Human coronaviruses and therapeutic drug discovery

Song, Lan-Gui; Xie, Qing-Xing; Lao, Hui-Lin; Lv, Zhi-Yue

doi:10.1186/s40249-021-00812-9

Infectious Diseases of Poverty

Table 1 Drugs aiming at the proliferation process

From: Human coronaviruses and therapeutic drug discovery

Step	Target		Drugs		Type	Reference number
Step	Target		Category	Example	Type	Reference number
Attachment and entry	Block receptor binding	S1-RBD	mAbs	m336, m337 and m338	MERS-CoV	[9]
			mAbs	Human-derived SARS mAbs	SARS-CoV	[10, 11]
			Receptor-derived proteins	P4 and P5 peptides	SARS-CoV	[12]
		Receptor	ACE2 antagonist	NAAE	SARS-CoV	[13]
		Receptor	DPP4 antagonist	Adenosine deaminase, anti-DPP4 mAbs	MERS-CoV	[14, 15]
		Oligosaccharide-rides on S	Antiviral protein	Griffithsin	SARS-CoV, MERS-CoV, HCoV‑229E, HCoV‑OC43	[16]
	Block endocytosis	Host proteases that cleavage S protein	TMPRSS2 inhibitor	Camostat, nafamostat	SARS-CoV,; MERS-CoV	[17, 18]
		Host proteases that cleavage S protein	Cathepsin L inhibitor	Teicoplanin, dalbavancin	SARS-CoV, MERS-CoV, SARS-CoV-2	[19]
		HR1/HR2	Peptide	HR2P and P1 peptide	MERS-CoV	[20, 21]
				229E-HR1P and 229E-HR2P	HCoV-229E	[22]
				OC43-HR2P	Broad spectrum	[23]
		Viral envelope	Antiviral drug	arbidol	Broad spectrum	[24]
		Viral envelope	Small molecules	LJ001	Broad spectrum	[25]
		NHR trimeric coiled coils	α-helical lipopeptides		MERS-CoV	[26]
		Endosomal acidification	Antimalarial	Chloroquine, chloroquine phosphate	SARS-CoV-2	[30,31,32]
		Clathrin-mediated endocytosis	Antagonist of DA receptor	Chlorpromazine	MERS-CoV	[30]
Replicase protein expression	PLpro; (Papain-like protease); (nsp3)		Thiopurine analogs	6-mercaptopurine (6MP) and 6-thioguanine (6TG)	MERS-CoV	[33]
			Immunosuppressive drug	Mycophenolic acid	MERS-CoV	[33]
			Alcohol-aversive drug	Disulfiram	SARS-CoV, MERS-CoV	[34]
			Protease inhibitor	Zinc ion (Zn²⁺) and zinc conjugate inhibitors	SARS-CoV	[35]
			Compound	F2124-0890	SARS-CoV, MERS-CoV	[36]
	Mpro; (3C-like protease); (nsp5)		Peptidomimetic inhibitors of enterovirus 3Cpro	6b, 6c and 6d	SARS-CoV, MERS-CoV	[37]
			1,2,3-triazole derivatives	Compounds 14d, 14n, 14q, 18f and 18i	HCoV-229E	[38]
			Protease inhibitor	Lopinavir/ritonavir	SARS-CoV, MERS-CoV, HCoV-229E	[30, 39, 46, 48, 49]
			Protease inhibitor	Darunavir/cobicistat	SARS-CoV-2	NCT04252274
			Protease inhibitor	Ti-containing polyoxometalates (POMs)	SARS-CoV	[40]
			Derivates of pyrithiobac (PTB)	Compound 6–5	SARS-CoV	[41]
			Peptide; mimic inhibitor	N3	Broad spectrum	[42]
			Synthesized compounds	Derivates of isatin, piperazineare and phenylisoserine	SARS-CoV	[44, 45]
			Synthesized compounds	Derivates of piperidine	MERS-CoV	[43]
Replication, transcription and translation	NSPs	NSP12	RdRp inhibitor	Remdesivir	Broad spectrum	[50,51,52,53,54]
				Doubly flexible nucleoside analogues such as compound 2	Broad spectrum	[55]
				Galidesivir (synthetic adenosine analogue)	Broad spectrum	[56]
				6′-fluorinated-aristeromycin analogues	Broad spectrum	[57]
				Favipiravir	broad spectrum	[58, 59]
		NSP13	Helicase inhibitor	Aryl diketoacids (ADK), SSYA10-001, halogenated triazole compounds	SARS-CoV, MERS-CoV	[61, 62, 65]
		NSP13	NTP enzyme inhibitor	Bananins, 2,6-bis-arylmethyloxy-5-hydroxychromones	SARS-CoV, SARS-associated CoV	[63, 64]
		NSP16	Drug targeting SAM	S-adenosine-1 homocysteine	SARS-CoV, HCoV 229E	[66]
				Paclitaxel		[66]
				Aurintricarboxylic acid (ATA)		[66]
			Drug interfering with the binding of NSP16 to NSP10	The peptide chain reversely designed according to the sequence of nsp16′s binding domain		[66]
	Host signaling pathways		Cyclophilin inhibitors	Cyclosporine, alisporivir	SARS-CoV, MERS- CoV, HCoV-NL63	[67,68,69]
	Host signaling pathways		Kinase signal transduction inhibitors	Trametinib, imatinib	MERS-CoV	[3, 70]
	Viral nucleic acid or RNA synthesis complex		siRNA	Specific siRNAs targeting the S/M/E/N/accessory protein gene	SARS-CoV, MERS-CoV	[71,72,73,74,75,76]
			Immunosuppressive drug	Mycophenolic acid	MERS-CoV	[77]
			Ribozyme	Synthetic chimeric DNA–RNA hammerhead ribozyme	SARS-CoV	[78]
			Synthesis	K22 (targeting membrane-bound viral RNA)	Broad spectrum	[79]
			Apoptosis inducer	dsRNA-activated caspase oligomerizer (DRACO)	Broad spectrum	[80]
	N protein		Compound	N-(6-oxo-5,6-dihydrophenanthridin-2-yl) (N,N-dimethylamino)acetamide hydrochloride (PJ34)	HCoV-OC43	[81]
			Intrabody	Fibronectin-based intrabodies	SARS-CoV	[82]
			Inhibitor	Resveratrol	MERS-CoV	[83]
Assembly and release	E protein		Ion channel blocker	Hexamethylene amiloride	HCoV-229E	[84]
Assembly and release	Cytoskeleton		Filament depolymerizing drug	NOC (nocodazole)	HCoV-229E, HCoV-NL6	[3, 85]

RBD: receptor binding domain; mAbs: monoclonal antibodies; SARS: Severe acute respiratory syndrome; MERS: Middle East respiratory syndrome; ACE2: Angiotensin converting enzyme 2; DPP4: dipeptidyl peptidase 4; NHR: N-terminal heptad repeat; HR1: Heptad repeat 1 domain; HR2: Heptad repeat 2 domain; DA: dopamine; 6MP: 6-mercaptopurine; 6-TG: 6-thioguanine; Zn²⁺: zinc ion; POM: polyoxometalate; PTB: derivates of pyrithiobac; NAAE: N-(2-aminoethyl)-1-aziridineethanamine; TMPRSS2: transmembrane protease serine 2; Nsps: non-structural proteins; RdRp: RNA-dependent RNA polymerase; ADK: aryl diketoacids; NTP: nucleoside triphosphate; SAM: S-adenosyl-l-methionine; ATA: aurintricarboxylic acid; dsRNA: double-stranded RNA; DRACO: dsRNA-activated caspase oligomerizer; siRNA: small interfering RNAs; PJ34: N-(6-oxo-5,6-dihydrophenanthridin-2-yl) (N,N-dimethylamino) acetamide hydrochloride; NOC: nocodazole

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ISSN: 2049-9957

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