Coronaviruses (CoVs) are a large group of enveloped single-stranded positive-sense RNA viruses, causing mild to severe respiratory disease, including fever, common cold, pneumonia and bronchiolitis. Based on the similarity of genome sequence and structure, the coronaviruses are classified into four genera: alpha-, beta-, gamma- and delta-CoV (Woo et al. 2012). The alpha- and beta-CoV family usually infect mammals and humans, whereas gamma- and delta-CoV family generally infects birds. From the mid-1960s to the present, seven coronaviruses have been recognized to infect and cause disease in humans. Of the seven human coronaviruses (HCoVs), two HCoVs (229E and NL63) belong to the alpha-CoV genus, and the other five (OC43, SARS, HKU1, MERS and SARS- 2) belong to the beta-CoV genus. Bats are considered the natural hosts for most of the HCoVs (Lau et al. 2020), whereas only HCoV-OC43 and HCoV-HKU1 originated in mice (Cui et al. 2019) . Importantly, the HCoVs originated in bats hold four major structural proteins (S, E, M and N), while in mice originated HCoVs, one more structural protein, hemagglutinin-esterase (HE), is observed along with the four proteins.

For entering in the host cell and development of virus infection, different human proteins or enzymes serve as receptors. For example, angiotensin-converting enzyme 2 (ACE2) has been identified as major entry receptor of human coronaviruses SARS-CoV (Li et al. 2003) and SARS-CoV-2 (Hoffmann et al. 2020a), as well as HCoV-NL63 (Hofmann et al. 2005). The aminopeptidase N (APN) and dipeptidyl peptidase 4 (DPP4) were discovered as entry receptor for HCoV-229E and MERS-CoV respectively, while mice originated beta-CoV HCoV-OC43 and HCoV-HKU1 use 9-O-aetylated sialic acid as viral receptor (Cui et al. 2019).

The first human coronaviruses, HCoV-229E, were identified in 1966. In the following year, another HCoV named HCoV-OC43 had emerged (Hendley et al. 1972). After a long gap, in November 2002, SARS-CoV first appeared in Guangdong province of China and the next year, the virus spread to more than twenty-five countries of four continents (Asia, Europe, North America and South America) (de Wit et al. 2016). According to WHO, SARS has had a total of 8,096 diagnosed cases and 774 deaths. Since 2004, no confirmed cases of SARS reported anywhere in the world. In the same decade, two more HCoVs, NL63 and HKU1 were appeared in the Netherlands (2004) and Hong Kong (2005), respectively (Pyrc et al. 2007). In June 2012, a highly pathogenic HCoV, MERS, were emerged in the middle east and as of 31 May 2020, it has caused a total of 2,562 confirmed cases with 34.4% fatality rate (881 deaths), the majority in Saudi Arabia. Until now, the virus is still infecting human. During 1 April and 31 May 2020, nine new cases were reported, including five deaths. SARS-CoV and the MERS-CoV studies have contributed the majority of current knowledge concerning the biological properties of coronaviruses, including the pathogenic mechanisms, functions of vital proteins, potential drug targets and treatment strategies. Also, the two previous disease outbreaks have provided valuable lessons about public health emergency response. These accumulated data and knowledge will shorten the path to effective treatments.

Once the S protein is attached to ACE2, it will be cleaved by the transmembrane protease serine 2 (TMPRSS2), and the S2 subunit will mediate the membrane fusion process. Alternatively, with the absence of TMPRSS2, the virus may also enter the cell through endosomes, in this way, the pH-dependent endosomal protease cathepsin L will cleave and activate the spike protein in a low pH circumstance (Ou et al. 2020) . After the viral RNA of SARS-CoV-2 being released into the cell cytoplasm, a series of processes are triggered to aid the replication of SARS-CoV-2. First, the host translational machinery is hijacked by SARS-CoV-2. The eIF4F complex and the 43S preinitiation complex are attached to the 5'-end of the capped SARS-CoV-2 genome, and then the 80S complex is assembled at the translation initiation point to start protein synthesis. This process will generate the polyprotein pp1a or pp1ab with programmed ribosomal frameshifting induced by the frameshift signal (Kelly et al. 2020). Subsequently, the two polyproteins are typically cleaved into 16 non-structural effector proteins (nsps) by 3CLpro (nsp5) and PLpro (nsp3). Nsp3 can also work together with nsp4 to aid the formation of viral-induced double-membrane vesicles (DMVs) necessary for viral replication. Nsp12(the RNA-dependent RNA polymerase, RdRp), nsp7 and nsp8 form a replication complex, enabling the synthesis of a full-length negative-strand RNA (Gao et al. 2020). This RNA is then used as a template to replicate the virus genome and generate other sub-genomic RNAs through discontinuous transcription (Kim et al. 2020). The structural and accessory proteins are translated from the sub-genomic RNAs and are trafficked to the ER-Golgi intermediate compartment (ERGIC), where new virions assemble in budding vesicles. Finally, the nascent virions are encapsulated and exocytosed from the host cell via the secretory pathway. These virions will, therefore, invade other host cells, and repeat this cycle. The invasion stimulates a systemic inflammatory response, which often ends with a cytokine storm leading to various damaging effects.

During the replication cycle of SARS-CoV-2, multiple components at different stages can be targeted to inhibit or block the corresponding process. This table shows the information of potential inhibitors and their targets.

Inhibitor	Virus/ Host	Previous treatment	Target	Stage	Phases	Advantage	Disadvantage	Ref.
ACEi/ ARBs	Human	SARS	ACE2	Virus attachment to the cells	Phase 4	Inhibit virus attachment	Multiorgan dysfunction with increased lung injury	Saavedra 2020
hrsACE2 (APN01)	Human	SARS	ACE2	Virus attachment to the cells	Phase 2	Could reduce viral growth in Vero E6 cells		Monteil et al. 2020
Chloroquine, Hydroxychloroquine	Human	Malarial	ACE2/ Endosome	Altering endosomal pH and affecting virus-cell fusion	Phase 3	Inhibit virus attachment and can elevate endosomal pH	High-risk exposure to COVID-19 patients and has suspended	Boulware et al. 2020; Wang et al. 2020
E-64d	Human	SARS, MERS	Cathepsin L	Cell entry, fusion	Preclinical			Hoffmann et al. 2020a; Liu et al. 2020
Camostat, Nafamostat	Virus	SARS, MERS	TMPRSS2	Viral entry	Phase 2/ Phase 3	Inhibit entry of SARS-CoV-2	Blood levels could be inferior to Nafamostat	Hoffmann et al. 2020a; Hoffmann et al. 2020b
EK1C4	Virus		Interaction of HR1 and HR2 domains in the viral S protein S2 subunit	Membrane fusion	Preclinical	Inhibit membrane fusion of virus in the host cell		Xia et al. 2020a; Xia et al. 2020b
Lopinavir- Ritonavir	Virus	HIV, SARS, severe influenza	3CLpro	3CLpro activity	Phase 3	Broad-spectrum	Some serious adverse effects on the immune system and has withdrawn	Bhatnagar et al. 2020; Cao et al. 2020a
GRL-0617	Virus		PLpro (Nsp3)	PLpro activity	Preclinical	Narrow spectrum	Effect on animal and clinical data are unknown	Freitas et al. 2020
Remdesivir	Virus	Ebola SARS MERS	RdRp (Nsp12)	Replication	Phase 3	Broad-spectrum	May have side effect and severe with high dose	Cao et al. 2020b; Wang et al. 2020
IFN-α	Human	Hepatitis B and C, MERS SARS		Viral replication	Phase 3	Broad antiviral activity in vitro		Mantlo et al. 2020
Ribavirin	Virus	SARS MERS	RdRp (Nsp12)	Replication	Phase 3	Approved for treating viral infections and side effects are known	Broad-spectrum and side effects should not be underestimated	Khalili et al. 2020