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Link to original content: http://pubmed.ncbi.nlm.nih.gov/32022370/
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. 2020 Mar 2;21(5):730-738.
doi: 10.1002/cbic.202000047. Epub 2020 Feb 25.

Learning from the Past: Possible Urgent Prevention and Treatment Options for Severe Acute Respiratory Infections Caused by 2019-nCoV

Jared S Morse  1 , Tyler Lalonde  1 , Shiqing Xu  1 , Wenshe Ray Liu  1
Affiliations

Learning from the Past: Possible Urgent Prevention and Treatment Options for Severe Acute Respiratory Infections Caused by 2019-nCoV

Jared S Morse et al. Chembiochem. .

Abstract

With the current trajectory of the 2019-nCoV outbreak unknown, public health and medicinal measures will both be needed to contain spreading of the virus and to optimize patient outcomes. Although little is known about the virus, an examination of the genome sequence shows strong homology with its better-studied cousin, SARS-CoV. The spike protein used for host cell infection shows key nonsynonymous mutations that might hamper the efficacy of previously developed therapeutics but remains a viable target for the development of biologics and macrocyclic peptides. Other key drug targets, including RNA-dependent RNA polymerase and coronavirus main proteinase (3CLpro), share a strikingly high (>95 %) homology to SARS-CoV. Herein, we suggest four potential drug candidates (an ACE2-based peptide, remdesivir, 3CLpro-1 and a novel vinylsulfone protease inhibitor) that could be used to treat patients suffering with the 2019-nCoV. We also summarize previous efforts into drugging these targets and hope to help in the development of broad-spectrum anti-coronaviral agents for future epidemics.

Keywords: 2019-nCoV; 3CLpro; RdRp; SARS; antiviral agents; coronavirus; spike proteins.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Lifecycle of a coronavirus entering a host cell and replicating inside. The (+)‐stranded RNA is released upon viral entry; this starts the process of generating the viral coat and replicating the RNA genome.
Figure 2
Figure 2
A) Sequence alignment for the amino acids between the 2019‐nCoV and SARS‐CoV spike RBD domains. Conserved (pink arrows) and nonconserved (black arrows) mutations are highlighted. Gray: hydrophobic aliphatic, orange: neutral aromatic, yellow: thiol and sulfide, green: hydroxy, red: basic, blue: carboxylic acid, brown: primary amide, pink: proline. B) Various binding interactions between the 2019‐nCov spike protein (pink) and ACE2 (blue; spike protein homology model built by using Modeller, based upon PDB ID: 2AJF) in regions 1 and 2. C)–E) Zoomed in views of several spike protein–ACE2 interactions depicted in (B). Residues before the forward slash refer to 2019‐nCoV; the amino acid after the slash refers to its corresponding identity in SARS‐CoV.
Figure 3
Figure 3
A) Sequence alignment for the amino acids between the 2019‐nCoV RdRp and the SARS‐CoV RdRp. Conserved (pink arrows) and nonconserved (black arrows) mutations are highlighted. Gray: hydrophobic aliphatic, orange: neutral aromatic, yellow: thiol and sulfide, green: hydroxy, red: basic, blue: carboxylic acid, brown: primary amide, pink: proline. B) Crystal structure of the SARS‐CoV RdRp active site (PDB ID: 6NUS).
Figure 4
Figure 4
Structure of compounds inhibiting SARS‐CoV viral replication through the mechanistic action of RdRp. The most promising candidate, remdesivir, is highlighted in the red box.
Figure 5
Figure 5
A) Sequence alignment for the amino acids between the 2019‐nCoV 3CLpro and the SARS‐CoV 3CLpro. Conserved (pink arrows) and nonconserved (black arrows) mutations are highlighted. Gray: hydrophobic aliphatic, orange: neutral aromatic, yellow: thiol and sulfide, green: hydroxy, red: basic, blue: carboxylic acid, brown: primary amide, pink: proline. B) A 2019‐nCoV 3CLpro structure modeled by using Modeller based on the SARS‐CoV 3CLpro structure (PDB ID: 2A5I); green: catalytic domain of the first monomeric unit, red: C‐terminal domain of the first monomeric unit, cyan: second monomeric unit. C) An alternative view of the predicted 2019‐nCoV 3CLpro monomeric structure (color‐coded by secondary structure) bound to an aza‐peptide inhibitor, showing conserved (pink) and nonconserved (black) mutations (not shown: S267/A). Residues before the forward slash refer to 2019‐nCoV; the amino acid after the slash refers to its corresponding identity in SARS‐CoV.
Figure 6
Figure 6
A) Sequence alignment for the amino acids between the 2019‐nCoV PLpro and the SARS‐CoV PLpro. Conserved (pink arrows) and nonconserved (black arrows) mutations are highlighted. Gray: hydrophobic aliphatic, orange: neutral aromatic, yellow: thiol and sulfide, green: hydroxy, red: basic, blue: carboxylic acid, brown: primary amide, pink: proline. B) Crystal structure of the SARS‐CoV PLpro in complex with ubiquitin aldehyde (PDB ID: 4MM3).
Figure 7
Figure 7
A representation of the top CoV protease inhibitors providing a scaffold to perform SAR studies in terms of designing novel small‐molecule protease inhibitors for 2019‐nCoV[40–45, 49]. 3CLpro‐1, the most potent inhibitor, is highlighted.
Figure 8
Figure 8
Lead vinylsulfone protease inhibitors that prevent the entry of CoV and, in combination with camostat, increase the survival rate of mice infected with SARS‐CoV.
Figure 9
Figure 9
Peptidyl bisulfide adducts that have been demonstrated to prevent viral replication in the feline coronavirus FIPV. The most promising candidate, GC376, was shown to produce similar levels of inhibition against SARS‐CoV 3CLpro in a FRET‐based activity assay.
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