Peptide structure stabilization by membrane anchoring and its general applicability to the development of potent cell-permeable inhibitors.
Chembiochem
; 12(6): 914-21, 2011 Apr 11.
Article
en En
| MEDLINE
| ID: mdl-21365731
ABSTRACT
Isolated protein motifs that are involved in interactions with their binding partners can be used to inhibit these interactions. However, peptides corresponding to protein fragments tend to have no defined secondary or tertiary structure in the absence of scaffolding by the rest of protein molecule. This results in low inhibitor potency. NMR and CD spectroscopy studies of lipopeptide inhibitors of the Hedgehog pathway revealed that membrane anchoring allows the cell membrane to function as a scaffold and facilitate the folding of short peptides. In addition, lipidation enhances cell permeability and increases the concentration of the compounds near the membrane, thus facilitating potent inhibition. The general applicability of this rational approach was further confirmed by the generation of selective antagonists of the insulin-like growth factor 1 receptor with GI(50) values in the nanomolar range. Lipopeptides corresponding to protein fragments were found to serve as potent and selective inhibitors of a number of nondruggable molecular targets.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Péptidos
/
Proteínas Hedgehog
Límite:
Humans
Idioma:
En
Revista:
Chembiochem
Asunto de la revista:
BIOQUIMICA
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos