Current status of antivirals and druggable targets of SARS CoV-2 and other human pathogenic coronaviruses
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Date
2020Author
Artese, Anna
Svicher, Valentina
Costa, Giosué
Salpini, Romina
Di Maio, Velia Chiara
Alkhatib, Mohammad
Ambrosio, Francesca Alessandra
Santoro, Maria Mercedes
Assaraf, Yehuda G.
Alcaro, Stefano
Ceccherini-Silberstein, Francesca
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Abstract
Coronaviridae is a peculiar viral family, with a very large RNA genome and characteristic
appearance, endowed with remarkable tendency to transfer from animals to humans. Since the
beginning of the 21st century, three highly transmissible and pathogenic coronaviruses have crossed
the species barrier and caused deadly pneumonia, inflicting severe outbreaks and causing human
health emergencies of inconceivable magnitude. Indeed, in the past two decades, two human
coronaviruses emerged causing serious respiratory illness: severe acute respiratory syndrome
coronavirus (SARS-CoV-1) and Middle Eastern respiratory syndrome coronavirus (MERS-CoV),
causing more than 10,000 cumulative cases, with mortality rates of 10% for SARS-CoV-1 and 34.4%
for MERS-CoV. More recently, the severe acute respiratory syndrome coronavirus virus 2 (SARSCoV-2) has emerged in China and has been identified as the etiological agent of the recent COVID19 pandemic outbreak. It has rapidly spread throughout the world, causing nearly 22 million cases
and ~ 770,000 deaths worldwide, with an estimated mortality rate of ~3.6%, hence posing serious
challenges for adequate and effective prevention and treatment. Currently, with the exception of the
nucleotide analogue prodrug remdesivir, and despite several efforts, there is no known specific,
proven, pharmacological treatment capable of efficiently and rapidly inducing viral containment and
clearance of SARS-CoV-2 infection as well as no broad-spectrum drug for other human pathogenic
coronaviruses. Another confounding factor is the paucity of molecular information regarding the
tendency of coronaviruses to acquire drug resistance, a gap that should be filled in order to optimize
the efficacy of antiviral drugs.
In this light, the present review provides a systematic update on the current knowledge of the marked
global efforts towards the development of antiviral strategies aimed at coping with the infection
sustained by SARS-CoV-2 and other human pathogenic coronaviruses, displaying drug resistance
profiles. The attention has been focused on antiviral drugs mainly targeting viral protease, RNA
polymerase and spike glycoprotein, that have been tested in vitro and/or in clinical trials as well as
on promising compounds proven to be active against coronaviruses by an in silico drug repurposing
approach. In this respect, novel insights on compounds, identified by structure-based virtual screening
on the DrugBank database endowed by multi-targeting profile, are also reported. We specifically
identified 14 promising compounds characterized by a good in silico binding affinity towards, at least,
two of the four studied targets (viral and host proteins). Among which, ceftolozane and NADH
showed the best multi-targeting profile, thus potentially reducing the emergence of resistant virus
strains. We also focused on potentially novel pharmacological targets for the development of
compounds with anti-pan coronavirus activity. Through the analysis of a large set of viral genomic
sequences, the current review provides a comprehensive and specific map of conserved regions across human coronavirus proteins which are essential for virus replication and thus with no or very limited
tendency to mutate. Hence, these represent key druggable targets for novel compounds against this
virus family. In this respect, the identification of highly effective and innovative pharmacological
strategies is of paramount importance for the treatment and/or prophylaxis of the current pandemic
but potentially also for future and unavoidable outbreaks of human pathogenic coronaviruses.
Palabras clave
SARS-CoV-2; Coronavirus; Outbreaks; Antiviral agents; Antiviral resistance; Conservation; RNA polymerase; Protease; Spike; Nucleoside analogs; Protease inhibitors; Entry inhibitorsLink to resource
https://doi.org/10.1016/j.drup.2020.100721Collections
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