Creation of an improved mutant TNF with TNFR1-selectivity and antagonistic activity by phage display technology.
Pharmazie
; 65(2): 93-6, 2010 Feb.
Article
em En
| MEDLINE
| ID: mdl-20225650
ABSTRACT
Tumor necrosis factor-alpha (TNF), which binds two types of TNF receptors (TNFR1 and TNFR2), regulates the onset and exacerbation of autoimmune diseases such as rheumatoid arthritis and Crohn's disease. In particular, TNFR1-mediated signals are predominantly related to the induction of inflammatory responses. We have previously generated a TNFR1-selective antagonistic TNF-mutant (mutTNF) and shown that mutTNF efficiently inhibits TNFR1-mediated bioactivity in vitro and attenuates inflammatory conditions in vivo. In this study, we aimed to improve the TNFR1-selectivity of mutTNF This was achieved by constructing a phage library displaying mutTNF-based variants, in which the amino acid residues at the predicted receptor binding sites were substituted to other amino acids. From this mutant TNF library, 20 candidate TNFR1-selective antagonists were isolated. Like mutTNF, all 20 candidates were found to have an inhibitory effect on TNFR1-mediated bioactivity. However, one of the mutants, N7, displayed significantly more than 40-fold greater TNFR1-selectivty than mutTNF. Therefore, N7 could be a promising anti-autoimmune agent that does not interfere with TNFR2-mediated signaling pathways.
Buscar no Google
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores de Necrose Tumoral
/
Receptores Tipo I de Fatores de Necrose Tumoral
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Pharmazie
Assunto da revista:
FARMACIA
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Japão