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

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TitleDe novo protein design enables the precise induction of RSV-neutralizing antibodies.
Publication TypeJournal Article
Year of Publication2020
AuthorsSesterhenn, F, Yang, C, Bonet, J, Cramer, JT, Wen, X, Wang, Y, Chiang, C-I, Abriata, LA, Kucharska, I, Castoro, G, Vollers, SS, Galloux, M, Dheilly, E, Rosset, S, Corthésy, P, Georgeon, S, Villard, M, Richard, C-A, Descamps, D, Delgado, T, Oricchio, E, Rameix-Welti, M-A, Más, V, Ervin, S, Eléouët, J-F, Riffault, S, Bates, JT, Julien, J-P, Li, Y, Jardetzky, T, Krey, T, Correia, BE
JournalScience
Volume368
Issue6492
Date Published2020 05 15
ISSN1095-9203
KeywordsAmino Acid Motifs, Antibodies, Neutralizing, Computational Biology, Humans, Immunodominant Epitopes, Protein Conformation, Protein Engineering, Recombinant Fusion Proteins, Respiratory Syncytial Virus Vaccines, Respiratory Syncytial Virus, Human, Single-Domain Antibodies
Abstract

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.

DOI10.1126/science.aay5051
Alternate JournalScience
PubMed ID32409444
Grant ListR01 AI137523 / AI / NIAID NIH HHS / United States