, viral replication, and pathophysiological consequences. SARS-CoV-2 entry into target cells requires spike protein binding to ACE2 and activation by TMPRSS2. After binding, several signals are triggered, allowing viral endocytosis and PAK1 activation, which reduces the adaptive immune response and antibody production against the virus. PAK1 also stimulates CCL2 production, which generates a fibrotic response. Viral infection induces nuclear transition factor NF-KB activation, generating local pro-inflammatory cytokine production. Propolis-derived compounds downregulate the expression of TMPRSS2 and the anchoring ACE2, which limits entry of the virus. Furthermore, they promote NF-KB and monocyte/macrophage immunomodulation, reducing pro-inflammatory cytokine overproduction, and they reduce PAK1 activation, increasing the production of antibodies against SARS-CoV-2.