Project description:SARS-CoV-2 infection is initiated by binding of the receptor-binding domain (RBD) of its spike glycoprotein to the peptidase domain (PD) of angiotensin-converting enzyme 2 (ACE2) receptors in host cells. Recently detected Omicron variant of SARS-CoV-2 (B.1.1.529) is heavily mutated on RBD. First the BA.1 and later the BA.2 variant became the most dominant strains of the Omicron variant. To investigate how the mutations of these strains affect RBD-PD interactions, we performed all-atom molecular dynamics simulations of the BA.1 and BA.2 RBD-PD in the presence of full-length glycans, explicit water, and ions. Simulations revealed that RBDs of BA.1 and BA.2 variants exhibit a more dispersed interaction network and make an increased number of salt bridges and hydrophobic interactions with PD compared to wild-type RBD. Although BA.1 and BA.2 differ in two residues at the RBD-ACE2 interface, no major difference in RBD-PD interactions and binding strengths were observed between these variants. Using the conformations sampled in each trajectory, the Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) method estimated ∼34% and ∼51% stronger binding free energies to PD for BA.1 and BA.2 RBD, respectively, than wild-type RBD, which may result in higher binding efficiency of the Omicron variant to infect host cells.

| S-EPMC9352197 | biostudies-literature

The SARS-CoV-2 spike S375F mutation characterizes the Omicron BA.1 variant.

Project description:Recent studies have revealed the unique virological characteristics of Omicron, particularly those of its spike protein, such as less cleavage efficacy in cells, reduced ACE2 binding affinity, and poor fusogenicity. However, it remains unclear which mutation(s) determine these three virological characteristics of Omicron spike. Here, we show that these characteristics of the Omicron spike protein are determined by its receptor-binding domain. Of interest, molecular phylogenetic analysis revealed that acquisition of the spike S375F mutation was closely associated with the explosive spread of Omicron in the human population. We further elucidated that the F375 residue forms an interprotomer pi-pi interaction with the H505 residue of another protomer in the spike trimer, conferring the attenuated cleavage efficiency and fusogenicity of Omicron spike. Our data shed light on the evolutionary events underlying the emergence of Omicron at the molecular level.

| S-EPMC9719929 | biostudies-literature

An ACE2-Based Decoy Inhibitor Effectively Neutralizes SARS-CoV-2 Omicron BA.5 Variant.

Project description:The recently circulating SARS-CoV-2 Omicron BA.5 is rampaging the world with elevated transmissibility compared to the original SARS-CoV-2 strain. Immune escape of BA.5 was observed after treatment with many monoclonal antibodies, calling for broad-spectrum, immune-escape-evading therapeutics. In retrospect, we previously reported Kansetin as an ACE2 mimetic and a protein antagonist against SARS-CoV-2, which proved potent neutralization bioactivity on the Reference, Alpha, Beta, Delta, and Omicron strains of SARS-CoV-2. Since BA.5 is expected to rely on the interaction of the Spike complex with human ACE2 for cell entry, we reasonably assumed the lasting efficacy of the ACE2-mimicking Kansetin for neutralizing the new SARS-CoV-2 variant. The investigation was accordingly performed on in vitro Kansetin-Spike binding affinity by SPR and cell infection inhibition ability with pseudovirus and live virus assays. As a result, Kansetin showed dissociation constant KD and half inhibition concentration IC50 at the nanomolar to picomolar level, featuring a competent inhibition effect against the BA.5 sublineage. Conclusively, Kansetin is expected to be a promising therapeutic option against BA.5 and future SARS-CoV-2 sublineages.

| S-EPMC9695261 | biostudies-literature

SARS-CoV-2 S Omicron Spike B.1.1.529

Project description: Not available

| EMPIAR-10947 | biostudies-other

Characterization of biotinylated human ACE2 and SARS-CoV-2 Omicron BA.4/5 spike protein reference materials.

Project description:Accurate diagnostic and serology assays are required for the continued management of the COVID-19 pandemic yet spike protein mutations and intellectual property concerns with antigens and antibodies used in various test kits render comparability assessments difficult. As the use of common, well-characterized reagents can help address this lack of standardization, the National Research Council Canada has produced two protein reference materials (RMs) for use in SARS-CoV-2 serology assays: biotinylated human angiotensin-converting enzyme 2 RM, ACE2-1, and SARS-CoV-2 Omicron BA.4/5 spike protein RM, OMIC-1. Reference values were assigned through a combination of amino acid analysis via isotope dilution liquid chromatography tandem mass spectrometry following acid hydrolysis, and ultraviolet-visible (UV-Vis) spectrophotometry at 280 nm. Vial-to-vial homogeneity was established using UV-Vis measurements, and protein oligomeric status, monitored by size exclusion liquid chromatography (LC-SEC), was used to evaluate transportation, storage, and freeze-thaw stabilities. The molar protein concentration in ACE2-1 was 25.3 ± 1.7 µmol L-1 (k = 2, 95% CI) and consisted almost exclusively (98%) of monomeric ACE2, while OMIC-1 contained 5.4 ± 0.5 µmol L-1 (k = 2) spike protein in a mostly (82%) trimeric form. Glycoprotein molar mass determination by LC-SEC with multi-angle light scattering detection facilitated calculation of corresponding mass concentrations. To confirm protein functionality, the binding of OMIC-1 to immobilized ACE2-1 was investigated with surface plasmon resonance and the resulting dissociation constant, KD ~ 4.4 nM, was consistent with literature values.

| S-EPMC11330416 | biostudies-literature

Single-particle cryo-EM unaligned micrographs of prefusion SARS-CoV-2 spike omicron B.1.1.529 variant

Project description: Not available

| EMPIAR-11871 | biostudies-other