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J Comput Chem. 2013 Apr 5;34(10):879-91. doi: 10.1002/jcc.23213. Epub 2013 Jan 8.

Structure-based redesign of proteins for minimal T-cell epitope content.

Author information

1
Department of Computer Science, Dartmouth College, New Hampshire 03755, USA.

Abstract

The protein universe displays a wealth of therapeutically relevant activities, but T-cell driven immune responses to non-"self" biological agents present a major impediment to harnessing the full diversity of these molecular functions. Mutagenic T-cell epitope deletion seeks to mitigate the immune response, but can typically address only a small number of epitopes. Here, we pursue a "bottom-up" approach that redesigns an entire protein to remain native-like but contain few if any immunogenic epitopes. We do so by extending the Rosetta flexible-backbone protein design software with an epitope scoring mechanism and appropriate constraints. The method is benchmarked with a diverse panel of proteins and applied to three targets of therapeutic interest. We show that the deimmunized designs indeed have minimal predicted epitope content and are native-like in terms of various quality measures, and moreover that they display levels of native sequence recovery comparable to those of non-deimmunized designs.

PMID:
23299435
PMCID:
PMC3763725
DOI:
10.1002/jcc.23213
[Indexed for MEDLINE]
Free PMC Article

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