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J Phys Chem Lett ; 11(12): 4785-4790, 2020 Jun 18.
Article in English | MEDLINE | ID: covidwho-548363


The severe acute respiratory syndrome coronavirus (SARS-CoV-2) pandemic is setting the global health crisis of our time, causing a devastating societal and economic burden. An idiosyncratic trait of coronaviruses is the presence of spike glycoproteins on the viral envelope, which mediate the virus binding to specific host receptor, enabling its entry into the human cells. In spite of the high sequence identity of SARS-CoV-2 with its closely related SARS-CoV emerged in 2002, the atomic-level determinants underlining the molecular recognition of SARS-CoV-2 to the angiotensin-converting enzyme 2 (ACE2) receptor and, thus, the rapid virus spread into human body, remain unresolved. Here, multi-microsecond-long molecular dynamics simulations enabled us to unprecedentedly dissect the key molecular traits liable of the higher affinity/specificity of SARS-CoV-2 toward ACE2 as compared to SARS-CoV. This supplies a minute per-residue contact map underlining its stunningly high infectivity. Harnessing this knowledge is pivotal for urgently developing effective medical countermeasures to face the ongoing global health crisis.

Betacoronavirus/metabolism , Glycoproteins/metabolism , Molecular Dynamics Simulation , Viral Proteins/metabolism , Amino Acid Motifs , Coronavirus Infections/pathology , Coronavirus Infections/virology , Glycoproteins/chemistry , Humans , Hydrogen Bonding , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Protein Binding , Protein Structure, Quaternary , Protein Structure, Tertiary , Quantum Theory , SARS Virus/metabolism , Viral Proteins/chemistry , Virus Attachment
Int J Antimicrob Agents ; 55(5): 105960, 2020 May.
Article in English | MEDLINE | ID: covidwho-65372


The recent emergence of the novel pathogenic SARS-coronavirus 2 (SARS-CoV-2) is responsible for a worldwide pandemic. Given the global health emergency, drug repositioning is the most reliable option to design an efficient therapy for infected patients without delay. The first step of the viral replication cycle [i.e. attachment to the surface of respiratory cells, mediated by the spike (S) viral protein] offers several potential therapeutic targets. The S protein uses the angiotension-converting enzyme-2 (ACE-2) receptor for entry, but also sialic acids linked to host cell surface gangliosides. Using a combination of structural and molecular modelling approaches, this study showed that chloroquine (CLQ), one of the drugs currently under investigation for SARS-CoV-2 treatment, binds sialic acids and gangliosides with high affinity. A new type of ganglioside-binding domain at the tip of the N-terminal domain of the SARS-CoV-2 S protein was identified. This domain (111-158), which is fully conserved among clinical isolates worldwide, may improve attachment of the virus to lipid rafts and facilitate contact with the ACE-2 receptor. This study showed that, in the presence of CLQ [or its more active derivative, hydroxychloroquine (CLQ-OH)], the viral S protein is no longer able to bind gangliosides. The identification of this new mechanism of action of CLQ and CLQ-OH supports the use of these repositioned drugs to cure patients infected with SARS-CoV-2. The in-silico approaches used in this study might also be used to assess the efficiency of a broad range of repositioned and/or innovative drug candidates before clinical evaluation.

Betacoronavirus/drug effects , Chloroquine/pharmacology , Coronavirus Infections/drug therapy , Hydroxychloroquine/pharmacology , Pneumonia, Viral/drug therapy , Amino Acid Sequence , Betacoronavirus/chemistry , Chloroquine/chemistry , Chloroquine/therapeutic use , Humans , Hydroxychloroquine/chemistry , Hydroxychloroquine/therapeutic use , Models, Molecular , Molecular Targeted Therapy , Pandemics , Protein Structure, Quaternary , Protein Structure, Tertiary , Sequence Analysis, Protein , Spike Glycoprotein, Coronavirus/chemistry
Emerg Microbes Infect ; 9(1): 601-604, 2020.
Article in English | MEDLINE | ID: covidwho-9940


The recent outbreak of pneumonia-causing COVID-19 in China is an urgent global public health issue with an increase in mortality and morbidity. Here we report our modelled homo-trimer structure of COVID-19 spike glycoprotein in both closed (ligand-free) and open (ligand-bound) conformation, which is involved in host cell adhesion. We also predict the unique N- and O-linked glycosylation sites of spike glycoprotein that distinguish it from the SARS and underlines shielding and camouflage of COVID-19 from the host the defence system. Furthermore, our study also highlights the key finding that the S1 domain of COVID-19 spike glycoprotein potentially interacts with the human CD26, a key immunoregulatory factor for hijacking and virulence. These findings accentuate the unique features of COVID-19 and assist in the development of new therapeutics.

Betacoronavirus/metabolism , Dipeptidyl Peptidase 4/chemistry , Polysaccharides/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Betacoronavirus/chemistry , Betacoronavirus/genetics , Coronavirus Infections/virology , Dipeptidyl Peptidase 4/metabolism , Humans , Models, Molecular , Pandemics , Pneumonia, Viral/virology , Polysaccharides/metabolism , Protein Binding , Protein Structure, Quaternary , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism