Computational maturation of a single-domain antibody against Aβ42 aggregation.
| Autor: | Lin J; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge Cambridge CB2 1EW UK ps589@cam.ac.uk mv245@cam.ac.uk., Figazzolo C; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge Cambridge CB2 1EW UK ps589@cam.ac.uk mv245@cam.ac.uk., Metrick MA 2nd; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge Cambridge CB2 1EW UK ps589@cam.ac.uk mv245@cam.ac.uk., Sormanni P; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge Cambridge CB2 1EW UK ps589@cam.ac.uk mv245@cam.ac.uk., Vendruscolo M; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge Cambridge CB2 1EW UK ps589@cam.ac.uk mv245@cam.ac.uk. |
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| Jazyk: | angličtina |
| Zdroj: | Chemical science [Chem Sci] 2021 Oct 07; Vol. 12 (41), pp. 13940-13948. Date of Electronic Publication: 2021 Oct 07 (Print Publication: 2021). |
| DOI: | 10.1039/d1sc03898b |
| Abstrakt: | The expansion of structural databases and the increase in computing power are enabling approaches for antibody discovery based on computational design. It has already been shown that it is possible to use this approach to generate antibodies for specific epitopes on challenging targets. Here we describe an application of this procedure for antibody maturation through the computational design of mutational variants of increased potency. We illustrate this procedure in the case of a single-domain antibody targeting an epitope in the N-terminal region of Aβ42, a peptide whose aggregation is closely associated with Alzheimer's disease. We show that this approach enables the generation of an antibody variant with over 200-fold increased potency against the primary nucleation process in Aβ42 aggregation. Our results thus demonstrate that potentiated antibody variants can be obtained by computational maturation. Competing Interests: There are no conflicts to declare. (This journal is © The Royal Society of Chemistry.) |
| Databáze: | MEDLINE |
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