Affinity-Selected Bicyclic Peptide G-Quadruplex Ligands Mimic a Protein-like Binding Mechanism.
J Am Chem Soc
; 142(18): 8367-8373, 2020 05 06.
Article
en En
| MEDLINE
| ID: mdl-32267689
ABSTRACT
The study of G-quadruplexes (G4s) in a cellular context has demonstrated links between these nucleic acid secondary structures, gene expression, and DNA replication. Ligands that bind to the G4 structure therefore present an excellent opportunity for influencing gene expression through the targeting of a nucleic acid structure rather than sequence. Here, we explore cyclic peptides as an alternative class of G4 ligands. Specifically, we describe the development of de novo G4-binding bicyclic peptides selected by phage display. Selected bicyclic peptides display submicromolar affinity to G4 structures and high selectivity over double helix DNA. Molecular simulations of the bicyclic peptide-G4 complexes corroborate the experimental binding strengths and reveal molecular insights into G4 recognition by bicyclic peptides via the precise positioning of amino acid side chains, a binding mechanism reminiscent of endogenous G4-binding proteins. Overall, our results demonstrate that selection of (bi)cyclic peptides unlocks a valuable chemical space for targeting nucleic acid structures.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Péptidos Cíclicos
/
Simulación de Dinámica Molecular
Idioma:
En
Revista:
J Am Chem Soc
Año:
2020
Tipo del documento:
Article
País de afiliación:
Reino Unido