TABLE 2.

Studies of 3C^pro or 3CL^pro inhibitors antiviral compounds [Correction added on 17 February 2021, after first online publication. The references were updated throughout Table 2 and in‐text citations.]

Research phase	Compound	Target	Results	Ref
In vitro validation	TG‐0205221	3CLpro of SARS‐CoV and HCoV‐229E	Reduces SARS‐CoV and HCoV‐229E replication by titer of 4.7 Log10	191
	Flavonoids: Apigenin, luteolin, quercetin, amentoflavone, aueretin, daidzein, puerarin, epigallocatechin gallate, gallocatechin gallate, kaempferol,rhoifolin, pectolinarin, herbacetin, flavonol	SARS‐CoV 3CLpro	Inhibit SARS‐CoV 3CLpro FRET protease assay catalytic activity	192
	Pyrazolone and pyrimidines inhibitors	SARS‐CoV 3CLpro	Show potent inhibitory activities against SARS‐CoV 3CLpro at micromolar range.	193
	Aryl methylene ketones, Mono‐, and difluorinated methylene ketones groups	SARS‐CoV 3CLpro	Improved version is stable and less toxic to cells. Potently inhibits SARS‐CoV 3CLpro at nanomolar range	194
	Heteroaromatic esters and benzotriazole esters derivatives	SARS‐CoV 3CLpro	Show potent inhibitory activities against SARS‐CoV 3CLpro at nanomolar range	195 , 196 , 197
	Boronic	SARS‐CoV 3CLpro	Significantly inhibits SARS‐CoV 3CLpro enzymatic activity in micromolar range	198
	Aza‐peptide epoxides derivatives	SARS‐CoV 3CLpro	Show irreversible inhibition against SARS‐CoV 3CLpro	199 , 200 , 201
	Etacrynic acid derivatives	SARS‐CoV PLpro and 3CLpro	Show more than 70% inhibition on SARS‐CoV at concentration of 100μM	202 , 203
	Peptides aldehydes derivatives	SARS‐CoV and HCoV‐229E 3CLpro	Suppress SARS‐CoV by 4.7 Log10 and HCoV‐229E by 5.2 Log10	191
	Modified version of HIV protease inhibitors	SARS‐CoV 3CLpro	Potent inhibitors against SARS‐CoV 3CLpro but not against HIV protease	204
	Sulfone and dihydroimidazole derivatives	SARS‐CoV 3CLpro	21 derivatives from these two analogs show EC50 less than 50 μM against SARS‐CoV 3CLpro	205 , 206
	Michael acceptor peptidomimetics	SARS‐CoV 3CLpro	Show potent inhibitory against SARS‐CoV 3CLpro	207 , 208
	Lignoids, di‐ and triterpenoid derivatives: Betulinic acid, savinin, ferruginol, pritimererin, tingenone, iguestrin and triterpenoids celastrol	SARS‐CoV 3CLpro	Abietane type diterpenoids are the most robust terpenoids on SARS‐CoV (EC50 = 9.1 μM)	207 , 209 , 211
	Metal conjugated: Zinc‐ or mercuric based	SARS‐CoV PLpro and 3CLpro,	Inhibition is pronounced in Zinc‐conjugated compounds	212 , 213
	α‐Ketoamides:	3Cpro of CVB3, &; HRV, EV‐D68, EV‐A713CLpro of SARS‐CoV, MERS, 229E	Display low toxicity &; low micromolar of EC50 against tested viruses	214
	Pyridyl, pyrazyl and Benzotriazole‐derivatives inhibitors	SARS‐CoV PLpro or 3CLpro	Robust inhibition on SARS‐CoV in vitro within micromolar range	215 , 216 , 217
	Rupintrivir (AG‐7088)	Targeting 3Cpro and 3CLpro encoding viruses	Shows robust activity against SARS‐CoV‐2 in vitro	218 , 219
	Boceprevir, Calpain inhibitors II, and XII	SARS‐CoV‐2 3CLpro	Inhibit SARS‐CoV‐2 in vitro with EC50 less than 5μM	220
	3CLpro‐1	Originally designed for 3Cpro of EV‐A71.	Shows robust efficacy of EC50 200 nM, effective against SARS‐CoV‐2 and MERS‐CoV.	221 , 222
	Isatin derivatives	Targeting 3Cpro and SARS‐CoV 3CLpro	Effectively inhibit SARS‐CoV 3CLpro through noncovalent bonding in low micromolar range	219 , 220
	Anilide derivaties: 2‐chloro‐4‐nitro anilineL‐phenylalanine, 4‐(dimethylamino)benzoic acid	SARS‐CoV 3CLpro	Potent and highly specific inhibitors against SARS‐CoV 3CLpro	225
Computational prediction (docking analysis)	Anti‐HIV‐1 drugs: Indinavir, Darunavir	SARS‐CoV‐2 3CLpro	Docking & binding free energy prediction shows high scores & high binding affinities against SARS‐CoV‐2 3CLpro	226
	Decahydroisoquinoline inhibitors	SARS‐CoV‐2 3CLpro	X‐ray crystallization studies confirmed that these inhibitors fit well into the cleft of 3CLpro	227
In vitro and in vivo validation	Peptides with halomethyl ketone derivatives	SARS‐CoV 3CLpro	Effectively inhibit SARS‐CoV infection, with low cytotoxicity in cells and in mice.	228
Widely tested in animals and now under trial on human for coronavirus disease‐2019	GC376	Targeting 3Cpro and 3CLpro encoding viruses	Shows robust activity against SARS‐CoV, SARS‐CoV‐2, and Norovirus	220

Abbreviations: HRV, human rhinovirus; MERS‐CoV, Middle East respiratory syndrome‐CoV; PLpro, papain‐like protease; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus‐2 3CL^pro/3C^pro, 3C‐like protease/3C protease.