Serine 477 plays a crucial role in the interaction of the SARS-CoV-2 spike protein with the human receptor ACE2.

Singh, Amit; Steinkellner, Georg; Köchl, Katharina; Gruber, Karl; Gruber, Christian

doi:10.21203/rs.3.rs-106969/v2

Cited by 15 publications

(16 citation statements)

References 40 publications

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“…Our findings, which demonstrate a reduced affinity of E484K to ACE2 however support the recent observations in which the E484K mutation has been found to prevent the formation of two salt bridges that help to form and stabilize the RBD-ACE2 complex, thus reducing ACE2 binding affinity (22). We also found S477N (51), and Q493L, a variant at a position which interfaces directly with ACE2, had enhanced affinity to ACE2, confirming observations from deep mutational scanning analysis (42). What these differences in affinity to the ACE2 receptor mean for the overall viral fitness and transmissibility of these variants is beginning to be explored (52).…”

Section: Discussionsupporting

confidence: 85%

Simultaneous evaluation of antibodies that inhibit SARS-CoV-2 RBD variants with a novel competitive multiplex assay

López

Haycroft

Adair

et al. 2021

Preprint

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The SARS-CoV-2 Receptor Binding Domain (RBD) is both the principal target of neutralizing antibodies, and one of the most rapidly evolving domains, which can result in the emergence of immune escape mutations limiting the effectiveness of vaccines and antibody therapeutics. To facilitate surveillance, we developed a rapid, high-throughput, multiplex assay able to assess the inhibitory response of antibodies to 24 RBD natural variants simultaneously. We demonstrate that immune escape can occur through two mechanisms, antibodies that fail to recognize mutations, along with antibodies that have reduced inhibitory capacity due to enhanced variant RBD-ACE2 affinity. A competitive approach where antibodies simultaneously compete with ACE2 for binding to the RBD may therefore more accurately reflect the physiological dynamics of infection. We describe the enhanced affinity of RBD variants N439K, S477N, Q493L, S494P and N501Y to the ACE2 receptor, and demonstrate the ability of this assay to bridge a major gap for SARS-CoV-2 research; informing selection of complementary monoclonal antibody candidates and the rapid identification of immune escape to emerging RBD variants following vaccination or natural infection.

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Section: Discussionsupporting

confidence: 85%

Simultaneous evaluation of antibodies that inhibit SARS-CoV-2 RBD variants with a novel competitive multiplex assay

López

Haycroft

Adair

et al. 2021

Preprint

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“…A diversity of coronaviruses in sewage samples highlights the potential for emerging coronaviruses among species in close proximity in the urban setting, especially given the propensity for coronaviruses to recombine [60]. Another detected mutation, S477N (in S gene), has been reported to increase the binding affinity of the virus to the host's angiotensin-converting enzyme 2 (ACE-2) receptor giving higher transmission capability [62,63]. Similarly, novel missense mutations detected in NSP12, NSP2, and N genes from sites in the same Ward indicated ongoing viral circulation in the community.…”

Section: Discussionmentioning

confidence: 99%

Rapid genomic surveillance of SARS-CoV-2 in a dense urban community using environmental (sewage) samples

Napit

Manandhar

Chaudhary

et al. 2021

Preprint

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Understanding disease burden and transmission dynamics in resource-limited, developing countries like Nepal is often challenging due to a lack of adequate surveillance systems. These issues are exacerbated by limited access to diagnostic and research facilities throughout the country. Nepal has one of the highest COVID-19 case rates (915 cases per 100,000 people) in South Asia, with densely-populated Kathmandu experiencing the highest number of cases. Swiftly identifying case clusters and introducing effective intervention programs is crucial to mounting an effective containment strategy. The rapid identification of circulating SARS-CoV-2 variants can also provide important information on viral evolution and epidemiology. Genomic-based environmental surveillance can help in the early detection of outbreaks before clinical cases are recognized, and identify viral micro-diversity that can be used for designing real-time risk-based interventions. This research aimed to develop a genomic-based environmental surveillance system by detecting and characterizing SARS-CoV-2 in sewage samples of Kathmandu using portable next-generation DNA sequencing devices. Out of 20 selected sites in the Kathmandu Valley, sewage samples from 16 (80%) sites had detectable SARS-CoV-2. A heat-map was created to visualize transmission activity in the community based on viral load intensity and corresponding geospatial data. Further, 41 mutations were observed in the SARS-CoV-2 genome. Some detected mutations (n=9, 2%) were novel and yet to be reported in the global database, with one indicating a frameshift deletion in the spike gene. We also observed more transition than transversion on detected mutations, indicating rapid viral evolution in the host. Our study has demonstrated the feasibility of rapidly obtaining vital information on community transmission and disease dynamics of SARS-CoV-2 using genomic-based environmental surveillance.

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“…S477N, N439K, N440K and G413V (Figure 2B, C). S477N occurs frequently almost similar to the D614G variant and studies show that S477N has potential to affect the RBD stability and strengthen the binding with the human ACE2 protein (Starr et al 2020; Singh et al 2020). In our study, S477N was most frequently co-occurring with D614G (Figure 2D).…”

Section: Discussionmentioning

confidence: 99%

Large-scale analysis of SARS-CoV-2 spike-glycoprotein mutants demonstrates the need for continuous screening of virus isolates

Schroers

Gudimella

Bukur

et al. 2021

Preprint

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Due to the widespread of the COVID-19 pandemic, the SARS-CoV-2 genome is evolving in diverse human populations. Several studies already reported different strains and an increase in the mutation rate. Particularly, mutations in SARS-CoV-2 spike-glycoprotein are of great interest as it mediates infection in human and recently approved mRNA vaccines are designed to induce immune responses against it. We analyzed 146,920 SARS-CoV-2 genome assemblies and 2,393 NGS datasets from GISAID, NCBI Virus and NCBI SRA archives focusing on non-synonymous mutations in the spike protein. Only around 13.6% of the samples contained the wild-type spike protein with no variation from the reference. Among the spike protein mutants, we confirmed a low mutation rate exhibiting less than 10 non-synonymous mutations in 99.98% of the analyzed sequences, but the mean and median number of spike protein mutations per sample increased over time. 2,592 distinct variants were found in total. The majority of the observed variants were recurrent, but only nine and 23 recurrent variants were found in at least 0.5% of the mutant genome assemblies and NGS samples, respectively. Further, we found high-confidence subclonal variants in about 15.1% of the NGS data sets with mutant spike protein, which might indicate co-infection with various SARS-CoV-2 strains and/or intra-host evolution. Lastly, some variants might have an effect on antibody binding or T-cell recognition. These findings demonstrate the increasing importance of monitoring SARS-CoV-2 sequences for an early detection of variants that require adaptations in preventive and therapeutic strategies.

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Serine 477 plays a crucial role in the interaction of the SARS-CoV-2 spike protein with the human receptor ACE2.

Cited by 15 publications

References 40 publications

Simultaneous evaluation of antibodies that inhibit SARS-CoV-2 RBD variants with a novel competitive multiplex assay

Simultaneous evaluation of antibodies that inhibit SARS-CoV-2 RBD variants with a novel competitive multiplex assay

Rapid genomic surveillance of SARS-CoV-2 in a dense urban community using environmental (sewage) samples

Large-scale analysis of SARS-CoV-2 spike-glycoprotein mutants demonstrates the need for continuous screening of virus isolates

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