scholarly journals Antibody binding and ACE2 binding inhibition is significantly reduced for the Omicron variant compared to all other variants of concern

2022 ◽  
Author(s):  
Daniel Junker ◽  
Matthias Becker ◽  
Teresa Wagner ◽  
Philipp D Kaiser ◽  
Sandra Maier ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Antibody Binding ◽  
Large Cohort ◽  
Converting Enzyme ◽  
Wild Type ◽  
Immune Control ◽  
Angiotensin Converting Enzyme 2 ◽  
Igg Binding ◽  
Binding Inhibition ◽  
Rapid Emergence

The rapid emergence of the Omicron variant and its large number of mutations has led to its classification as a variant of concern (VOC) by the WHO. Initial studies on the neutralizing response towards this variant within convalescent and vaccinated individuals have identified substantial reductions. However many of these sample sets used in these studies were either small, uniform in nature, or were compared only to wild-type (WT) or, at most, a few other VOC. Here, we assessed IgG binding, (Angiotensin-Converting Enzyme 2) ACE2 binding inhibition, and antibody binding dynamics for the omicron variant compared to all other VOC and variants of interest (VOI), in a large cohort of infected, vaccinated, and infected and then vaccinated individuals. While omicron was capable of binding to ACE2 efficiently, antibodies elicited by infection or immunization showed reduced IgG binding and ACE2 binding inhibition compared to WT and all VOC. Among vaccinated samples, antibody binding responses towards omicron were only improved following administration of a third dose. Overall, our results identify that omicron can still bind ACE2 while pre-existing antibodies can bind omicron. The extent of the mutations appear to inhibit the development of a neutralizing response, and as a result, omicron remains capable of evading immune control.

scholarly journals Mutations in two SARS-CoV-2 variants of concern reflect two distinct strategies of antibody escape

2021 ◽  
Author(s):  
Sebastian Fiedler ◽  
Viola Denninger ◽  
Alexey S. Morgunov ◽  
Alison Ilsley ◽  
Roland Worth ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Cell Receptor ◽  
Converting Enzyme ◽  
Wild Type ◽  
Angiotensin Converting Enzyme 2 ◽  
Binding Domains ◽  
Host Cell Receptor

Understanding the factors that contribute to antibody escape of SARS-CoV-2 and its variants is key for the development of drugs and vaccines that provide broad protection against a variety of virus variants. Using microfluidic diffusional sizing, we determined the dissociation constant ((KD)) for the interaction between receptor binding domains (RBDs) of SARS-CoV-2 in its original version (WT) as well as alpha and beta variants with the host-cell receptor angiotensin converting enzyme 2 (ACE2). For RBD-alpha, the ACE2-binding affinity was increased by a factor of ten when compared with RBD-WT, while ACE2-binding of RBD-beta was largely unaffected. However, when challenged with a neutralizing antibody that binds to both RBD-WT and RBD-alpha with low nanomolar (KD) values, RBD-beta displayed no binding, suggesting a substantial epitope change. In SARS-CoV-2 convalescent sera, RBD-binding antibodies showed low nanomolar affinities to both wild-type and variant RBD proteins—strikingly, the concentration of antibodies binding to RBD-beta was half that of RBD-WT and RBD-alpha, again indicating considerable epitope changes in the beta variant. Our data therefore suggests that one factor contributing to the higher transmissibility and antibody evasion of SARS-CoV-2 alpha and beta is a larger fraction of viruses that can form a complex with ACE2. However, the two variants employ different mechanisms to achieve this goal. While SARS-CoV-2 alpha RBD binds with greater affinity to ACE2 and is thus more difficult to displace from the receptor by neutralizing antibodies, RBD-beta is less accessible to antibodies due to epitope changes which increases the chances of ACE2-binding and infection.

scholarly journals Broad and Differential Animal Angiotensin-Converting Enzyme 2 Receptor Usage by SARS-CoV-2

2020 ◽  
Vol 94 (18) ◽  
Author(s):  
Xuesen Zhao ◽  
Danying Chen ◽  
Robert Szabla ◽  
Mei Zheng ◽  
Guoli Li ◽  
...  
Keyword(s):  
Animal Models ◽  
Angiotensin Converting Enzyme ◽  
Cleavage Site ◽  
Interspecies Transmission ◽  
Converting Enzyme ◽  
Wild Type ◽  
Furin Cleavage ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Furin Cleavage Site

ABSTRACT The COVID-19 pandemic has caused an unprecedented global public health and economic crisis. The origin and emergence of its causal agent, SARS-CoV-2, in the human population remains mysterious, although bat and pangolin were proposed to be the natural reservoirs. Strikingly, unlike the SARS-CoV-2-like coronaviruses (CoVs) identified in bats and pangolins, SARS-CoV-2 harbors a polybasic furin cleavage site in its spike (S) glycoprotein. SARS-CoV-2 uses human angiotensin-converting enzyme 2 (ACE2) as its receptor to infect cells. Receptor recognition by the S protein is the major determinant of host range, tissue tropism, and pathogenesis of coronaviruses. In an effort to search for the potential intermediate or amplifying animal hosts of SARS-CoV-2, we examined receptor activity of ACE2 from 14 mammal species and found that ACE2s from multiple species can support the infectious entry of lentiviral particles pseudotyped with the wild-type or furin cleavage site-deficient S protein of SARS-CoV-2. ACE2 of human/rhesus monkey and rat/mouse exhibited the highest and lowest receptor activities, respectively. Among the remaining species, ACE2s from rabbit and pangolin strongly bound to the S1 subunit of SARS-CoV-2 S protein and efficiently supported the pseudotyped virus infection. These findings have important implications for understanding potential natural reservoirs, zoonotic transmission, human-to-animal transmission, and use of animal models. IMPORTANCE SARS-CoV-2 uses human ACE2 as a primary receptor for host cell entry. Viral entry mediated by the interaction of ACE2 with spike protein largely determines host range and is the major constraint to interspecies transmission. We examined the receptor activity of 14 ACE2 orthologs and found that wild-type and mutant SARS-CoV-2 lacking the furin cleavage site in S protein could utilize ACE2 from a broad range of animal species to enter host cells. These results have important implications in the natural hosts, interspecies transmission, animal models, and molecular basis of receptor binding for SARS-CoV-2.

scholarly journals Directed evolution of angiotensin-converting enzyme 2 (ACE2) variants with enhanced peptidase activity profiles for novel therapeutic applications

2022 ◽  
Author(s):  
Pete Heinzelman ◽  
Philip A Romero
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Directed Evolution ◽  
Peptidase Activity ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Wild Type ◽  
Peptide Substrate ◽  
Angiotensin Converting Enzyme 2 ◽  
Therapeutic Applications ◽  
Target Peptide

Mutants of the Angiotensin Converting-Enzyme 2 (ACE2) carboxypeptidase possessing enhanced hydrolytic activity and specificity hold potential to beneficially modulate the Angiotensin receptor (ATR) therapeutic axis with increased efficacy and reduced potential side effects relative to wild type ACE2. In pursuing this goal, we established a yeast display-based liquid chromatography screen that enabled use of directed evolution to identify ACE2 mutants with improved target peptide substrate, Angiotensin-II (Ang-II), activity and specificity relative to Apelin-13, an off-target peptide substrate. Screening yeast-displayed ACE2 active site residue saturation mutant libraries revealed three substitution-tolerant positions that can be mutated to enhance ACE2's activity profile. Double mutant libraries combining substitutions at these positions, M360, T371 and Y510, yielded candidate improved ACE2 mutants that were recombinantly expressed and purified at 1 mg/L yield and > 90% homogeneity. Relative to wild type, the leading mutant, T371L/Y510Ile, has seven-fold increased kcat toward Ang-II and six-fold decreased kcat/Km for Apelin-13 hydrolysis. In single substrate hydrolysis assays featuring physiologically relevant substrate concentrations T371L/Y510Ile hydrolyzes more Ang-II than wild type with concomitant Ang-II:Apelin-13 specificity improvements reaching 30-fold. Additionally, T371L/Y510Ile hydrolyzed Ang-II at rates greater than wild type, with Apelin-13 hydrolysis reductions of up to 80 percent, in multiplex assays containing a mixture of peptides relevant to the ATR therapeutic axis. Our efforts have delivered ATR axis-acting therapeutic candidates with relevance to established and unexplored ACE2 therapeutic applications and demonstrate the feasibility of developing ACE2 variants for use in biomedical contexts unrelated to the ATR axis such as localized activation of peptide-based prodrugs.

Thermodynamics of the interaction between the spike protein of severe acute respiratory syndrome- coronavirus-2 and the receptor of human angiotensin converting enzyme 2. Effects of possible ligands

2020 ◽  
Author(s):  
Cristina Garcia-Iriepa ◽  
Cecilia Hognon ◽  
Antonio Francés-Monerris ◽  
Isabel Iriepa ◽  
Tom Miclot ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Molecular Mechanisms ◽  
Molecular Design ◽  
Binding Free Energy ◽  
Transmembrane Protein ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Rational Molecular Design ◽  
Rational Evaluation

<div><p>Since the end of 2019, the coronavirus SARS-CoV-2 has caused more than 180,000 deaths all over the world, still lacking a medical treatment despite the concerns of the whole scientific community. Human Angiotensin-Converting Enzyme 2 (ACE2) was recently recognized as the transmembrane protein serving as SARS-CoV-2 entry point into cells, thus constituting the first biomolecular event leading to COVID-19 disease. Here, by means of a state-of-the-art computational approach, we propose a rational evaluation of the molecular mechanisms behind the formation of the complex and of the effects of possible ligands. Moreover, binding free energy between ACE2 and the active Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein is evaluated quantitatively, assessing the molecular mechanisms at the basis of the recognition and the ligand-induced decreased affinity. These results boost the knowledge on the molecular grounds of the SARS-CoV-2 infection and allow to suggest rationales useful for the subsequent rational molecular design to treat severe COVID-19 cases.</p></div>

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