Effects of common mutations in the SARS-CoV-2 Spike RBD domain and its ligand the human ACE2 receptor on binding affinity and kinetics

Barton, Michael I; MacGowan, Stuart A.; Kutuzov, Mikhail A.; Dushek, Omer; Barton, Geoffrey J.; Merwe, P. Anton van der

doi:10.1101/2021.05.18.444646

Cited by 16 publications

(23 citation statements)

References 51 publications

(106 reference statements)

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“…Similarly, p.Ser19Pro also does not introduce any new Spike contacts according to the mCSM-PPI2 model and so the enhanced affinity is difficult to explain but it is has been suggested that the Pro mutant stabilises the helix to favour Spike interaction 22 . ACE2 p.Ser19Pro is of further interest because of its proximity to Spike Ser477, which has mutated to Asn in circulating SARS-CoV-2 strains and these ACE2 and RBD variants have been found to interact 28 . The mCSM-PPI2 structural models of the p.Asp355Asn, p.Glu37Lys and p.Gly352Val were discussed in detail in our previous work 23 .…”

Section: Resultsmentioning

confidence: 99%

Missense variants in human ACE2 modify binding to SARS-CoV-2 Spike

MacGowan

Barton

Kutuzov

et al. 2021

Preprint

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SARS-CoV-2 infection begins with the interaction of the SARS-CoV-2 Spike (Spike) and human angiotensin-converting enzyme 2 (ACE2). To explore whether population variants in ACE2 might influence Spike binding and hence infection, we selected 10 ACE2 variants based on affinity predictions and prevalence in gnomAD and measured their affinities for Spike receptor binding domain through surface plasmon resonance (SPR). We discovered variants that enhance and reduce binding, including two variants with distinct population distributions that enhanced affinity for Spike. ACE2 p.Ser19Pro (ΔΔG = 0.59 ± 0.08 kcal mol-1) is often seen in the gnomAD African cohort (AF = 0.003) whilst p.Lys26Arg (ΔΔG = 0.26 ± 0.09 kcal mol-1) is predominant in the Ashkenazi Jewish (AF = 0.01) and European non-Finnish (AF = 0.006) cohorts. Carriers of these alleles may be more susceptible to infection or severe disease and these variants may influence the global epidemiology of Covid-19. We also identified three rare ACE2 variants that strongly inhibited (p.Glu37Lys, ΔΔG = -1.33 ± 0.15 kcal mol-1 and p.Gly352Val, predicted ΔΔG = -1.17 kcal mol-1) or abolished (p.Asp355Asn) Spike binding. These variants may confer resistance to infection. Finally, we calibrated the mCSM-PPI2 ΔΔG prediction algorithm against our SPR data, give new predictions for all possible ACE2 missense variants at the Spike interface and estimate the overall burden of ACE2 variants on Covid-19 phenotypes.

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Section: Resultsmentioning

confidence: 99%

Missense variants in human ACE2 modify binding to SARS-CoV-2 Spike

MacGowan

Barton

Kutuzov

et al. 2021

Preprint

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“…As the most exposed region, the RBD is targeted by approximately 90% of the nABs in COVID-19 convalescent sera and has been subject to multiple mutations that contribute to human adaption, viral fitness and immune escape [40][41][42][43][44][45][46][47][48]. A key mutation that is shared by the Alpha, Beta, Gamma, Theta, Mu and C.1.2 variants is N501Y, which contributes to a substantial transmission advantage of these variants mediated by increased binding affinity to the ACE2 receptor [18,[49][50][51][52][53][54][55][56][57][58]. However, studies using sera of BNT162b2-immunized patients demonstrated no reduced susceptibility to the neutralization of S proteins with only the N501Y SNP [59,60].…”

Section: Origin and Evolution Of Sars-cov-2 In Humansmentioning

confidence: 99%

“…However, studies using sera of BNT162b2-immunized patients demonstrated no reduced susceptibility to the neutralization of S proteins with only the N501Y SNP [59,60]. Additional mutations in the RBD with high global prevalence are N439K, L452Q, S477N and E484K, which also enhance ACE2 binding and, in case of N439K, increase viral loads [56][57][58]61]. The substitution K417N/T, present in the Beta and Gamma variants, is reported to reduce the receptor interaction by disruption of a salt bridge formed by K417 with D30 in ACE2 [56,57].…”

Section: Origin and Evolution Of Sars-cov-2 In Humansmentioning

confidence: 99%

“…Additional mutations in the RBD with high global prevalence are N439K, L452Q, S477N and E484K, which also enhance ACE2 binding and, in case of N439K, increase viral loads [56][57][58]61]. The substitution K417N/T, present in the Beta and Gamma variants, is reported to reduce the receptor interaction by disruption of a salt bridge formed by K417 with D30 in ACE2 [56,57]. In nature, however, substitutions of K417 mostly occur in combination with N501Y and E484K, which appear to rescue the interaction with ACE2 [62].…”

Section: Origin and Evolution Of Sars-cov-2 In Humansmentioning

confidence: 99%

“…Besides affecting the interaction with ACE2, RBD mutations K417N, N439K and F490S also contribute to immune escape (Figure 1, upper right panel) [44,45,57,[61][62][63][64][65][66][67]. Interestingly, as in case of the K417N mutation, the substitution of Y449 to a histidine, which recently emerged on the RBD surface of C. 1.2 variants has also been reported to reduce ACE2 receptor binding but confers immune escape to certain class 1 and class 3 antibodies [56,64,65,67].…”

Section: Origin and Evolution Of Sars-cov-2 In Humansmentioning

confidence: 99%

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Shooting at a Moving Target—Effectiveness and Emerging Challenges for SARS-CoV-2 Vaccine Development

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Since late 2019 the newly emerged pandemic SARS-CoV-2, the causative agent of COVID‑19, has hit the world with recurring waves of infections necessitating the global implementation of non-pharmaceutical interventions, including strict social distancing rules, the wearing of masks and the isolation of infected individuals in order to restrict virus transmissions and prevent the breakdown of our healthcare systems. These measures are not only challenging on an economic level but also have a strong impact on social lifestyles. Using traditional and novel technologies, highly efficient vaccines against SARS-CoV-2 were developed and underwent rapid clinical evaluation and approval to accelerate the immunization of the world population, aiming to end the pandemic and return to normality. However, the emergence of virus variants with improved transmission, enhanced fitness and partial immune escape from the first generation of vaccines poses new challenges, which are currently being addressed by scientists and pharmaceutical companies all over the world. In this ongoing pandemic, the evaluation of SARS-CoV-2 vaccines underlies diverse unpredictable dynamics, posed by the first broad application of the mRNA vaccine technology and their compliance, the occurrence of unexpected side effects and the rapid emergence of variations in the viral antigen. However, despite these hurdles, we conclude that the available SARS-CoV-2 vaccines are very safe and efficiently protect from severe COVID-19 and are thereby the most powerful tools to prevent further harm to our healthcare systems, economics and individual lives. This review summarizes the unprecedented pathways of vaccine development and approval during the ongoing SARS-CoV-2 pandemic. We focus on the real-world effectiveness and unexpected positive and negative side effects of the available vaccines and summarize the timeline of the applied adaptations to the recommended vaccination strategies in the light of emerging virus variants. Finally, we highlight upcoming strategies to improve the next generations of SARS-CoV-2 vaccines.

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Epitope mapping of neutralising anti‐SARS‐CoV‐2 monoclonal antibodies: Implications for immunotherapy and vaccine design

Ghotloo

Maghsood

Golsaz‐Shirazi

et al. 2022

Reviews in Medical Virology

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Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is the causative agent of the coronavirus disease 2019 (COVID‐19) pandemic. This disease has currently affected more than 346 million people and resulted in more than 5.5 million deaths in many countries. Neutralising monoclonal antibodies (MAbs) against the SARS‐CoV‐2 virus could serve as prophylactic/therapeutic agents in COVID‐19 infection by providing passive protection against the virus in individuals. Until now, no Food and Drug Administration/European Medicines Agency‐approved neutralising MAb against SARS‐CoV‐2 virus exists in the market, though a number of MAbs have been authorised for emergency use. Therefore, there is an urgent need for development of efficient anti‐SARS‐CoV‐2 neutralising MAbs for use in the clinic. Moreover, neutralising anti‐SARS‐CoV‐2 MAbs could be used as beneficial tools for designing epitope‐based vaccines against the virus. Given that the target epitope of a MAb is a crucial feature influencing its neutralising potency, target epitopes of neutralising anti‐SARS‐CoV‐2 MAbs already reported in the literature and reactivity of these MAbs with SARS‐CoV‐2 variants are reviewed herein.

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Effects of common mutations in the SARS-CoV-2 Spike RBD domain and its ligand the human ACE2 receptor on binding affinity and kinetics

Cited by 16 publications

References 51 publications

Missense variants in human ACE2 modify binding to SARS-CoV-2 Spike

Missense variants in human ACE2 modify binding to SARS-CoV-2 Spike

Shooting at a Moving Target—Effectiveness and Emerging Challenges for SARS-CoV-2 Vaccine Development

Epitope mapping of neutralising anti‐SARS‐CoV‐2 monoclonal antibodies: Implications for immunotherapy and vaccine design

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