Highlight of potential impact of new viral genotypes of SARS-CoV-2 on vaccines and anti-viral therapeutics.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of the coronavirus disease (COVID-19) pandemic, has infected millions of people globally. Genetic variation and selective pressures lead to the accumulation of single nucleotide polymorphism (SNP) within the viral genome that may affect virulence, transmission rate, viral recognition and the efficacy of prophylactic and interventional measures. To address these concerns at the genomic level, we assessed the phylogeny and SNPs of the SARS-CoV-2 mutant population collected to date in Iran in relation to globally reported variants. Phylogenetic analysis of mutant strains revealed the occurrence of the variants known as B.1.1.7 (Alpha), B.1.525 (Eta), and B.1.617 (Delta) that appear to have delineated independently in Iran. SNP analysis of the Iranian sequences revealed that the mutations were predominantly positioned within the S protein-coding region, with most SNPs localizing to the S1 subunit. Seventeen S1-localizing SNPs occurred in the RNA binding domain that interacts with ACE2 of the host cell. Importantly, many of these SNPs are predicted to influence the binding of antibodies and anti-viral therapeutics, indicating that the adaptive host response appears to be imposing a selective pressure that is driving the evolution of the virus in this closed population through enhancing virulence. The SNPs detected within these mutant cohorts are addressed with respect to current prophylactic measures and therapeutic interventions.

The fatty acid site is coupled to functional motifs in the SARS-CoV-2 spike protein and modulates spike allosteric behaviour.

The SARS-CoV-2 spike protein is the first contact point between the SARS-CoV-2 virus and host cells and mediates membrane fusion. Recently, a fatty acid binding site was identified in the spike (Toelzer et al. Science 2020). The presence of linoleic acid at this site modulates binding of the spike to the human ACE2 receptor, stabilizing a locked conformation of the protein. Here, dynamical-nonequilibrium molecular dynamics simulations reveal that this fatty acid site is coupled to functionally relevant regions of the spike, some of them far from the fatty acid binding pocket. Removal of a ligand from the fatty acid binding site significantly affects the dynamics of distant, functionally important regions of the spike, including the receptor-binding motif, furin cleavage site and fusion-peptide-adjacent regions. Simulations of the D614G mutant show differences in behaviour between these clinical variants of the spike: the D614G mutant shows a significantly different conformational response for some structural motifs relevant for binding and fusion. The simulations identify structural networks through which changes at the fatty acid binding site are transmitted within the protein. These communication networks significantly involve positions that are prone to mutation, indicating that observed genetic variation in the spike may alter its response to linoleate binding and associated allosteric communication.

Analysis of SARS-COV2 spike protein variants among Iraqi isolates.

The ongoing pandemic of COVID-19 caused by the SARS-COV2 virus has triggered millions of deaths around the globe. Emerging several variants of the virus with increased transmissibility, the severity of disease, and the ability of the virus to escape from the immune system has a cause for concerns. Here, we compared the spike protein sequence of 91 human SARS CoV2 strains of Iraq to the first reported sequence of SARS-CoV2 isolate from Wuhan Hu-1/China. The strains were isolated between June 2020 and March 2021. Twenty-two distinct mutations were identified within the spike protein regions which were: L5F, L18F, T19R, S151T, G181A, A222V, A348S, L452 (Q or M), T478K, N501Y, A520S, A522V, A570D, S605A, D614G, Q675H, N679K, P681H, T716I, S982A, A1020S, D1118H. The most frequently mutations occurred at the D614G (87/91), followed by S982A (50/91), and A570D (48/91), respectively. In addition, a distinct shift was observed in the type of SARS-COV2 variants present in 2020 compared to 2021 isolates. In 2020, B.1.428.1 lineage was appeared to be a dominant variant (85%). However, the diversity of the variants increased in 2021, and the majority (73%) of the isolated were appeared to belong to B.1.1.7 lineage (VOC/alpha variants). To our knowledge, this is the first major genome analysis of SARS-CoV2 in Iraq. The data from this research could provide insights into SARS-CoV2 evolution, and can be potentially used to recognize the effective vaccine against the disease.

Unlocking COVID therapeutic targets: A structure-based rationale against SARS-CoV-2, SARS-CoV and MERS-CoV Spike.

There are no approved target therapeutics against SARS-CoV-2 or other beta-CoVs. The beta-CoV Spike protein is a promising target considering the critical role in viral infection and pathogenesis and its surface exposed features. We performed a structure-based strategy targeting highly conserved druggable regions resulting from a comprehensive large-scale sequence analysis and structural characterization of Spike domains across SARSr- and MERSr-CoVs. We have disclosed 28 main consensus druggable pockets within the Spike. The RBD and SD1 (S1 subunit); and the CR, HR1 and CH (S2 subunit) represent the most promising conserved druggable regions. Additionally, we have identified 181 new potential hot spot residues for the hSARSr-CoVs and 72 new hot spot residues for the SARSr- and MERSr-CoVs, which have not been described before in the literature. These sites/residues exhibit advantageous structural features for targeted molecular and pharmacological modulation. This study establishes the Spike as a promising anti-CoV target using an approach with a potential higher resilience to resistance development and directed to a broad spectrum of Beta-CoVs, including the new SARS-CoV-2 responsible for COVID-19. This research also provides a structure-based rationale for the design and discovery of chemical inhibitors, antibodies or other therapeutic modalities successfully targeting the Beta-CoV Spike protein.

Minireview of progress in the structural study of SARS-CoV-2 proteins.

A severe form of pneumonia, named coronavirus disease 2019 (COVID-19) by the World Health Organization, broke out in China and rapidly developed into a global pandemic, with millions of cases and hundreds of thousands of deaths reported globally. The novel coronavirus, which was designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the etiological agent of COVID-19. On the basis of experience accumulated following previous SARS-CoV and MERS-CoV outbreaks and research, a series of studies have been conducted rapidly, and major progress has been achieved with regard to the understanding of the phylogeny and genomic organization of SARS-CoV-2 in addition its molecular mechanisms of infection and replication. In the present review, we summarized crucial developments in the elucidation of the structure and function of key SARS-CoV-2 proteins, especially the main protease, RNA-dependent RNA polymerase, spike glycoprotein, and nucleocapsid protein. Results of studies on their associated inhibitors and drugs have also been highlighted.