Introduction

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a highly transmissible and pathogenic coronavirus that mainly affects the human respiratory system. SARS-CoV-2 is responsible for two distinct endemics like Middle East respiratory syndrome (MERS) and acute respiratory syndrome (SARS), which have significant affected on public health (Raoult et al. 2020). SARS-CoV-2 is named due to the presence of crown-like spikes on their surface and consisted of four sub-groups, called as alpha, beta, gamma, and delta (Fehr and Perlman, 2015). It is a positive sense-stranded RNA virus with 29,891 bases; among these, 96% bases are identical to a bat coronavirus (CoVs), at the full level of genome stage, and share 79.6% of gene similarity with SARS-CoV (Denison et al. 2011). SARS-CoV-2 encodes spike (S) protein consisting of a receptor-binding domain (RBD) that binds to the angiotensin-converting enzyme-2 (ACE-2) of humans and facilitates membrane fusion as well as virus uptake into human lungs (Fig. 1) (Hofmann and Pöhlmann, 2004). SARS-CoV-2 enter into human cells and capture the protein synthesis machinery to synthesize the viral proteins for replication and proliferation (Hofmann and Pöhlmann, 2004). SARS-CoV-2 contains the largest genomic structure (26.4–31.7 kb) among all known RNA viruses. Large numbers of small open reading frames (ORFs) are present between the various conserved genes [ORF1ab, spike (S), envelope (E), membrane (M), nucleocapsid (N)] and the nucleocapsid genes of various CoVs lineages (Mousavizadeh and Ghasemi, 2020). The viral genomes consist of distinctive characteristics, including a unique N-terminal fragment within the spike protein. Genes for main structural proteins in all SARS-CoV-2 occur in 5′–3′ order, such as S, E, M, and N. A typical SARS-CoV-2 contains at least six ORFs in their genome. ORF1a and ORF1b provide a frameshift between two polypeptides that are pp1a and pp1ab (Prajapat et al. 2020). These polypeptides are converted into 16 nsps (nsp1-16) by virally encoded chymotrypsin-like protease (3CLpro) or main protease (Mpro) and one or two papain-like proteases. ORFs 10,11 encode four specific structural proteins containing S, E, M, N proteins on one-third of the genome near to the 3′-terminus (van Boheemen et al. 2012). In addition to these four main structural proteins, such as HE protein, 3a/b protein and 4a/b protein are encoded by various CoVs (Fig. 2) (Chen et al. 2020). Such mature proteins are responsible for maintaining genomic structural integrity maintenance and virus replication roles.

Fig. 1
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Structure of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)

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Fig. 2
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The genomic structure and phylogenetic of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2): a The phylogenetic tree of coronavirus with the new COVID-19 shown in green color. b The genome structure of four genera of coronaviruses (CoVs): two long polypeptides with 16 nonstructural proteins initiated from Pp1a to pp1b represent. E, S, M, and N are consisted of the four structural proteins envelope, spike, membrane, and nucleocapsid. Abbreviations: CoVs, coronavirus; HE, hemagglutinin-esterase. HCoV, human coronavirus; HKU, coronaviruses identified by Hong Kong University; MHV, murine hepatitis virus; IBV, infectious bronchitis virus; TGEV, transmissible gastroenteritis virus; HCoV-229E, human coronavirus OC43; MERS‐CoV, Middle East respiratory syndrome coronavirus

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The genome gets transcribed after the virus enters into host cell. The reproduction and transcription of the CoVs genome occur on cytoplasmic membrane and regulate by the viral replicate (Shulla et al. 2011). It is assumed that the replicase complex has consisted of approximately 16 subunits and a various cellular protein. In addition to RNA-dependent RNA polymerase (RdRp), RNA helicase, and activities of proteases which are common in many RNA viruses, CoVs replicase is known to use a variety of RNA-dependent processing enzymes which are not present in other RNA viruses, including a putative specific sequence of endoribonuclease, 3′- to 5′-exoribonuclease, 2′-O-ribose methyltransferase, ADP ribose 1′-phosphatase, and cyclic phosphodiesterase behaviors in a subset of group 2 CoVs (Sola et al. 2015; Ziebuhr, 2005). The proteins are packaged on the cellular membranes and genomic RNA is introduced by budding from the internal cell membrane as the mature particles emerge (Almazán et al. 2006). SARS-CoV-2 N-proteins have 3 distinct and highly conserved domains include 2 structural and independently folded structural regions, known as N terminal domain (NTD/domain 1) and C-terminal domain (CTD/domain 3), separated by intrinsic disordered central region (RNA-binding domain/domain 2) (Fig. 3) (Huang et al. 2004).

Fig. 3
figure 3

Structure of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) nucleocapsid protein and target sites of potential antiviral agents. The virion enters by endocytosis or direct fusion of cell through viral membranes. The viral genome is translated into two polyproteins, which are cleaved by two viral proteases (3CLpro PLpro) to generate a large replication and transcription complex orchestrating genome replication and synthesis of mRNAs. New viral genomes recruit viral structural proteins to generate new virions released by exocytosis process. Red arrow indicates the potential inhibitors used to inhibit various targets. Abbreviations: 3CLpro, chymotrypsin-like protease; PLpro, papain-like protease; 3UTR, 3 untranslated region; 5UTR, 5 untranslated region; pp 1 ab, polypeptide 1ab; CYP, cyclophilin; RdRP, RNA-dependent RNA polymerase

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Number of patients were hospitalized with initial diagnosis of unknown pneumonia in December 2019. Available studies have indicated that bat may be the potential reservoir of SARS-CoV, which cause serious illness in humans and agricultural animals. However, there is no confirmation to date that SARS-CoV-2 was originated from the seafood market but bats are the ideal repository for a variety of SARS-CoV-2, including MERS-CoV and SARS-CoV (Guo et al., 2020). The genome sequencing of COVID-19 was analyzed and found 96.2% similar to Bat CoV RaTG13 because both types of viruses might be shared the same ancestor (Zhang et al. 2020). The exact in vivo effect of these drugs is yet unclear, however, and further finding may confirm the mechanism of inhibiting SARS‐CoV‐2 and reducing associated infections.

Table 1 List of potential therapeutic drugs for COVID-19. Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; IFNs, interferons; IL-6; interleukin 6; mAb, monoclonal antibody; ACE2, angiotensin-converting enzyme 2; RdRP, RNA-dependent RNA polymerase; mTOR, mechanistic target of rapamycin; i.v., intravenous; p.o., per oral; PaO2, arterial oxygen partial pressure; FiO2, fractional inspired oxygen
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Neuraminidase and M2 ion-channel protein

Neuraminidase plays an important role in cleavage of terminal sialic acid residues from glycoconjugates and is essential for virus replication and infectivity (Akhtar, 2020). Neuraminidase inhibitors (oseltamivir, zanamivir, and peramivir) are not expected to be effective against COVID-19 due to absence of this enzyme in SARS-CoV-2. Moreover, oseltamivir with ganciclovir and lopinavir/ritonavir was found beneficial to treat COVID-19 infections in Wuhan city (Chu et al. 2020; Huang et al. 2020). In silico study also found that combination of oseltamivir-lopinavir-ritonavir c had synergistic effects against SARS-CoV-2 (Muralidharan et al. 2020). In Indonesia and Singapore, oseltamivir is currently being used as a recommended COVID-19 treatment option.

The M2 channel protein is essential viral envelope protein for maintaining pH across the viral envelope, and plays an important role during entry and movement across the trans-Golgi host cell membrane during viral maturation (Skehel et al. 1978). Previous studies have shown that amantadine could block the p7 protein of HCV, which is crucial to form ion channels in host cell membranes (Griffin et al. 2003). In 1973, amantadine was found to have a potent antiviral effect against coronavirus 229E in vitro, and later, it was able to block SARS-CoV’s protein-membrane channel activity. Furthermore, amantadine showed good antiviral activity against SARS-CoV-2 (Frediansyah et al. 2020) but more molecular analysis determines its specificity toward particular statin.

Conclusion and future perspective

SARS-CoV-2 a is single-stranded positive RNA virus and uses several host viral proteins and cellular components to complete its replication cycle, including the steps of viral entry, replication. Development of drug and vaccine against the SARS-CoV-2 is a challenging job due to lack of predictive in vitro and animal model, insufficient knowledge regarding underlying mechanism of action of disease, lack of targets and biomarkers, and a high rate of failed clinical trials. We need to know more structural biology, life cycle details, which can speed up the drug/vaccine development process against SARS-CoV-2. Again, to avoid these types of pandemic insult, strict vigilance of viral infection and understanding of viral protein and enzyme structure are necessary. Several series of small-molecule SARS-CoV-2 inhibitors targeting these protein and enzymes (eIF4A, cyclophilin, nucleocapsid protein, spike protein, ACE2, 3CLpro, and RdRp) have discussed in our article. However, most of them were tested in vitro, while only a small percentage of these compounds have been evaluated in animal study, and few have advanced into clinical trial study. Therefore, further studies should be focused on exploring novel strategies to identify new anti-CoVs compounds, elaborated their mechanism of action, improving the efficacy of anti-CoVs compounds, and evaluating the in vivo efficacy and safety of these compounds in different preclinical and clinical studies. Furthermore, development of small-molecule CoVs inhibitors with high efficacy and low toxicity will be brought for treatment of SARS-CoV-2 infection and related disease in the future.