MHCEpitopeEnergy, a Flexible Rosetta-Based Biotherapeutic Deimmunization Platform
| Autor: | Sagar D. Khare, Chris Bailey-Kellogg, Vikram Khipple Mulligan, Brahm J. Yachnin |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Computer science
General Chemical Engineering Protein design Epitopes T-Lymphocyte Computational biology Library and Information Sciences Protein Engineering 01 natural sciences Article Epitope 0103 physical sciences Humans Deimmunization 010304 chemical physics Sequence design Computational Biology Proteins food and beverages General Chemistry Protein engineering 0104 chemical sciences Computer Science Applications Term (time) 010404 medicinal & biomolecular chemistry Benchmark (computing) Sequence space (evolution) |
| Zdroj: | J Chem Inf Model |
| ISSN: | 1549-960X 1549-9596 |
| DOI: | 10.1021/acs.jcim.1c00056 |
| Popis: | As non-"self" macromolecules, biotherapeutics can trigger an immune response that can reduce drug efficacy, require patients to be taken off therapy, or even cause life-threatening reactions. To enable the flexible and facile design of protein biotherapeutics while reducing the prevalence of T-cell epitopes that drive immune recognition, we have integrated into the Rosetta protein design suite a new scoring term that allows design protocols to account for predicted or experimentally identified epitopes in the optimized objective function. This flexible scoring term can be used in any Rosetta design trajectory, can be targeted to specific regions of a protein, and can be readily extended to work with a variety of epitope predictors. By performing extensive design runs with varied design parameter choices for three case study proteins as well as a larger diverse benchmark, we show that the incorporation of this scoring term enables the effective exploration of an alternative, deimmunized sequence space to discover diverse proteins that are potentially highly deimmunized while retaining physical and chemical qualities similar to those yielded by equivalent nondeimmunizing sequence design protocols. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|