4 Concluding remarks
In the past twenty years, two new coronaviruses have been emerged mainly causing the acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) responsible for the epidemics in 2002 and 2012, respectively (World Health Organization, 2003; World Health Organization, 2013). Since the pandemic outbreak of novel coronavirus (2019-nCoV) and the rapidly increasing number of patients by minutes (155175 Deaths by April 18, 2020), the focus has been on the assessments to of recruite the existing antiviral compounds which must be complemented by the new drug discovery programs in the future. Nevertheless, the current urgent demand is addressing by the clinical trials of 30 drugs to approve the effectiveness of the existing antiviral drugs on 2019-nCoV.
The potential molecular targets in anti 2019-nCoV drug discovery is surveyed in the paper that can be employed in HTS programs for systematic drug discovery for 2019-nCoV infection. Little is currently known about the biology of 2019-nCoV specially, viral protein synthesis and assembly and most of what we know have been for the last 4 months. Due to the high virus transmission and the global spread of coronavirus, the foremost controversial issue is the mitigation of its pathogenicity using the existing anti-viral compounds. Therefore, in silico or practical screening of molecular targets are being conducted on structural information obtained from all major variants of the virus. Although, the ongoing clinical trials are evaluating the potential treatments of more than 30 drugs, there are currently no specifically certified drugs or vaccines for 2019-nCoV. In addition to the above approach, detailed studying the viral life cycle can lead to assigning some even more effective drug targets. In this direction, some drug targets based on bioinformatics analysis and relative similarities of this new virus with other members of its family like host cell receptors, spike glycoproteins, papain-like and 3C-like protease, RdRp have been documented so far. However, an approximate half of the potent drug candidates and nearly one-third of the drugs registered on the www.clinicaltrials.gov webpage, solely inhibit proteases affecting the replicase protein expression step in the viral life cycle.
While full-length S proteins of 2019-nCoV and SARS-CoV share up to 76% identities in amino acid sequences, the N terminal domain that binds to the receptor show only 53.5% of homology reflecting its ability to bind different sugars. Therefore, emphasizing on other virus entry related factors like cathepsin seems valuable for 2019-nCoV drug discovery. Based on a recent report (Walls et al., 2020), host proteases cathepsin L and TMPRSS2 prepare the 2019-nCoV S protein for cell entry. Considering the results of repurposing strategies and clinical tests until now, remdesivir seems a promising drug. Nevertheless, HIV protease inhibitors (ritonavir/lopinavir/ASC09), favipiravir and chloroquine need further investigations.