PeIA-5466: A Novel Peptide Antagonist Containing Non-natural Amino Acids That Selectively Targets α3ß2 Nicotinic Acetylcholine Receptors.
J Med Chem
; 62(13): 6262-6275, 2019 07 11.
Article
em En
| MEDLINE
| ID: mdl-31194549
ABSTRACT
Pharmacologically distinguishing α3ß2 nicotinic acetylcholine receptors (nAChRs) from closely related subtypes, particularly α6ß2, has been challenging due to the lack of subtype-selective ligands. We created analogs of α-conotoxin (α-Ctx) PeIA to identify ligand-receptor interactions that could be exploited to selectively increase potency and selectivity for α3ß2 nAChRs. A series of PeIA analogs were synthesized by replacing amino acid residues in the second disulfide loop with standard or nonstandard residues and assessing their activity on α3ß2 and α6/α3ß2ß3 nAChRs heterologously expressed in Xenopus laevis oocytes. Asparagine11 was found to occupy a pivotal position, and when replaced with negatively charged amino acids, selectivity for α3ß2 over α6/α3ß2ß3 nAChRs was substantially increased. Second generation peptides were then designed to further improve both potency and selectivity. One peptide, PeIA-5466, was â¼300-fold more potent on α3ß2 than α6/α3ß2ß3 and is the most α3ß2-selective antagonist heretofore reported.
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1
Base de dados:
MEDLINE
Assunto principal:
Peptídeos
/
Receptores Nicotínicos
/
Antagonistas Nicotínicos
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article