Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants

Weisblum, Yiska; Schmidt, Fabian; Zhang, Fengwen; DaSilva, Justin; Poston, Daniel; Lorenzi, Julio C. C.; Muecksch, Frauke; Rutkowska, Magdalena; Hoffmann, Hans-Heinrich; Michailidis, Eleftherios; Gaebler, Christian; Agudelo, Marianna; Cho, Alice; Wang, Zijun; Gazumyan, Anna; Cipolla, Melissa; Luchsinger, Larry L.; Hillyer, Christopher D.; Caskey, Marina; Robbiani, Davide F.; Rice, Charles M.; Nussenzweig, Michel C.; Hatziioannou, Théodora; Bieniasz, Paul D.

doi:10.1101/2020.07.21.214759

Cited by 71 publications

(82 citation statements)

References 35 publications

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“…2b), likely explaining observed escape at residue L455 RBD ( Fig. 1f) in C144 selection experiments 40 . Despite adjacent hydrophobic residues (F100 D and W100 E ) likely to be solventexposed before antigen binding, C144 IgG showed no evidence of non-specific binding in a polyreactivity assay (Extended Data Fig.…”

Section: Class 1: Vh3-53/short Cdrh3 Hnabs That Block Ace2 Binding Anmentioning

confidence: 87%

“…1b). 40 An interesting feature of C144 binding is that its long CDRH3 bridges between adjacent "down"…”

Section: Class 1: Vh3-53/short Cdrh3 Hnabs That Block Ace2 Binding Anmentioning

confidence: 99%

“…VSV reporter viruses pseudotyped with SARS-CoV-2 S can escape by mutation from hNAbs C121, C135, or C144 40 , three of the antibodies used for the structural studies reported here.…”

Section: Rbd Substitutions Affect Hnab Binding To Varying Extentsmentioning

confidence: 99%

“…or SARS-CoV natural infections, respectively, and bind outside of the ACE2 binding site, provides the potential for additive neutralization effects when combined with hNAbs that block ACE2, while also limiting viral escape 1,40 . A pair of antibodies in human clinical trials that includes REGN10987 8 , a hNAb that binds distal to the ACE2 binding site, prevented SARS-CoV-2 viral escape in vitro, but did not show synergistic neutralization 6 .…”

mentioning

confidence: 99%

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Structural classification of neutralizing antibodies against the SARS-CoV-2 spike receptor-binding domain suggests vaccine and therapeutic strategies

Barnes

Jette

Abernathy

et al. 2020

Preprint

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The COVID-19 pandemic presents an urgent health crisis. Human neutralizing antibodies (hNAbs) that target the host ACE2 receptor-binding domain (RBD) of the SARS-CoV-2 spike1–5 show therapeutic promise and are being evaluated clincally6–8. To determine structural correlates of SARS-CoV-2 neutralization, we solved 8 new structures of distinct COVID-19 hNAbs5 in complex with SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed classification into categories: (1) VH3-53 hNAbs with short CDRH3s that block ACE2 and bind only to “up” RBDs, (2) ACE2-blocking hNAbs that bind both “up” and “down” RBDs and can contact adjacent RBDs, (3) hNAbs that bind outside the ACE2 site and recognize “up” and “down” RBDs, and (4) Previously-described antibodies that do not block ACE2 and bind only “up” RBDs9. Class 2 comprised four hNAbs whose epitopes bridged RBDs, including a VH3-53 hNAb that used a long CDRH3 with a hydrophobic tip to bridge between adjacent “down” RBDs, thereby locking spike into a closed conformation. Epitope/paratope mapping revealed few interactions with host-derived N-glycans and minor contributions of antibody somatic hypermutations to epitope contacts. Affinity measurements and mapping of naturally-occurring and in vitro-selected spike mutants in 3D provided insight into the potential for SARS-CoV-2 escape from antibodies elicited during infection or delivered therapeutically. These classifications and structural analyses provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects, suggesting combinations for clinical use, and providing insight into immune responses against SARS-CoV-2.

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Section: Class 1: Vh3-53/short Cdrh3 Hnabs That Block Ace2 Binding Anmentioning

confidence: 87%

“…1b). 40 An interesting feature of C144 binding is that its long CDRH3 bridges between adjacent "down"…”

Section: Class 1: Vh3-53/short Cdrh3 Hnabs That Block Ace2 Binding Anmentioning

confidence: 99%

“…VSV reporter viruses pseudotyped with SARS-CoV-2 S can escape by mutation from hNAbs C121, C135, or C144 40 , three of the antibodies used for the structural studies reported here.…”

Section: Rbd Substitutions Affect Hnab Binding To Varying Extentsmentioning

confidence: 99%

mentioning

confidence: 99%

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Structural classification of neutralizing antibodies against the SARS-CoV-2 spike receptor-binding domain suggests vaccine and therapeutic strategies

Barnes

Jette

Abernathy

et al. 2020

Preprint

Self Cite

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“…However, RNA viruses are known to have higher mutation rates 11,12 . Many SARS-CoV-2 mutations have already been identified such as D614G [13][14][15][16] . This means that resultant mutation strains could make current SARS-CoV-2 neutralizing antibodies ineffective in the future.…”

mentioning

confidence: 99%

Engineered Trimeric ACE2 Binds and Locks “Three-up” Spike Protein to Potently Inhibit SARS-CoVs and Mutants

Guo

Wang

et al. 2020

Preprint

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SARS-CoV-2 enters cells via ACE-2, which binds the spike protein with moderate affinity. Despite a constant background mutational rate, the virus must retain binding with ACE2 for infectivity, providing a conserved constraint for SARS-CoV-2 inhibitors. To prevent mutational escape of SARS-CoV-2 and to prepare for future related coronavirus outbreaks, we engineered a de novo trimeric ACE2 (T-ACE2) protein scaffold that binds the trimeric spike protein with extremely high affinity (KD < 1 pM), while retaining ACE2 native sequence. T-ACE2 potently inhibits all tested pseudotyped viruses including SARS-CoV-2, SARS-CoV, eight naturally occurring SARS-CoV-2 mutants, two SARSr-CoVs as well as authentic SARS-CoV-2. The cryo-EM structure reveals that T-ACE2 can induce the transit of spike protein to “three-up” RBD conformation upon binding. T-ACE2 thus represents a promising class of broadly neutralizing proteins against SARS-CoVs and mutants.

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Synthesis, crystal structure elucidation, DFT analysis, drug‐likeness and ADMET evaluation and molecular docking studies of triazole derivatives: Binary inhibition of spike protein and ACE2 receptor protein of COVID‐19

Murugavel¹,

Vasudevan²,

Chandrasekaran³

et al. 2022

J Chinese Chemical Soc

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The recent incidence of terrible acute respiratory syndrome coronavirus 2 (SARS CoV‐2) has presently experienced some noteworthy mutations since its discovery in 2019 in Wuhan, China. The present research work focuses on the synthesis of three triazole derivatives (BMTPP, BMTTP, and BMTIP) and their inhibition activities against SARS‐Cov‐2 spike and ACE2 receptor proteins. The crystal structure for BMTTP was determined by the SCXRD method and optimized geometrical parameters for the three triazole derivatives were obtained by DFT calculations. HOMO‐LUMO, Global reactive descriptors [GRD], and Molecular electrostatic potential (MEP) investigations exposed that all three compounds have biological properties. The drug‐likeness ability of the synthesized compounds was examined using Molinspiration and a pre‐ADMET online Server. Further, to explore the binding nature of three synthesized compounds with SARS‐Cov‐2 spike proteins/ACE2 receptor molecular docking studies were executed. The outcomes we obtained from molecular docking simulation studies suggest that the synthesized triazole derivatives may be well utilized as curing medicines against COVID‐19. Ultimately, animal tests and precise clinical tests are required to prove the potent nature of these compounds against COVID‐19. Finally, the present outcomes must be proved to utilize in‐vitro and in‐vivo antiviral methods.

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Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants

Cited by 71 publications

References 35 publications

Structural classification of neutralizing antibodies against the SARS-CoV-2 spike receptor-binding domain suggests vaccine and therapeutic strategies

Structural classification of neutralizing antibodies against the SARS-CoV-2 spike receptor-binding domain suggests vaccine and therapeutic strategies

Engineered Trimeric ACE2 Binds and Locks “Three-up” Spike Protein to Potently Inhibit SARS-CoVs and Mutants

Synthesis, crystal structure elucidation, DFT analysis, drug‐likeness and ADMET evaluation and molecular docking studies of triazole derivatives: Binary inhibition of spike protein and ACE2 receptor protein of COVID‐19

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