聚乙二醇化
鲑鱼降钙素
人生长激素
化学
降钙素
组织谷氨酰胺转胺酶
选择性
生长激素
药理学
激素
生物化学
内分泌学
生物
聚乙二醇
酶
催化作用
作者
Anna Mero,Mariano Schiavon,Francesco M. Veronese,Gianfranco Pasut
标识
DOI:10.1016/j.jconrel.2011.04.024
摘要
Modification of therapeutic proteins and peptides by polyethylene glycol (PEG) conjugation is a well-known approach to improve the pharmacological properties of drugs. Several chemical procedures of PEG coupling are already in use but an alternative method based on microbial transglutaminase (mTGase) was recently devised. The enzyme catalyzes the link of mPEG-NH(2) to glutamines (Gln) of a substrate protein. In this case the advantage resides in the fact that usually only few Gln(s) in a protein are substrate of mTGase. In order to further restrict the selectivity of the enzyme, we investigated a new approach leading to the formation of a single conjugate isomer as well as for those proteins containing two or more Gln(s) as mTGase substrates. It was found that the addition of co-solvents in the reaction mixture influenced both the secondary structure of the targeted protein and the mTGase activity. The enzymatic PEGylation under these conditions yielded only mono- and selectively modified conjugates. The method was investigated with salmon calcitonin (sCT) and human growth hormone (hGH). In the case of sCT we also demonstrated the importance of site-selective conjugation for the preservation of in vivo activity.
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