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Article ; Online: Discovery of VH domains that allosterically inhibit ENPP1.

Solomon, Paige E / Bracken, Colton J / Carozza, Jacqueline A / Wang, Haoqing / Young, Elizabeth P / Wellner, Alon / Liu, Chang C / Sweet-Cordero, E Alejandro / Li, Lingyin / Wells, James A

Nature chemical biology

2023 Volume 20, Issue 1, Page(s) 30–41

Abstract: Ectodomain phosphatase/phosphodiesterase-1 (ENPP1) is overexpressed on cancer cells and functions as an innate immune checkpoint by hydrolyzing extracellular cyclic guanosine monophosphate adenosine monophosphate (cGAMP). Biologic inhibitors have not yet ...

Abstract	Ectodomain phosphatase/phosphodiesterase-1 (ENPP1) is overexpressed on cancer cells and functions as an innate immune checkpoint by hydrolyzing extracellular cyclic guanosine monophosphate adenosine monophosphate (cGAMP). Biologic inhibitors have not yet been reported and could have substantial therapeutic advantages over current small molecules because they can be recombinantly engineered into multifunctional formats and immunotherapies. Here we used phage and yeast display coupled with in cellulo evolution to generate variable heavy (VH) single-domain antibodies against ENPP1 and discovered a VH domain that allosterically inhibited the hydrolysis of cGAMP and adenosine triphosphate (ATP). We solved a 3.2 Å-resolution cryo-electron microscopy structure for the VH inhibitor complexed with ENPP1 that confirmed its new allosteric binding pose. Finally, we engineered the VH domain into multispecific formats and immunotherapies, including a bispecific fusion with an anti-PD-L1 checkpoint inhibitor that showed potent cellular activity.
MeSH term(s)	Phosphoric Diester Hydrolases/metabolism ; Phosphoric Monoester Hydrolases ; Cryoelectron Microscopy ; Single-Domain Antibodies
Chemical Substances	Phosphoric Diester Hydrolases (EC 3.1.4.-) ; Phosphoric Monoester Hydrolases (EC 3.1.3.2) ; Single-Domain Antibodies
Language	English
Publishing date	2023-07-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2202962-X
ISSN	1552-4469 ; 1552-4450
ISSN (online)	1552-4469
ISSN	1552-4450
DOI	10.1038/s41589-023-01368-5
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Article ; Online: Switchable assembly and function of antibody complexes in vivo using a small molecule.

Martinko, Alexander J / Simonds, Erin F / Prasad, Suchitra / Ponce, Alberto / Bracken, Colton J / Wei, Junnian / Wang, Yung-Hua / Chow, Tiffany-Lynn / Huang, Zhong / Evans, Michael J / Wells, James A / Hill, Zachary B

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 9

Abstract: The antigen specificity and long serum half-life of monoclonal antibodies have made them a critical part of modern therapeutics. These properties have been coopted in a number of synthetic formats, such as antibody-drug conjugates, bispecific antibodies, ...

Abstract	The antigen specificity and long serum half-life of monoclonal antibodies have made them a critical part of modern therapeutics. These properties have been coopted in a number of synthetic formats, such as antibody-drug conjugates, bispecific antibodies, or Fc-fusion proteins to generate novel biologic drug modalities. Historically, these new therapies have been generated by covalently linking multiple molecular moieties through chemical or genetic methods. This irreversible fusion of different components means that the function of the molecule is static, as determined by the structure. Here, we report the development of a technology for switchable assembly of functional antibody complexes using chemically induced dimerization domains. This approach enables control of the antibody's intended function in vivo by modulating the dose of a small molecule. We demonstrate this switchable assembly across three therapeutically relevant functionalities in vivo, including localization of a radionuclide-conjugated antibody to an antigen-positive tumor, extension of a cytokine's half-life, and activation of bispecific, T cell-engaging antibodies.
MeSH term(s)	Antibodies/metabolism ; Antibody Specificity ; Humans ; Immunoconjugates/metabolism ; Small Molecule Libraries/metabolism
Chemical Substances	Antibodies ; Immunoconjugates ; Small Molecule Libraries
Language	English
Publishing date	2022-02-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2117402119
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Article ; Online: Targeting Phosphotyrosine in Native Proteins with Conditional, Bispecific Antibody Traps.

Zhou, Xin X / Bracken, Colton J / Zhang, Kaihua / Zhou, Jie / Mou, Yun / Wang, Lei / Cheng, Yifan / Leung, Kevin K / Wells, James A

Journal of the American Chemical Society

2020 Volume 142, Issue 41, Page(s) 17703–17713

Abstract: Engineering sequence-specific antibodies (Abs) against phosphotyrosine (pY) motifs embedded in folded polypeptides remains highly challenging because of the stringent requirement for simultaneous recognition of the pY motif and the surrounding folded ... ...

Abstract	Engineering sequence-specific antibodies (Abs) against phosphotyrosine (pY) motifs embedded in folded polypeptides remains highly challenging because of the stringent requirement for simultaneous recognition of the pY motif and the surrounding folded protein epitope. Here, we present a method named phosphotyrosine Targeting by Recombinant Ab Pair, or pY-TRAP, for
MeSH term(s)	Amino Acid Sequence ; Antibodies/chemistry ; Binding Sites ; Biotinylation ; Models, Molecular ; Peptide Library ; Phosphorylation ; Phosphotyrosine/chemistry ; Protein Binding ; Protein Conformation ; Protein Folding ; Receptors, Thrombin/chemistry ; Recombinant Proteins/chemistry ; Signal Transduction ; Ubiquitin/chemistry
Chemical Substances	Antibodies ; Peptide Library ; Receptors, Thrombin ; Recombinant Proteins ; Ubiquitin ; Phosphotyrosine (21820-51-9)
Language	English
Publishing date	2020-09-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.0c08458
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Article: Targeting Phosphotyrosine in Native Proteins with Conditional, Bispecific Antibody Traps

Zhou, Xin X / Bracken, Colton J / Zhang, Kaihua / Zhou, Jie / Mou, Yun / Wang, Lei / Cheng, Yifan / Leung, Kevin K / Wells, James A

Journal of the American Chemical Society. 2020 Sept. 14, v. 142, no. 41

2020

Abstract	Engineering sequence-specific antibodies (Abs) against phosphotyrosine (pY) motifs embedded in folded polypeptides remains highly challenging because of the stringent requirement for simultaneous recognition of the pY motif and the surrounding folded protein epitope. Here, we present a method named phosphotyrosine Targeting by Recombinant Ab Pair, or pY-TRAP, for in vitro engineering of binders for native pY proteins. Specifically, we create the pY protein by unnatural amino acid misincorporation, mutagenize a universal pY-binding Ab to create a first binder B1 for the pY motif on the pY protein, and then select against the B1–pY protein complex for a second binder B2 that recognizes the composite epitope of B1 and the pY-containing protein complex. We applied pY-TRAP to create highly specific binders to folded Ub-pY59, a rarely studied Ub phosphoform exclusively observed in cancerous tissues, and ZAP70-pY248, a kinase phosphoform regulated in feedback signaling pathways in T cells. The pY-TRAPs do not have detectable binding to wild-type proteins or to other pY peptides or proteins tested. This pY-TRAP approach serves as a generalizable method for engineering sequence-specific Ab binders to native pY proteins.
Keywords	amino acids ; antibodies ; epitopes ; polypeptides
Language	English
Dates of publication	2020-0914
Size	p. 17703-17713.
Publishing place	American Chemical Society
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.0c08458
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Bispecific VH/Fab antibodies targeting neutralizing and non-neutralizing Spike epitopes demonstrate enhanced potency against SARS-CoV-2.

Lim, Shion A / Gramespacher, Josef A / Pance, Katarina / Rettko, Nicholas J / Solomon, Paige / Jin, Jing / Lui, Irene / Elledge, Susanna K / Liu, Jia / Bracken, Colton J / Simmons, Graham / Zhou, Xin X / Leung, Kevin K / Wells, James A

mAbs

2021 Volume 13, Issue 1, Page(s) 1893426

Abstract: Numerous neutralizing antibodies that target SARS-CoV-2 have been reported, and most directly block binding of the viral Spike receptor-binding domain (RBD) to angiotensin-converting enzyme II (ACE2). Here, we deliberately exploit non-neutralizing RBD ... ...

Abstract	Numerous neutralizing antibodies that target SARS-CoV-2 have been reported, and most directly block binding of the viral Spike receptor-binding domain (RBD) to angiotensin-converting enzyme II (ACE2). Here, we deliberately exploit non-neutralizing RBD antibodies, showing they can dramatically assist in neutralization when linked to neutralizing binders. We identified antigen-binding fragments (Fabs) by phage display that bind RBD, but do not block ACE2 or neutralize virus as IgGs. When these non-neutralizing Fabs were assembled into bispecific VH/Fab IgGs with a neutralizing VH domain, we observed a ~ 25-fold potency improvement in neutralizing SARS-CoV-2 compared to the mono-specific bi-valent VH-Fc alone or the cocktail of the VH-Fc and IgG. This effect was epitope-dependent, reflecting the unique geometry of the bispecific antibody toward Spike. Our results show that a bispecific antibody that combines both neutralizing and non-neutralizing epitopes on Spike-RBD is a promising and rapid engineering strategy to improve the potency of SARS-CoV-2 antibodies.
MeSH term(s)	Antibodies, Bispecific/genetics ; Antibodies, Bispecific/immunology ; Antibodies, Bispecific/therapeutic use ; Antibodies, Neutralizing/genetics ; Antibodies, Neutralizing/immunology ; Antibodies, Neutralizing/therapeutic use ; Antibodies, Viral/genetics ; Antibodies, Viral/immunology ; Antibodies, Viral/therapeutic use ; COVID-19/genetics ; COVID-19/immunology ; Epitopes/genetics ; Epitopes/immunology ; HEK293 Cells ; Humans ; Immunoglobulin Fab Fragments/genetics ; Immunoglobulin Fab Fragments/immunology ; Immunoglobulin Fab Fragments/therapeutic use ; SARS-CoV-2/genetics ; SARS-CoV-2/immunology ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/immunology ; COVID-19 Drug Treatment
Chemical Substances	Antibodies, Bispecific ; Antibodies, Neutralizing ; Antibodies, Viral ; Epitopes ; Immunoglobulin Fab Fragments ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2021-03-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2537838-7
ISSN	1942-0870 ; 1942-0870
ISSN (online)	1942-0870
ISSN	1942-0870
DOI	10.1080/19420862.2021.1893426
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Article ; Online: Calibration between trigger and color: Neutralization of a genetically encoded coulombic switch and dynamic arrest precisely tune reflectin assembly.

Levenson, Robert / Bracken, Colton / Sharma, Cristian / Santos, Jerome / Arata, Claire / Malady, Brandon / Morse, Daniel E

The Journal of biological chemistry

2019 Volume 294, Issue 45, Page(s) 16804–16815

Abstract: Reflectin proteins are widely distributed in reflective structures in cephalopods. However, only in loliginid squids are they and the subwavelength photonic structures they control dynamically tunable, driving changes in skin color for camouflage and ... ...

Abstract	Reflectin proteins are widely distributed in reflective structures in cephalopods. However, only in loliginid squids are they and the subwavelength photonic structures they control dynamically tunable, driving changes in skin color for camouflage and communication. The reflectins are block copolymers with repeated canonical domains interspersed with cationic linkers. Neurotransmitter-activated signal transduction culminates in catalytic phosphorylation of the tunable reflectins' cationic linkers; the resulting charge neutralization overcomes coulombic repulsion to progressively allow condensation, folding, and assembly into multimeric spheres of tunable well-defined size and low polydispersity. Here, we used dynamic light scattering, transmission EM, CD, atomic force microscopy, and fluorimetry to analyze the structural transitions of reflectins A1 and A2. We also analyzed the assembly behavior of phosphomimetic, deletion, and other mutants in conjunction with pH titration as an
MeSH term(s)	Amino Acid Sequence ; Animals ; Calibration ; Cephalopoda/genetics ; Cephalopoda/metabolism ; Color ; Computational Biology ; Intrinsically Disordered Proteins/chemistry ; Intrinsically Disordered Proteins/genetics ; Intrinsically Disordered Proteins/metabolism
Chemical Substances	Intrinsically Disordered Proteins
Language	English
Publishing date	2019-09-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA119.010339
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Article ; Online: Cyclable Condensation and Hierarchical Assembly of Metastable Reflectin Proteins, the Drivers of Tunable Biophotonics.

Levenson, Robert / Bracken, Colton / Bush, Nicole / Morse, Daniel E

The Journal of biological chemistry

2015 Volume 291, Issue 8, Page(s) 4058–4068

Abstract: Reversible changes in the phosphorylation of reflectin proteins have been shown to drive the tunability of color and brightness of light reflected from specialized cells in the skin of squids and related cephalopods. We show here, using dynamic light ... ...

Abstract	Reversible changes in the phosphorylation of reflectin proteins have been shown to drive the tunability of color and brightness of light reflected from specialized cells in the skin of squids and related cephalopods. We show here, using dynamic light scattering, electron microscopy, and fluorescence analyses, that reversible titration of the excess positive charges of the reflectins, comparable with that produced by phosphorylation, is sufficient to drive the reversible condensation and hierarchical assembly of these proteins. The results suggest a two-stage process in which charge neutralization first triggers condensation, resulting in the emergence of previously cryptic structures that subsequently mediate reversible, hierarchical assembly. The extent to which cyclability is seen in the in vitro formation and disassembly of complexes estimated to contain several thousand reflectin molecules suggests that intrinsic sequence- and structure-determined specificity governs the reversible condensation and assembly of the reflectins and that these processes are therefore sufficient to produce the reversible changes in refractive index, thickness, and spacing of the reflectin-containing subcellular Bragg lamellae to change the brightness and color of reflected light. This molecular mechanism points to the metastability of reflectins as the centrally important design principle governing biophotonic tunability in this system.
MeSH term(s)	Animals ; Decapodiformes/chemistry ; Light ; Protein Stability ; Protein Structure, Tertiary ; Proteins/chemistry
Chemical Substances	Proteins
Language	English
Publishing date	2015-12-30
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M115.686014
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Article: Bi-paratopic and multivalent human VH domains neutralize SARS-CoV-2 by targeting distinct epitopes within the ACE2 binding interface of Spike.

Bracken, Colton J / Lim, Shion A / Solomon, Paige / Rettko, Nicholas J / Nguyen, Duy P / Zha, Beth Shoshana / Schaefer, Kaitlin / Byrnes, James R / Zhou, Jie / Lui, Irene / Liu, Jia / Pance, Katarina / Zhou, Xin X / Leung, Kevin K / Wells, James A

bioRxiv : the preprint server for biology

2020

Abstract: Neutralizing agents against SARS-CoV-2 are urgently needed for treatment and prophylaxis of COVID-19. Here, we present a strategy to rapidly identify and assemble synthetic human variable heavy (VH) domain binders with high affinity toward neutralizing ... ...

Abstract	Neutralizing agents against SARS-CoV-2 are urgently needed for treatment and prophylaxis of COVID-19. Here, we present a strategy to rapidly identify and assemble synthetic human variable heavy (VH) domain binders with high affinity toward neutralizing epitopes without the need for high-resolution structural information. We constructed a VH-phage library and targeted a known neutralizing site, the angiotensin-converting enzyme 2 (ACE2) binding interface of the trimeric SARS-CoV-2 Spike receptor-binding domain (Spike-RBD). Using a masked selection approach, we identified 85 unique VH binders to two non-overlapping epitopes within the ACE2 binding site on Spike-RBD. This enabled us to systematically link these VH domains into multivalent and bi-paratopic formats. These multivalent and bi-paratopic VH constructs showed a marked increase in affinity to Spike (up to 600-fold) and neutralization potency (up to 1400-fold) on pseudotyped SARS-CoV-2 virus when compared to the standalone VH domains. The most potent binder, a trivalent VH, neutralized authentic SARS-CoV-2 with half-minimal inhibitory concentration (IC
Keywords	covid19
Language	English
Publishing date	2020-08-10
Publishing country	United States
Document type	Preprint
DOI	10.1101/2020.08.08.242511
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Article ; Online: Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2.

Nature chemical biology

2020 Volume 17, Issue 1, Page(s) 113–121

Abstract: Neutralizing agents against SARS-CoV-2 are urgently needed for the treatment and prophylaxis of COVID-19. Here, we present a strategy to rapidly identify and assemble synthetic human variable heavy (VH) domains toward neutralizing epitopes. We ... ...

Abstract	Neutralizing agents against SARS-CoV-2 are urgently needed for the treatment and prophylaxis of COVID-19. Here, we present a strategy to rapidly identify and assemble synthetic human variable heavy (VH) domains toward neutralizing epitopes. We constructed a VH-phage library and targeted the angiotensin-converting enzyme 2 (ACE2) binding interface of the SARS-CoV-2 Spike receptor-binding domain (Spike-RBD). Using a masked selection approach, we identified VH binders to two non-overlapping epitopes and further assembled these into multivalent and bi-paratopic formats. These VH constructs showed increased affinity to Spike (up to 600-fold) and neutralization potency (up to 1,400-fold) on pseudotyped SARS-CoV-2 virus when compared to standalone VH domains. The most potent binder, a trivalent VH, neutralized authentic SARS-CoV-2 with a half-maximal inhibitory concentration (IC
MeSH term(s)	Angiotensin-Converting Enzyme 2/antagonists & inhibitors ; Angiotensin-Converting Enzyme 2/chemistry ; Angiotensin-Converting Enzyme 2/genetics ; Angiotensin-Converting Enzyme 2/immunology ; Animals ; Antibodies, Neutralizing/chemistry ; Antibodies, Neutralizing/genetics ; Antibodies, Neutralizing/immunology ; Antibodies, Viral/chemistry ; Antibodies, Viral/genetics ; Antibodies, Viral/immunology ; Binding Sites, Antibody/genetics ; Binding Sites, Antibody/immunology ; Chlorocebus aethiops ; Cryoelectron Microscopy ; HEK293 Cells ; Humans ; Models, Molecular ; Peptide Library ; Protein Binding ; Protein Conformation, alpha-Helical ; Protein Conformation, beta-Strand ; Protein Interaction Domains and Motifs ; SARS-CoV-2 ; Single-Chain Antibodies/chemistry ; Single-Chain Antibodies/genetics ; Single-Chain Antibodies/immunology ; Spike Glycoprotein, Coronavirus/antagonists & inhibitors ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/immunology ; Vero Cells
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Peptide Library ; Single-Chain Antibodies ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Keywords	covid19
Language	English
Publishing date	2020-10-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2202962-X
ISSN	1552-4469 ; 1552-4450
ISSN (online)	1552-4469
ISSN	1552-4450
DOI	10.1038/s41589-020-00679-1
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Article: Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2

Nat. chem. biol

Abstract	Neutralizing agents against SARS-CoV-2 are urgently needed for the treatment and prophylaxis of COVID-19. Here, we present a strategy to rapidly identify and assemble synthetic human variable heavy (VH) domains toward neutralizing epitopes. We constructed a VH-phage library and targeted the angiotensin-converting enzyme 2 (ACE2) binding interface of the SARS-CoV-2 Spike receptor-binding domain (Spike-RBD). Using a masked selection approach, we identified VH binders to two non-overlapping epitopes and further assembled these into multivalent and bi-paratopic formats. These VH constructs showed increased affinity to Spike (up to 600-fold) and neutralization potency (up to 1,400-fold) on pseudotyped SARS-CoV-2 virus when compared to standalone VH domains. The most potent binder, a trivalent VH, neutralized authentic SARS-CoV-2 with a half-maximal inhibitory concentration (IC50) of 4.0 nM (180 ng ml-1). A cryo-EM structure of the trivalent VH bound to Spike shows each VH domain engaging an RBD at the ACE2 binding site, confirming our original design strategy.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #882912
Database	COVID19

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