A mating mechanism to generate diversity for the Darwinian selection of DNA-encoded synthetic molecules.
Journal
Nature chemistry
ISSN: 1755-4349
Titre abrégé: Nat Chem
Pays: England
ID NLM: 101499734
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
09
09
2020
accepted:
30
09
2021
pubmed:
8
12
2021
medline:
23
2
2022
entrez:
7
12
2021
Statut:
ppublish
Résumé
DNA-encoded library technologies enable the screening of synthetic molecules but have thus far not tapped into the power of Darwinian selection with iterative cycles of selection, amplification and diversification. Here we report a simple strategy to rapidly assemble libraries of conformationally constrained peptides that are paired in a combinatorial fashion (suprabodies). We demonstrate that the pairing can be shuffled after each amplification cycle in a process similar to DNA shuffling or mating to regenerate diversity. Using simulations, we show the benefits of this recombination in yielding a more accurate correlation of selection fitness with affinity after multiple rounds of selection, particularly if the starting library is heterogeneous in the concentration of its members. The method was validated with selections against streptavidin and applied to the discovery of PD-L1 binders. We further demonstrate that the binding of self-assembled suprabodies can be recapitulated by smaller (∼7 kDa) synthetic products that maintain the conformational constraint of the peptides.
Identifiants
pubmed: 34873299
doi: 10.1038/s41557-021-00829-5
pii: 10.1038/s41557-021-00829-5
doi:
Substances chimiques
B7-H1 Antigen
0
Ligands
0
Peptide Nucleic Acids
0
Small Molecule Libraries
0
DNA
9007-49-2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
141-152Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
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