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2.
Viruses ; 14(3)2022 03 06.
Article in English | MEDLINE | ID: covidwho-1732247

ABSTRACT

Our previous studies have shown that cholesterol-conjugated, peptide-based pan-coronavirus (CoV) fusion inhibitors can potently inhibit human CoV infection. However, only palmitic acid (C16)-based lipopeptide drugs have been tested clinically, suggesting that the development of C16-based lipopeptide drugs is feasible. Here, we designed and synthesized a C16-modified pan-CoV fusion inhibitor, EK1-C16, and found that it potently inhibited infection by SARS-CoV-2 and its variants of concern (VOCs), including Omicron, and other human CoVs and bat SARS-related CoVs (SARSr-CoVs). These results suggest that EK1-C16 could be further developed for clinical use to prevent and treat infection by the currently circulating MERS-CoV, SARS-CoV-2 and its VOCs, as well as any future emerging or re-emerging coronaviruses.


Subject(s)
COVID-19 , Middle East Respiratory Syndrome Coronavirus , COVID-19/drug therapy , Humans , Lipopeptides/pharmacology , Palmitic Acid/pharmacology , SARS-CoV-2
3.
J Gen Virol ; 102(1)2021 01.
Article in English | MEDLINE | ID: covidwho-910383

ABSTRACT

The emerging pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused social and economic disruption worldwide, infecting over 9.0 million people and killing over 469 000 by 24 June 2020. Unfortunately, no vaccine or antiviral drug that completely eliminates the transmissible disease coronavirus disease 2019 (COVID-19) has been developed to date. Given that coronavirus nonstructural protein 1 (nsp1) is a good target for attenuated vaccines, it is of great significance to explore the detailed characteristics of SARS-CoV-2 nsp1. Here, we first confirmed that SARS-CoV-2 nsp1 had a conserved function similar to that of SARS-CoV nsp1 in inhibiting host-protein synthesis and showed greater inhibition efficiency, as revealed by ribopuromycylation and Renilla luciferase (Rluc) reporter assays. Specifically, bioinformatics and biochemical experiments showed that by interacting with 40S ribosomal subunit, the lysine located at amino acid 164 (K164) was the key residue that enabled SARS-CoV-2 nsp1 to suppress host gene expression. Furthermore, as an inhibitor of host-protein expression, SARS-CoV-2 nsp1 contributed to cell-cycle arrest in G0/G1 phase, which might provide a favourable environment for virus production. Taken together, this research uncovered the detailed mechanism by which SARS-CoV-2 nsp1 K164 inhibited host gene expression, laying the foundation for the development of attenuated vaccines based on nsp1 modification.


Subject(s)
Host-Pathogen Interactions/genetics , Lysine/genetics , Ribosomal Proteins/genetics , Ribosome Subunits, Small, Eukaryotic/genetics , SARS-CoV-2/genetics , Viral Nonstructural Proteins/genetics , Amino Acid Sequence , Amino Acid Substitution , Computational Biology/methods , G1 Phase Cell Cycle Checkpoints/genetics , Gene Expression Regulation , Genes, Reporter , HEK293 Cells , Humans , Luciferases/genetics , Luciferases/metabolism , Lysine/metabolism , Mutation , Ribosomal Proteins/antagonists & inhibitors , Ribosomal Proteins/metabolism , Ribosome Subunits, Small, Eukaryotic/metabolism , Ribosome Subunits, Small, Eukaryotic/virology , SARS Virus/genetics , SARS Virus/metabolism , SARS-CoV-2/metabolism , Sequence Alignment , Sequence Homology, Amino Acid , Signal Transduction , Viral Nonstructural Proteins/metabolism
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