Exploration of candidate compounds that overcome infectious disease by inducing TRAF6 degradation

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K08352
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Environmental and hygienic pharmacy
• Research Institution: Musashino University
• Principal Investigator: Muroi Masashi 武蔵野大学, 薬学部, 教授 (70311389)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 感染症疾患 / Toll-like receptor / 炎症性疾患 / エンドトキシン

Outline of Final Research Achievements

I previously found that IRAK-1, a kinase involved in Toll-like receptor signaling, induced degradation of TRAF6, an indispensable molecule for Toll-like receptor signaling. This study explored a minimal structural region of IRAK-1 for the degradation, which may applicable to the treatment of infectious diseases through inhibition of exacerbated production of inflammatory mediators.
Among 712 amino acids of IRAK-1, I found that only Death Domain（D: amino acid 1-102）and C1 (amino acid 523-618) or C2 (amino acid 619-712) were required for the degradation of TRAF6. C1 and C2 contain three potential TRAF6-binding sequences, each of which consists of five amino acids, and I also found that expression of these sequence structures in cells induced degradation of TRAF6.
These results provide a possibility for obtaining a therapeutic drug, which inhibits exacerbated production of inflammatory mediators, for infectious diseases, and shed light on the treatment of unovercome infectious diseases.

Free Research Field

自然免疫

Academic Significance and Societal Importance of the Research Achievements

細菌感染症疾患は、米国内だけでもこれによる死者が年間に数十万人にも達すると推定されている臨床上の重大な問題であるにもかかわらず、現在、効果的な治療法がなく、有効な治療薬の開発が切に望まれている。本研究では感染症疾患につながる炎症性メディエーター産生に関与するTRAF6を効果的に分解するペプチドを見出した。このペプチド構造を擬態する低分子化学物質が得られれば細菌感染症疾患治療薬の開発に多大に貢献するものである。また、TRAF6蛋白質の機能抑制は骨新生を促すことも報告されており、TRAF6の分解を誘導する薬物は、骨粗鬆症、関節リウマチなどの運動器疾患の治療薬の開発にもつながるものと期待できる。