Table 1.

Potential pathways through which propolis and its components could attenuate SARS-CoV-2 infection and its consequences.

N	Targets	Aspect of SARS-CoV-2 infection	Propolis Components	Effect of the components and type of evidence
1	Viral RNA-dependent RNA polymerase (RdRp) and Spike glycoprotein (SGp)	Viral component that attaches to host cell	Limonin, Quercetin and Kaempferol	Inhibitory potential with high binding energy to viral components from -9 to -7.1 kcal/mol (in silico) [15]
2	3a Channel Protein	Viral component that attaches to host cell	Kaempferol	Blocks the 3a channel that is encoded by ORF 3a of SARS-CoV (in vitro) [238]
3	ACE2	Main receptor for viral entry	Myricetin, Caffeic Acid Phenethyl Ester, Hesperetin and Pinocembrin	Inhibitory potential with high binding energy to ACE2 (-8.97 kcal/mol) (in silico) [26]
			Kaempferol	Inhibitory potential with high binding energy to ACE2 (-7.5 kcal/mol) (in silico) [239]
			Quercetin	Inhibitory potential with high binding energy to ACE2 (-10.4 kcal/mol) (in silico) [25]
3	TMPRSS2	Serine protease that mediates spike protein priming for viral entry	Kaempferol	Downregulates androgen receptors such as PSA and TMPRSS2 in a prostate cancer model (in vitro) [83]
4	PAK-1	PAK-1 (RAC/CDC42-activated kinases) - Responsible for suppression of immune system in hosts	Caffeic Acid and Caffeic Acid Phenethyl Ester	Downregulates PAK-1 associated with Rac1 activation (in vitro) [18]
				Inhibits PAK-1 directly or up-stream, blocking coronaviral infection (Review) [10]
5	3C-like protease	Mediates the proteolytic processing of replicase polypeptides 1a and 1ab into functional proteins in SARS-CoV-2 infection	Hesperetin	Inhibits cleavage activity of 3CLpro (in vitro) [240]
6	Inflammatory response	Response to viral infection that leads to organ injury	Propolis Extract	Inhibits NF-kB activation (in vitro) [241]
				Induces Ca2+ signaling in dendritic cells in Peyer’s patches, improving the immune response (in vitro) [242]
				Attenuates the inflammatory response through intracellular ROS and NO levels with downregulation of IL‐1β and IL‐6 expression (in vitro) [27]
				Regulates IFN-γ, IL-6, and IL-10 cytokines in an experimental asthma model (in vivo) [243]
				Increases TGF-β and IL-10 levels, which contribute to the regulation of the inflammatory process in Acute Pulmonary Inflammation (in vivo) [24]
				Inhibits the production of ROS, RNS, NO, cytokines IL-1α, IL-1β, IL-4, IL-6, IL-12p40, IL-13, TNF-α, G-CSF, GM-CSF, MCP-1, MIP-1α, MIP-1β, and RANTES in stimulated J774A.1 macrophages (in vitro) [244]
			Kaempferol	Reduces TNF-α, IL-6, VEGF via the ERK-NFkB-cMyc-p21 pathway (in vitro) [83]
			Caffeic Acid Phenethyl Ester	Inhibits NF-kB activation in HTLV-1 infection (in vitro) [245]
				Modulates JAK/STAT signaling and attenuates oxidative stress and inflammation [87].
	Immunomodulation	Adaptive immune response against viral infection	Propolis Extract	Increases humoral and cellular response in mice immunized with Suid herpesvirus type 1[106]
				Suppresses the differentiation of Th17 cells by inhibition of IL-6-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) (in vivo) [88]
7	Thrombosis	Blood clotting dysregulation caused by viral infection	Quercetin	Inhibits thrombin in thrombotic manifestations (in vitro) [246]
8	Viral replication	Viral translation	Kaempferol and Hesperetin	Inhibits internal ribosomal entry site (IRES) activity required for viral protein translation (in vitro) [247]
		Transcription	Kaempferol	Inhibits human immunodeficiency virus reverse transcriptase-associated DNA polymerase as well as RNAase H and RNase H activities (in vitro) [248]
				Presents potent anti-HIV-1 reverse transcriptase activity (in vitro) [249]
		Endocytosis	Quercetin	Decreases Akt phosphorylation and viral endocytosis of Rhinovirus (in vivo) [250]
		Replication and virion integrity		Prevents up-regulation of diacylglycerol acyltransferase (DGAT) required for hepatitis C virus replication (in vitro) [251]
		Replication		Decreases heat shock proteins and Hepatitis B virus transcription levels (in vitro) [252]
		Endocytosis	Caffeic Acid	Inhibits Hepatitis B virus-DNA replication (in vivo & in vitro) [253]
		Endocytosis		Inhibits influenza A virus (IAV) replication (in vitro) [254]
		Endocytosis		Inhibits influenza A virus (IAV) activity through neuraminidases (in vitro) [255]
		Transcription	Caffeic Acid Phenethyl Ester	Inhibits HIV-1 integrase (Review) [256]