Lysine-deficient lymphotoxin-α mutant for site-specific PEGylation.
Cytokine
; 56(2): 489-93, 2011 Nov.
Article
em En
| MEDLINE
| ID: mdl-21871814
ABSTRACT
The cytokine lymphotoxin-α (LTα) is a promising anticancer agent; however, its instability currently limits its therapeutic potential. Modification of proteins with polyethylene glycol (PEGylation) can improve their in vivo stability, but PEGylation occurs randomly at lysine residues and the N-terminus. Therefore, PEGylated proteins are generally heterogeneous and have lower bioactivity than their non-PEGylated counterparts. Previously, we created phage libraries expressing mutant LTαs in which the lysine residues of wild-type LTα (wtLTα) were substituted for other amino acids. Here, we attempted to create a lysine-deficient mutant LTα with about the same bioactivity as wtLTα by using these libraries and site-specific PEGylation of the N-terminus. We isolated a lysine-deficient mutant LTα, LT-K0, with almost identical bioactivity to that of wtLTα against mouse LM cells. The bioactivity of wtLTα decreased to 10% following random PEGylation, whereas that of LT-K0 decreased to 50% following site-specific PEGylation; PEGylated LT-K0 retained five times the bioactivity of randomly PEGylated wtLTα. These results suggest that site-specific PEGylated LT-K0 may be useful in cancer therapy.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Polietilenoglicóis
/
Linfotoxina-alfa
/
Lisina
/
Mutação
Limite:
Animals
Idioma:
En
Revista:
Cytokine
Assunto da revista:
ALERGIA E IMUNOLOGIA
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Japão