Macrocyclic Modalities Combining Peptide Epitopes and Natural Product Fragments.
J Am Chem Soc
; 142(10): 4904-4915, 2020 03 11.
Article
em En
| MEDLINE
| ID: mdl-32058716
ABSTRACT
"Hot loop" protein segments have variable structure and conformation and contribute crucially to protein-protein interactions. We describe a new hot loop mimicking modality, termed PepNats, in which natural product (NP)-inspired structures are incorporated as conformation-determining and -restricting structural elements into macrocyclic hot loop-derived peptides. Macrocyclic PepNats representing hot loops of inducible nitric oxide synthase (iNOS) and human agouti-related protein (AGRP) were synthesized on solid support employing macrocyclization by imine formation and subsequent stereoselective 1,3-dipolar cycloaddition as key steps. PepNats derived from the iNOS DINNN hot loop and the AGRP RFF hot spot sequence yielded novel and potent ligands of the SPRY domain-containing SOCS box protein 2 (SPSB2) that binds to iNOS, and selective ligands for AGRP-binding melanocortin (MC) receptors. NP-inspired fragment absolute configuration determines the conformation of the peptide part responsible for binding. These results demonstrate that combination of NP-inspired scaffolds with peptidic epitopes enables identification of novel hot loop mimics with conformationally constrained and biologically relevant structure.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peptídeos Cíclicos
/
Receptores de Melanocortina
/
Proteínas Supressoras da Sinalização de Citocina
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Am Chem Soc
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Alemanha