De novo protein design enables the precise induction of RSV-neutralizing antibodies

De novo protein design has been successful in expanding the natural protein repertoire. However, most de novo proteins lack biological function, presenting a major methodological challenge. In vaccinology, the induction of precise antibody responses remains a cornerstone for next-generation vaccines...

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Bibliographic Details
Published in:	IDEAS Working Paper Series from RePEc Vol. 368; no. 6492
Main Authors:	Sesterhenn, Fabian, Yang, Che, Bonet, Jaume, Cramer, Johannes T, Wen, Xiaolin, Wang, Yimeng, Chiang, Chi-I, Abriata, Luciano A, Kucharska, Iga, Castoro, Giacomo, Vollers, Sabrina S, Galloux, Marie, Dheilly, Elie, Rosset, Stéphane, Corthésy, Patricia, Georgeon, Sandrine, Villard, Mélanie, Richard, Charles-Adrien, Descamps, Delphyne, Delgado, Teresa, Oricchio, Elisa, Rameix-Welti, Marie-Anne, Más, Vicente, Ervin, Sean, Eléouët, Jean-François, Riffault, Sabine, Bates, John T, Julien, Jean-Philippe, Li, Yuxing, Jardetzky, Theodore, Krey, Thomas, Correia, Bruno E
Format:	Journal Article Paper
Language:	English
Published:	United States Federal Reserve Bank of St. Louis 15.05.2020
Subjects:	Amino Acid Motifs Antibodies, Neutralizing - biosynthesis Computational Biology - methods Humans Immunodominant Epitopes - chemistry Immunodominant Epitopes - immunology Protein Conformation Protein Engineering - methods Proteins Recombinant Fusion Proteins - chemistry Recombinant Fusion Proteins - immunology Respiratory Syncytial Virus Vaccines - chemistry Respiratory Syncytial Virus Vaccines - immunology Respiratory Syncytial Virus, Human - immunology Single-Domain Antibodies - chemistry Single-Domain Antibodies - immunology Vaccines
ISSN:	1095-9203, 1095-9203
Online Access:	Get full text
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Summary:	De novo protein design has been successful in expanding the natural protein repertoire. However, most de novo proteins lack biological function, presenting a major methodological challenge. In vaccinology, the induction of precise antibody responses remains a cornerstone for next-generation vaccines. Here, we present a protein design algorithm called TopoBuilder, with which we engineered epitope-focused immunogens displaying complex structural motifs. In both mice and nonhuman primates, cocktails of three de novo-designed immunogens induced robust neutralizing responses against the respiratory syncytial virus. Furthermore, the immunogens refocused preexisting antibody responses toward defined neutralization epitopes. Overall, our design approach opens the possibility of targeting specific epitopes for the development of vaccines and therapeutic antibodies and, more generally, will be applicable to the design of de novo proteins displaying complex functional motifs.
Bibliography:	SourceType-Working Papers-1 ObjectType-Working Paper/Pre-Print-1 content type line 50 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1095-9203 1095-9203
DOI:	10.1126/science.aay5051