A trimeric structural fusion of an antagonistic tumor necrosis factor-alpha mutant enhances molecular stability

2017 Fiscal Year Final Research Report

• Project/Area Number: 16K18918
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: Kobe Gakuin University
• Principal Investigator: Inoue Masaki 神戸学院大学, 薬学部, 助手 (80757097)
• Research Collaborator: TSUNODA Shinichi ; KAMADA Haruhiko
• Project Period (FY): 2016-04-01 – 2018-03-31
• Keywords: 腫瘍壊死因子 / TNF / アンタゴニスト / TNFR1 / 自己免疫疾患 / 一本鎖化 / 構造最適化

Outline of Final Research Achievements

We have been investigating the use of TNFR1-selective antagonistic TNF mutant (R1antTNF) to reveal the pharmacological effect of TNFR1-selective inhibition as a new therapeutic modality. This study aimed to further improve and optimize the activity and behavior of this mutant protein both in vitro and in vivo. Especially, we examined a trimeric structural fusion of R1antTNF, formed via the introduction of short peptide linkers, as a strategy to enhance bioactivity and molecular stability. The trimeric fusion, referred to as single-chain R1antTNF (scR1antTNF), was found to retain in vitro molecular properties of receptor selectivity and antagonistic activity but displayed a marked increase in thermal stability. Furthermore, molecular modification of scR1antTNF using polyethylene glycol (PEG) significantly prolonged the residence time in vivo. Therefore, scR1antTNF is considered useful for therapeutic drug application.

Free Research Field

創薬化学