Table 1.

Anti-SARS-CoV-2 natural compounds with different chemical profiles tested in different assessment methods. NI: not identified. The papain-like protease (PL^pro).

Name	Source	Structure	Target	IC50 value	Reference
Apamin	Bee venom A. mellifera	C79H131N31O24S4	IKK, TNF-α IL-1β, IL-6, NF-κB pathway and MMP-9	NI	(Lin and Hsieh 2020)
Apigenin	Honey and propolis		S protein, 3CLpro	280.8 μM	(Ryu et al. 2010)
Bradykinin-potentiating peptide	Snake venom		hACE2, NO	NI	(Gouda and Mégarbane 2021)
Caffeic acid phenethyl ester	Propolis		3CLpro	–5.68 Kcal/mol	(Kumar et al. 2021)
Catechins	Honey, propolis, and royal jelly		3CLpro, cathepsin L, RBD of S protein, nsp6, PLpro , ionophores for zinc ions, IL-1β and IL-6 signalling pathways	–73 ± 2 μM (3CLpro) -Range (–7.59 to –37.39 kcal/mol) (cathepsin L, RBD of S protein, nsp6)	(Chourasia et al. 2021; Mhatre et al. 2021; Mishra et al. 2021)
Chimyl alcohol	Desmapsamma anchorata sponge		Mpro	NI	(Hamoda et al. 2021)
Chlorogenic acid	Propolis		RBD domain, S protein, hACE2	–0.87 kcal/mol	(Yu et al. 2020)
Chrysin	Honey, bee pollen and royal jelly		S protein, 3CLpro, NF-кB signalling pathway	400 μM	(Abedi et al. 2021)
Cordycepin	Cordyceps militaris fungus		S protein, Mpro	NI	(Verma 2020)
p-coumaric acid	Honey, propolis and bee pollen		S protein, HSPA5, endoribonuclease	5.63 kcal/mol	(Elfiky 2021)
Dictyosphaeric acid A	Green alga Dictyosphaeria versluyii		TMPRSS2-S PPIs, hACE2-S	NI	(Senapati et al. 2021)
Dieckol and eckol	Brown algae Ecklonia cava		3 CLpro	Dieckol: –11.51 kcal/mol, Eckol: –8.19 kcal/mol	(Arunkumar et al. 2021)
Esculetin-4-carboxylic acid methyl ester	Marine sponge Axinella cf. corrugata		Mpro	46 μM 112 μM (depends on used assay)	(Coelho et al. 2020; Hamoda et al. 2021)
Excavatolide M	Soft coral Formosan gorgonian Briareum		TMPRSS2-S PPIs, hACE2-S	NI	(Rahman et al. 2020)
Galangin	Honey		S protein	–8.2 Kcal/mol	(Jain et al. 2021)
Gallic acid	Honey		RdRp	–7.55 kcal/mol	(Abdo et al. 2021)
Gallinamide A	Marine cyanobacterial		Cathepsin	IC90 of 88 nM in	(Ashhurst et al. 2020)
Glycosaminoglycan	Marine bacteria, Pseudomonas		Mpro	–7.98 kcal/mol	(Vijayaraj et al. 2020)
Griffithsin	Red alga Griffithsia sp		S protein	293 nmol/L 3 nmol/L 323 nmol/L (depends on used assay)	(Cai et al. 2020)
Fucoidan	Brown seaweeds (Phaeophyceae)		S protein	15.6 μg/mL	(Fitton et al. 2020)
Hamigeran b	Marine sponge, Hamigera tarangaensis		3CLpro	7.98 kcal/mol	(Vijayaraj et al. 2020)
Hesperetin	Honey and royal jelly		hACE2, 3CLpro	–7.45 kcal/mol (hACE2) 8.3 μM (3CLpro) 60 μM (3CLpro)	(Guler et al. 2021)
Ilimaquinone	marine sponge Hippospongia metachromia		PLpro, 3CLpro, nsp10, nsp14	–8.1 kcal/mol (PLpro) –7.1 kcal/mol (3CLpro) –7.6 kcal/mol (nsp10) –8.1 kcal/mol (nsp14)	(Surti et al. 2020)
Indolyl diketopiperazines (IDPKs)	Fungi Aspergillus versicolour	R1 = α-OCH2CH3 R2 = α-H R3 = H aspamides A R1 = β-OCH2CH3 R2 = α-H R3 = H aspamides B R1 = H R2 = OH R3 = H brevianamide Q R1 = H R2 = CH3 aspamides F R1 = H R2 = CH2CH3 aspamides G R1 = H R2 = H brevianamide M	3CLpro	Aspamides A: –5.389 Aspamides B: –4.772, Aspamides F: –5.146 Aspamides G: –4.962 Brevianamide M: –5.158 Kcal/mol	(Ding et al. 2020)
Inorganic polyphosphate (polyP)	Marine sponges, bacteria (Cyanobacterium synepchcoccus) t		hACE2, RBD, NF-κB	1 μg/mL to 100 μg/mL	(Neufurth et al. 2020)
Iota-carrageenan	Red algae (Rhodophyta)		S protein	2.6 μg/mL	(Morokutti-Kurz et al. 2021)
Isorhamnetin	Propolis, bee pollen and royal jelly		S protein, hACE2	2.51 μM	(Zhan et al. 2021)
Kaempferol	Honey, bee pollen, royal jelly		3a channel, TMPRSS2, IL-6, TNF-α, VEGF	–9.41 kcal/mol	(Berretta et al. 2020)
Limonin	Propolis		RdRp, hACE2	9 to –7.1 kcal/mol	(Berretta et al. 2020)
Lumichrome	Honey and propolis		3CLpro	–5.205 Kcal/mol	(Hashem 2020)
Luteolin	Honey and propolis		NF-κB	NI	(Khalil and Tazeddinova 2020)
Luteolin 7-rutinoside	Propolis		RdRp	–9.8 kcal/mol	(Alamri et al. 2020)
Melittin	Bee venom A. mellifera	C131H229N39O31	IKK, TNF-α IL-1β, IL-6, NF-κB pathway, MMP-9	NI	(Lin and Hsieh 2020)
Myricetin	Honey and propolis		hACE2	–7.59 kcal/mol	(Guler et al. 2021)
Omega-3 fatty acids	Fish, other seafoods and algeas	DHA EPA	IL-1β, IL-TNF-α, COX, LOX pathway	NI	(Hathaway et al. 2020)
3‐Phenyllactic acid	Honeybee and propolis		3CLpro	–5.867 Kcal/mol	(Hashem 2020)
Phycocyanobilins (PCBs)	Cyanobacteria, algae rhodophytes		RdRp, Mpro, S protein	–7.2 kcal/mol	(Geahchan et al. 2021)
Pinocembrin	Honey, propolis and royal jelly		hACE2	–7.16 kcal/mol	(Guler et al. 2021)
Plitidepsin	Tunicate Aplidium albicans		eEF1A	IC90 of 0.88 nM	(Taglialatela-Scafati 2021)
Polycyclic guanidine alkaloids (PGAs) (Rambescidin 786, Crambescidin 826)	Marine Poeciloscleridsponges		Mpro, nucleocapsid phosphoprotein, nsp10	Ranhe from –9.06–6.49 kcal/mol)	(El-Demerdash et al. 2021)
Pseudotheonamides C and D	Marine sponge Theonella swinhoei	Pseudotheonamides C Pseudotheonamides D	Mpro	Pseudotheonamides C: 11.6 kcal/mol Pseudotheonamides D: –10.7 kcal/mol	(Gentile et al. 2020)
Quercetin	Honey, propolis, and royal jelly		3CLpro, PLpro, RdRp, S protein hACE2, COX2, iNOS, NF-κB, ionophores for zinc ions	73 μM (3CLpro) 4.48 μM (hACE2) –40.9 (PLpro) – 5.41 kcal/mol (RdRp) 83.4 µM (S protein)	(Kandeel et al. 2020; Saakre et al. 2021)
Rutin	Propolis and bee pollen		3CLpro helicase, RdRp, PLpro, hACE2, TLRs	–9.2 kcal/mol (3CLpro) –6.9 kcal/mol (hACE2) Range –5.29 to –9.76 kcal/mol) (TLRs)	(Hu et al. 2020; Rehman et al. 2020; Agrawal et al. 2021)
Syringic acid	Honey		IL-4, IL-5, IL-13, and TNF-α ROS	NI	(Li et al. 2019)
Trifucol	Brown alga Himanthalia elongate		S protein, 3CLpro	–7.5 kcal/mol (S protein) –6.3 kcal/mol (3CLpro)	(Arunkumar et al. 2021)
Vanillic acid	Honey and propolis		NFκB pathway	NI	(Khalil and Tazeddinova 2020)