Bioinformatics analysis of the differences in the binding profile of the wild-type and mutants of the SARS-CoV-2 spike protein variants with the ACE2 receptor

The virus responsible for the COVID-19 global health crisis, SARS-CoV-2, has been shown to utilize the ACE2 protein as an entry point to its target cells. The virus has been shown to rely on the actions of TMPRSS2 (a serine protease), as well as FURIN (a peptidase), for the critical priming of its spike protein. It has been postulated that variations in the sequence and expression of SARS-CoV-2’s receptor (ACE2) and the two priming proteases (TMPRSS2 and FURIN) may be critical in contributing to SARS-CoV-2 infectivity. This study aims to examine the different expression levels of FURIN in various tissues and age ranges in light of ACE2 and TMPRSS2 expression levels using the LungMAP database. Furthermore, we retrieved expression quantitative trait loci (eQTLs) of the three genes and their annotation. We analyzed the frequency of the retrieved variants in data from various populations and compared it to the Egyptian population. We highlight FURIN’s potential interplay with the immune response to SARS-CoV-2 and showcase a myriad of variants of the three genes that are differentially expressed across populations. Our findings provide insights into potential genetic factors that impact SARS-CoV-2 infectivity in different populations and shed light on the varying expression patterns of FURIN.

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The Potential for SARS-CoV-2 to Evade Both Natural and Vaccine-induced Immunity

10.1101/2020.12.13.422567 ◽

2020 ◽

Cited By ~ 1

Author(s):

Emily Shang ◽

Paul Axelsen

Keyword(s):

Human Infection ◽

Antibody Binding ◽

Spike Protein ◽

Wild Type ◽

Binding Interface ◽

Naturally Occurring ◽

Binding Interfaces ◽

Induced Immunity ◽

Wild Type Form

SARS-CoV-2 attaches to the surface of susceptible cells through extensive interactions between the receptor binding domain (RBD) of its spike protein and angiotensin converting enzyme type 2 (ACE2) anchored in cell membranes. To investigate whether naturally occurring mutations in the spike protein are able to prevent antibody binding, yet while maintaining the ability to bind ACE2 and viral infectivity, mutations in the spike protein identified in cases of human infection were mapped to the crystallographically-determined interfaces between the spike protein and ACE2 (PDB entry 6M0J), antibody CC12.1 (PDB entry 6XC2), and antibody P2B-2F6 (PDB entry 7BWJ). Both antibody binding interfaces partially overlap with the ACE2 binding interface. Among 16 mutations that map to the RBD:CC12.1 interface, 11 are likely to disrupt CC12.1 binding but not ACE2 binding. Among 12 mutations that map to the RBD:P2B-2F6 interface, 8 are likely to disrupt P2B-2F6 binding but not ACE2 binding. As expected, none of the mutations observed to date appear likely to disrupt the RBD:ACE2 interface. We conclude that SARS-CoV-2 with mutated forms of the spike protein may retain the ability to bind ACE2 while evading recognition by antibodies that arise in response to the original wild-type form of the spike protein. It seems likely that immune evasion will be possible regardless of whether the spike protein was encountered in the form of infectious virus, or as the immunogen in a vaccine. Therefore, it also seems likely that reinfection with a variant strain of SARS-CoV-2 may occur among people who recover from Covid-19, and that vaccines with the ability to generate antibodies against multiple variant forms of the spike protein will be necessary to protect against variant forms of SARS-CoV-2 that are already circulating in the human population.

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Bioinformatics analysis of the recent MERS-CoV with special reference to the virus-encoded Spike protein

Molecular Enzymology and Drug Targets ◽

10.21767/2572-5475.10001 ◽

2015 ◽

Vol 01 (01) ◽

Cited By ~ 2

Author(s):

Mahmoud Kandeel

Keyword(s):

Special Reference ◽

Bioinformatics Analysis ◽

Spike Protein

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Transmission, infectivity, and antibody neutralization of an emerging SARS-CoV-2 variant in California carrying a L452R spike protein mutation

10.1101/2021.03.07.21252647 ◽

2021 ◽

Author(s):

Xianding Deng ◽

Miguel A Garcia-Knight ◽

Mir M. Khalid ◽

Venice Servellita ◽

Candace Wang ◽

...

Keyword(s):

Genome Sequencing ◽

Cell Cultures ◽

Spike Protein ◽

Nasopharyngeal Swab ◽

Whole Genome ◽

Wild Type ◽

Antibody Neutralization ◽

Protein Mutation ◽

Viral Shedding

AbstractWe identified a novel SARS-CoV-2 variant by viral whole-genome sequencing of 2,172 nasal/nasopharyngeal swab samples from 44 counties in California. Named B.1.427/B.1.429 to denote its 2 lineages, the variant emerged around May 2020 and increased from 0% to >50% of sequenced cases from September 1, 2020 to January 29, 2021, exhibiting an 18.6-24% increase in transmissibility relative to wild-type circulating strains. The variant carries 3 mutations in the spike protein, including an L452R substitution. Our analyses revealed 2-fold increased B.1.427/B.1.429 viral shedding in vivo and increased L452R pseudovirus infection of cell cultures and lung organoids, albeit decreased relative to pseudoviruses carrying the N501Y mutation found in the B.1.1.7, B.1.351, and P.1 variants. Antibody neutralization assays showed 4.0 to 6.7-fold and 2.0-fold decreases in neutralizing titers from convalescent patients and vaccine recipients, respectively. The increased prevalence of a more transmissible variant in California associated with decreased antibody neutralization warrants further investigation.

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“Vaccine-Induced Covid-19 Mimicry” Syndrome:Splice reactions within the SARS-CoV-2 Spike open reading frame result in Spike protein variants that may cause thromboembolic events in patients immunized with vector-based vaccines

10.21203/rs.3.rs-558954/v1 ◽

2021 ◽

Author(s):

Eric Kowarz ◽

Lea Krutzke ◽

Jenny Reis ◽

Silvia Bracharz ◽

Stefan Kochanek ◽

...

Keyword(s):

Side Effects ◽

Underlying Disease ◽

Open Reading Frames ◽

Spike Protein ◽

Severe Side Effect ◽

Thromboembolic Events ◽

Reading Frame ◽

Vein Thrombosis ◽

Vaccination Campaigns ◽

Protein Variants

Abstract During the last months many countries have started the immunization of millions of people by using vector-based vaccines. Unfortunately, severe side effects became overt during these vaccination campaigns: cerebral venous sinus thromboses (CVST), absolutely rare under normal life conditions, were found as a severe side effect that occured 4-14 days after first vaccinations. Besides CVST, Splanchnic Vein Thrombosis (SVT) was also observed. This type of adverse event has not been observed in the clinical studies of AstraZeneca, and therefore led immediately to a halt in vaccinations in several european countries. These events were mostly associated with thrombocytopenia, and thus, similar to the well-known Heparin-induced thrombocytopenia (HIT). Meanwhile, scientists have proposed a mechanism to explain this vaccine-induced thrombocytopenia. However, they do not provide a satisfactory explanation for the late thromboembolic events. Here, we present data that may explain these severe side effects which have been attributed to adenoviral vaccines. According to our results, transcription of wildtype and codon-optimized Spike open reading frames enables alternative splice events that lead to C-terminal truncated, soluble Spike protein variants. These soluble Spike variants may initiate severe side effects when binding to ACE2-expressing endothelial cells in blood vessels. In analogy to the thromboembolic events caused by Spike protein encoded by the SARS-CoV-2 virus, we termed the underlying disease mechanism the “Vaccine-Induced Covid-19 Mimicry” syndrome (VIC19M syndrome).

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Inferring the stabilization effects of SARS-CoV-2 variants on the binding with ACE2 receptor

10.1101/2021.04.18.440345 ◽

2021 ◽

Author(s):

Mattia Miotto ◽

Lorenzo Di Rienzo ◽

Giorgio Gosti ◽

Leonardo Bo ◽

Giacomo Parisi ◽

...

Keyword(s):

Control Systems ◽

South African ◽

Negative Control ◽

Spike Protein ◽

Special Focus ◽

Wild Type ◽

Shape Complementarity ◽

The Stability ◽

The Moment ◽

Dynamics Simulations

With the progression of the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic, several variants of the virus are emerging with mutations distributed all over the viral sequence. While most of them are expected to have little to no effects at the phenotype level, some of these variants presenting specific mutations on the Spike protein are rapidly spreading, making urgent the need of characterizing their effects on phenotype features like contagiousness and antigenicity. With this aim, we performed extensive molecular dynamics simulations on a selected set of possible Spike variants in order to assess the stabilizing effect of particular amino acid substitutions, with a special focus on the mutations that are both characteristic of the top three most worrying variants at the moment, i.e the English, South African and Amazonian ones, and that occur at the molecular interface between SARS-CoV-2 Spike protein and its human ACE2 receptor. We characterize these variants' effect in terms of (i) residues mobility, (ii) compactness, studying the network of interactions at the interface, and (iii) variation of shape complementarity via expanding the molecular surfaces in the Zernike basis. Overall, our analyses highlighted greater stability of the three variant complexes with respect to both the wild type and two negative control systems, especially for the English and Amazonian variants. In addition, in the three variants, we investigate the effects a not-yet observed mutation in position 501 could provoke on complex stability. We found that a phenylalanine mutation behaves similarly to the English variant and may cooperate in further increasing the stability of the South African one, hinting at the need for careful surveillance for the emergence of such kind of mutations in the population. Ultimately, we show that the observables we propose describe key features for the stability of the ACE2-spike complex and can help to monitor further possible spike variants.

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SARS-CoV-2 B.1.1.7 sensitivity to mRNA vaccine-elicited, convalescent and monoclonal antibodies

10.1101/2021.01.19.21249840 ◽

2021 ◽

Cited By ~ 4

Author(s):

Dami A. Collier ◽

Anna De Marco ◽

Isabella A.T.M. Ferreira ◽

Bo Meng ◽

Rawlings Datir ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Immune Responses ◽

Antibody Responses ◽

Spike Protein ◽

Binding Motif ◽

Wild Type ◽

Emerging Viruses ◽

Transmission Potential ◽

Amino Acid Mutations ◽

The Uk

AbstractSevere Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) transmission is uncontrolled in many parts of the world, compounded in some areas by higher transmission potential of the B1.1.7 variant now seen in 50 countries. It is unclear whether responses to SARS-CoV-2 vaccines based on the prototypic strain will be impacted by mutations found in B.1.1.7. Here we assessed immune responses following vaccination with mRNA-based vaccine BNT162b2. We measured neutralising antibody responses following a single immunization using pseudoviruses expressing the wild-type Spike protein or the 8 amino acid mutations found in the B.1.1.7 spike protein. The vaccine sera exhibited a broad range of neutralising titres against the wild-type pseudoviruses that were modestly reduced against B.1.1.7 variant. This reduction was also evident in sera from some convalescent patients. Decreased B.1.1.7 neutralisation was also observed with monoclonal antibodies targeting the N-terminal domain (9 out of 10), the Receptor Binding Motif (RBM) (5 out of 31), but not in neutralising mAbs binding outside the RBM. Introduction of the E484K mutation in a B.1.1.7 background to reflect newly emerging viruses in the UK led to a more substantial loss of neutralising activity by vaccine-elicited antibodies and mAbs (19 out of 31) over that conferred by the B.1.1.7 mutations alone. E484K emergence on a B.1.1.7 background represents a threat to the vaccine BNT162b.

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The TNFRSF13B rs34562254 Polymorphism is Associated with Hepatitis C Infection Risk in the Han Chinese Population

10.21203/rs.3.rs-147629/v1 ◽

2021 ◽

Author(s):

Haozhi Fan ◽

Zuqiang Fu ◽

Zhijun Ge ◽

Chen Dong ◽

Chunhui Wang ◽

...

Keyword(s):

Hepatitis C ◽

Tumor Necrosis Factor ◽

Chinese Population ◽

Tumor Necrosis ◽

Blood Donors ◽

Bioinformatics Analysis ◽

Hcv Infection ◽

Wild Type ◽

Han Chinese Population ◽

Necrosis Factor

Abstract Background Genetic variations in the tumor necrosis factor receptor superfamily (TNFRSF) 13B have been reported to be associated with immune-related diseases. This study aimed to explore the relationship of tumor necrosis factor superfamily (TNFSF) 13, TNFRSF13B, and TNFRSF14 missense mutations with hepatitis C virus (HCV) infection susceptibility. Methods Single-nucleotide polymorphisms (SNPs) in TNFSF13 (rs3803800, rs11552708), TNFRSF13B (rs34562254), and TNFRSF14 (rs4870) were genotyped in 469 intravenous drug users, 728 hemodialysis patients, and 1636 paid blood donors using a TaqMan real-time PCR assay. The USCS browser and RNAfold web servers were used to predict the biological functions of these selected SNPs. Results After adjusting for gender, age, levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and route of infection, a logistic regression analysis showed that subjects carrying a homozygous TNFRSF13B rs34562254 TT mutant were more likely to be infected by HCV compared to those homozygous with the rs34562254 CC wild type (co-dominant model: OR = 1.52, 95% CI: 1.17–1.98, P = 0.002; recession model: OR = 1.41, 95% CI: 1.10–1.81, P = 0.007; additive model: OR = 1.21, 95% CI: 1.07–1.37, P = 0.002). The effect of the risk allele rs34562254-T was stronger in subjects that were female, older (≥ 50 years old), paid blood donors, and with lower ALT and AST levels (≤ 40 U/L). A bioinformatics analysis via the UCSC genome browser found that rs34562254 was located at the highest peak of the H3K4Me1 histone marker. Using the RNAfold web servers, the minimum free energy of the centroid secondary structure was found to be higher for the mutant rs34562254-T allele (-38.90 kcal/mol) than its wild type C allele (-45.60 kcal/mol). Additionally, the RegulomeDB score of rs34562254 was 3a. Altogether, the results of the bioinformatics analysis indicate that rs34562254 may affect gene expression levels by regulating the transcriptional activity of corresponding gene regions. Conclusions The rs34562254 polymorphisms in TNFRSF13B were significantly associated with HCV infection among the Han Chinese population.

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Ultrapotent bispecific antibodies neutralize emerging SARS-CoV-2 variants

10.1101/2021.04.01.437942 ◽

2021 ◽

Author(s):

Hyeseon Cho ◽

Kristina Kay Gonzales-Wartz ◽

Deli Huang ◽

Meng Yuan ◽

Mary Peterson ◽

...

Keyword(s):

Bispecific Antibody ◽

Complete Loss ◽

Memory B Cells ◽

Spike Protein ◽

Bispecific Antibodies ◽

Wild Type Virus ◽

Type Virus ◽

Wild Type ◽

Hamster Model

The emergence of SARS-CoV-2 variants that threaten the efficacy of existing vaccines and therapeutic antibodies underscores the urgent need for new antibody-based tools that potently neutralize variants by targeting multiple sites of the spike protein. We isolated 216 monoclonal antibodies targeting SARS-CoV-2 from plasmablasts and memory B cells of COVID-19 patients. The three most potent antibodies targeted distinct regions of the RBD, and all three neutralized the SARS-CoV-2 variants B.1.1.7 and B.1.351. The crystal structure of the most potent antibody, CV503, revealed that it binds to the ridge region of SARS-CoV-2 RBD, competes with the ACE2 receptor, and has limited contact with key variant residues K417, E484 and N501. We designed bispecific antibodies by combining non-overlapping specificities and identified five ultrapotent bispecific antibodies that inhibit authentic SARS-CoV-2 infection at concentrations of <1 ng/mL. Through a novel mode of action three bispecific antibodies cross-linked adjacent spike proteins using dual NTD/RBD specificities. One bispecific antibody was >100-fold more potent than a cocktail of its parent monoclonals in vitro and prevented clinical disease in a hamster model at a 2.5 mg/kg dose. Notably, six of nine bispecific antibodies neutralized B.1.1.7, B.1.351 and the wild-type virus with comparable potency, despite partial or complete loss of activity of at least one parent monoclonal antibody against B.1.351. Furthermore, a bispecific antibody that neutralized B.1.351 protected against SARS-CoV-2 expressing the crucial E484K mutation in the hamster model. Thus, bispecific antibodies represent a promising next-generation countermeasure against SARS-CoV-2 variants of concern.

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A rigorous framework for detecting SARS-CoV-2 spike protein mutational ensemble from genomic and structural features

10.1101/2021.02.17.431625 ◽

2021 ◽

Author(s):

Saman Fatihi ◽

Surabhi Rathore ◽

Ankit Pathak ◽

Deepanshi Gahlot ◽

Mitali Mukerji ◽

...

Keyword(s):

Genomic Data ◽

Structural Features ◽

Antigenic Drift ◽

Spike Protein ◽

Wild Type ◽

Genome Sequences ◽

Host Interactions ◽

Rigorous Framework ◽

Dynamics Simulations ◽

Viral Host Interactions

AbstractThe recent release of SARS-CoV-2 genomic data from several countries has provided clues into the potential antigenic drift of the coronavirus population. In particular, the genomic instability observed in the spike protein necessitates immediate action and further exploration in the context of viral-host interactions. Here we dynamically track 3,11,795 genome sequences of spike protein, which comprises 2,584 protein mutations. We reveal mutational genomic ensemble at different timing and geographies, that evolves on four distinct residues. In addition to the well-established N501 mutational cluster, we detect the presence of three novel clusters, namely A222, N439, and S477. The robust examination of structural features from 44 known cryo-EM structures showed that the virus is deploying many mutations within these clusters on structurally heterogeneous regions. One such dominant variant D614G was also simulated using molecular dynamics simulations and, as compared to wild-type, we found higher stability with human ACE2 receptor. There is also a significant overlap of mutational clusters on known epitopes, indicating putative interference with antibody binding. Thus, we propose that the resulting coaxility of mutational clusters is the most efficient feature of SARS-CoV-2 evolution and provides precise mutant combinations that can enable future vaccine re-positioning.

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