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

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. While little is known about the virus, an examination of the genome sequence shows strong homology with its more well-studied cousin, SARS-CoV. The spike protein used for host cell infection shows key nonsynonymous mutations which may hamper efficacy of previously developed therapeutics but remains a viable target for the development of biologics and macrocyclic peptides. Other key drug targets, including RdRp and 3CLpro, share a strikingly high (>95%) homology to SARS-CoV. Herein, we suggest 4 potential drug candidates (an ACE2-based peptide, remdesivir, 3CLpro-1 and a novel vinylsulfone protease inhibitor) that can 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.

Figure 1.

Lifecycle of a coronavirus entering and replicating inside of a host cell. The (+)-stranded RNA is released upon viral entry, which starts the process of generating the viral coat and replicating the RNA genome

Figure 2.

A) Sequence alignment for the amino acids between the 2019-nCoV and SARS-CoV spike RBD domain. Conserved and non-conserved mutations are highlighted. B-E) Various binding interactions between the 2019-nCov spike protein (homology model built using Modeller, based upon PDB entry 2AJF) and ACE2 in regions 1 and 2

Figure 3.

A) Sequence alignment for the amino acids between the 2019-nCoV RdRp and the SARS-CoV RdRp. Conserved and non-conserved mutations are highlighted. B) Crystal structure of the SARS-CoV RdRp active site (PDB entry: 6NUS)

Figure 4.

Structure of drugs inhibiting SARS-CoV viral replication via the mechanistic action of RdRp

Figure 5.

A) Sequence alignment for the amino acids between the 2019-nCoV 3CLpro and the SARS-CoV 3CLpro. Conserved and non-conserved mutations are highlighted. B-C) A modeled 2019-nCoV 3CLpro structure using Modeller based on the SARS-CoV 3CLpro structure (PDB entry: 2A5I)

Figure 6.

A) Sequence alignment for the amino acids between the 2019-nCoV PLpro and the SARS-CoV PLpro. Conserved and non-conserved mutations are highlighted. B) Crystal structure of the SARS-CoV PLpro (PDB entry: 4MM3)

Figure 7.

This is a representation of the top CoV protease inhibitors providing a scaffold to perform SAR in terms of design novel small molecule protease inhibitors for 2019-nCoV^,,,,,,. 3CLpro-1 is highlight as the most potent inhibitor

Figure 8.

Lead vinylsulfone protease inhibitors that prevent the entry of the CoV and in combination with camostat increase the survival rate of a mice model suffering with SARS-CoV infection

Figure 9.

Peptidyl bisulfide adducts which have been demonstrated to prevent viral replication in the feline coronavirus FIPV. GC376 (left) was shown to produce similar levels of inhibition against SARS-CoV 3CLpro in a FRET-based activity assay