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

SUBMITTER: Sesterhenn F

PROVIDER: S-EPMC7391827 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Sesterhenn Fabian F Yang Che C Bonet Jaume J Cramer Johannes T JT Wen Xiaolin X Wang Yimeng Y Chiang Chi-I CI Abriata Luciano A LA Kucharska Iga I Castoro Giacomo G Vollers Sabrina S SS Galloux Marie M Dheilly Elie E Rosset Stéphane S Corthésy Patricia P Georgeon Sandrine S Villard Mélanie M Richard Charles-Adrien CA Descamps Delphyne D Delgado Teresa T Oricchio Elisa E Rameix-Welti Marie-Anne MA Más Vicente V Ervin Sean S Eléouët Jean-François JF Riffault Sabine S Bates John T JT Julien Jean-Philippe JP Li Yuxing Y Jardetzky Theodore T Krey Thomas T Correia Bruno E BE

Science (New York, N.Y.) 20200501 6492

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, cocktail ...[more]

PMID: 32409444

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Project description:Proteins are molecular machines whose function depends on their ability to achieve complex folds with precisely defined structural and dynamic properties. The rational design of proteins from first-principles, or de novo, was once considered to be impossible, but today proteins with a variety of folds and functions have been realized. We review the evolution of the field from its earliest days, placing particular emphasis on how this endeavor has illuminated our understanding of the principles underlying the folding and function of natural proteins, and is informing the design of macromolecules with unprecedented structures and properties. An initial set of milestones in de novo protein design focused on the construction of sequences that folded in water and membranes to adopt folded conformations. The first proteins were designed from first-principles using very simple physical models. As computers became more powerful, the use of the rotamer approximation allowed one to discover amino acid sequences that stabilize the desired fold. As the crystallographic database of protein structures expanded in subsequent years, it became possible to construct proteins by assembling short backbone fragments that frequently recur in Nature. The second set of milestones in de novo design involves the discovery of complex functions. Proteins have been designed to bind a variety of metals, porphyrins, and other cofactors. The design of proteins that catalyze hydrolysis and oxygen-dependent reactions has progressed significantly. However, de novo design of catalysts for energetically demanding reactions, or even proteins that bind with high affinity and specificity to highly functionalized complex polar molecules remains an importnant challenge that is now being achieved. Finally, the protein design contributed significantly to our understanding of membrane protein folding and transport of ions across membranes. The area of membrane protein design, or more generally of biomimetic polymers that function in mixed or non-aqueous environments, is now becoming increasingly possible.

Dataset Information

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

Publications

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

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