Beclabuvir can inhibit the RNA-dependent RNA polymerase of newly emerged novel coronavirus (SARS-CoV-2)

Recent emergence of novel coronavirus (SARS-CoV-2) in Wuhan, China has resulted more than 14,510 global deaths. To date well-established therapeutics modules for infected patients are unknown. In this present initiative, molecular interactions between well-known antiviral drugs against the Hepatitis-C virus (HCV) have been investigated theoretically against the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2. HCV and SARS-CoV-2 are both +ssRNA viruses. At 25 o C beclabuvir, a non-nucleoside inhibitor of the RdRp of the HCV can efficiently bind to RdRp of the SARS-CoV-2 (ΔG AutoDock = -9.95 kcal mol -1 ) with an inhibition constant of only 51.03 nM. Both the ΔG London and ΔG GBVI / WSA values were - 9.06 and - 6.67 kcal mol -1 , respectively for SARS-CoV-2. In addition, beclabuvir also shows better binding free energy (ΔG vina = 9.7 kcal mol -1 ) than that of the Thumb 1 domain of RdRp of HCV (ΔG vina = 7.7 kcal mol -1 ). InterProScan has suggested the RNA-directed 5'-3' polymerase activity existed within 549 to 776 amino acid residues of RdRp. Moreover, major interacting amino acid residues were I591, Y621, C624, D625, A690, N693, L760, D762, D763 and E813-N817. Molecular interaction suggests occupancy of beclabuvir inside the active site environment of the RdRp which is essential for viral RNA synthesis. In conclusion, results suggest beclabuvir has high therapeutic potential as an anti-SARS-CoV-2 drug.


Introduction
The newly emerged novel coronavirus (SARS-CoV-2) was first reported from patients with connection history at the Wuhan Seafood market in Hubei province of Freedman 2020). In the beginning, governments of different nations evacuated their citizens from China and initiated quarantine protocols to save them. In certain serious areas of China and Italy citizens have been locked-down in their homes as they are at the fourth stage of the Pandemic (Fanelli and Piazza 2020). Due to the severity of virus outbreak, the World Health Organisation (WHO) has declared this new novel coronavirus outbreak as a Pandemic (Gates 2020). Flowing China, Italy has now become the new epicenter of SARS-CoV-2 infection where 41035 positive cases and 3423 deaths of SARS-CoV-2 infection have been recorded with in a few weeks (Porcheddu, Serra et al. 2020).
In the South-East Asian region, India ranks as the third most-affected country after Indonesia and Thailand respectively (WHO 2020). India, has reported 295 confirmed positive cases and 10 deaths from SARS-CoV-2 infection as of 20 th March 2020. Maharastra, the state of India, has become the most affected state, which indicates its vulnerbility to infectious diseases. Patients with an international travel history and symptoms of viral-flu were suspected and tested with expensive SARS-CoV-2 test costing nearly 67 US$. The respiratory illness caused by this new SARS-CoV-2 collectively called, coronavirus disease 2019 (COVID-19) (WHO 2020). In the very beginning of 2020, and the new decade, COVID-19 has impacted on the global economy and resulted in a near shutdown of the global equity market, for example on 19 th February 2020 Tesla, Inc. ended the day down by 17 %, which is the secondworst drop ever. The global airline industry has also been badly knocked-down by the COVID-19 global Pandemic.
Coronavirus is a member of a large virus family, the coronaviridae and subfamily orthocoronavirinae which usually causes respiratory illness to humans and animals (Van Der Hoek, Pyrc et al. 2004). Soon after the first report of the outbreak, a research group lead by Dr. Zhang at Fudan University, China has sequenced the complete genome which is nearly 30,000 nucleotides long and encodes 10 proteins (MN908947.3), (Wu, Zhao et al. 2020). Like SARS-CoV, the newly emerged novel coronavirus (SARS-CoV-2) is about 60 -140 nm in diameter and has trimeric spike glycoprotein (S), membrane capsid protein (M), small membrane protein, viral nucleoprotein (N) and an RNA dependent RNA polymerase (RdRp), which are essential for virus replication (Zhu, Zhang et al. 2020). Usually, entry of human coronavirus is mediated by interactions of spike glycoprotein with angiotensin converting enzyme 2 (ACE2), aminopeptidase N (AmoPep-N) and dipeptidyl peptidase 4 (DP-4), (Li, Moore et al. 2003;Raj, Mou et al. 2013). The new SARS-CoV-2 is phylogenetically closer to known coronavirus strains of bat-SL-CoVZC45 and bat-SL-CoVZXC21 than SARS-CoV (Lu, Zhao et al. 2020).
Research has suggested nonstructural proteins (NSPs) and structural proteins (SPs) of SARS-CoV-2 have linked a function. For example, NSP can block the host innate immune response and the viral envelope promotes viral assembly and release (Phan 2020). However, optimal therapeutic drug for treating the infected patients are still unknown. In the entire genome of SARS-CoV-2, 93 mutations were detected out of which 29 mis-sense mutations were found in the ORF1ab polyprotein that encodes the RdRp (Phan 2020). SARS-CoV-2 and HCV, are both +ssRNA viruses and have 22.22 % sequence similarities between their RdRps. In this study, an attempt has been made to identify the most efficient RdRp inhibitor of SARS-CoV-2 with the help of computational approaches by screening the inhibitory properties of commonly used RdRp inhibitors of the HCV.

Discussion
Upon entry inside the host cell, viral RdRp enables multiplication of the +ssRNA virus that ATP binding domain and RNA-directed 5'-3' polymerase activity of the RdRp exist within 549-776 amino acid residues (GO:0003968) and this stretch of amino acids is crucial for RNA synthesis (Figure 3). Beclabuvir is a non-nucleoside polymerase inhibitor that potentially inhibit nonstructural protein 5B (NS5B) of HCV (Garimella, Tao et al. 2018). Upon intracellular uptake beclabuvir allosterically binds to the noncatalytic Thumb 1 site (Figure 4) of viral RdRp which slowdown the RNA synthesis process (Garimella, Tao et al. 2018). However, in the case of SARS-CoV-2 beclabuvir occupies the active site environment (ASE), (Figure 5) of the RdRp which is essential for the RNA-dependent polymerase activity (Fouad, Soliman et al. 2019) ). The major interacting residues were I591, Y621, C624, D625, A690, N693, L760, D762, D763 and E813-N817 (Figure 1). Moreover, beclabuvir also showed better binding free energy (ΔGvina = 8.0 kcal mol -1 ) for the active site environment (ACE) of RdRp than that of HCV (ΔGvina = 7.7 kcal mol -1 ). Hence the present study finds a high potential for beclabuvir to be effective as therapeutic agent against SARS-CoV-2 multiplication as well as infection. Properties of molecular interaction of beclabuvir and other FDA approved antiviral drugs against HCV infection are summarized in Table 1 which could also be effective to use against SARS-CoV-2 infection. This preliminary study may be contributory towards the anti-epidemic efforts against the newly emerged SARS-CoV-2 (Corman, Landt et al. 2020;Huang, Wang et al. 2020;Hui, I Azhar et al. 2020;Zhu, Zhang et al. 2020) and may help to shorlist antiviral drugs against SARS-CoV-2 for clinical trials.

Conclusion
Throughout history, the human race had been challenged by multiple of globalpandemics. However, with the advancement of medical science and at the age of Artificial Intelligence, global health disaster of this scale, probablly would not be difficult to manage. However, the things that matter most are the time and the supply of resources. As reported by WHO, the original outbreak began in December-2019 and within three months, global death toll due to SARS-CoV-2 has reached the tragic milestone of 14,000. In conclusion, this rapid study suggests beclabuvir, and other commonly used antiviral drugs for HCV could be utilized as anti-SARS-CoV-2 drugs to control the devastation of the outbreak. However, more studies are required before the practical use of these antiviral drugs.

Acknowledgement
Council of Scientific and Industrial Research (CSIR), Govt. of India, New Delhi, India is also sincerely acknowledged by K.D. for Senior Research Fellowship (SRF), sanction letter no. 09/599 (0082) 2K19 EMR-Z. All co-authors are sincerely ackowledged for different data resources created especially for SARS-CoV-2.

Declaration of interests
The author declares no competing financial interests.