| Project/Area Number |
15K09574
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Infectious disease medicine
|
|---|
| Research Institution | Kumamoto University |
|---|
Principal Investigator |
Amano Masayuki 熊本大学, 医学部附属病院, 特任助教 (30575080)
|
|---|
| Project Period (FY) |
2015-04-01 – 2019-03-31
|
| Project Status |
Completed (Fiscal Year 2018)
|
| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
|
|---|
| Keywords | HIV-1 / capsid蛋白 / 蛋白自己崩壊 / 薬剤開発 / 新規抗HIV-1剤開発 / HIV-1 キャプシド蛋白 / キャプシド構造蛋白 / 蛋白崩壊 / 創薬 / HIV-1 Capsid 蛋白 (CA) / 新規薬剤開発 / HIV-1構造蛋白阻害 / CA 自己崩壊 / 新規 HIV CA 阻害剤 |
|---|
| Outline of Final Research Achievements |
The aim of our research is to develop the novel anti-HIV-1 (HIV) agents which bind to HIV capsid structural protein (CA) and induce significant CA degradation. We carried out in silico docking simulation of each of 8 million compounds data with a target cavity we identified on the surface of CA N-terminal domain (NTD), then evaluated in vitro anti-HIV activity of compounds with good binding score. We have newly identified ~50 compounds which have anti-HIV activity, among them, 3 compounds significantly induced CA degradation. Such compounds induce degradation both of newly generated CA in the infected cells and conical core-formed CAs within mature HIV virion by penetrating through viral membrane. We also identified that the CA-degradation-inducing compound bind to the NTD of CA. We have newly synthesized structurally-related compounds with CA-degradation-inducing compounds for the optimization, and applied for domestic/international patents regarding CA-degradation-inducing compounds.
|
| Academic Significance and Societal Importance of the Research Achievements |
既存の多剤併用化学療法はHIVの酵素群を標的としているが、対して本研究の標的CAは、HIV内でウイルス遺伝子を包む円錐状殻を構成する蛋白である。本研究はHIVの“本丸”を攻める戦略であり、既存薬とは一線を画す。
HIV逆転写酵素に起因する高い突然変異発生率・HIV酵素群の持つ変異への高許容性より薬剤耐性株出現が惹起される。対してCAはよく保存された領域であり遺伝子変異出現への許容性が低い事が示唆され、CA阻害剤にHIVが薬剤耐性を獲得する事は困難と推測される。CA自壊の誘導及びそれに起因するHIV感染・増殖阻害といった、前例の無い作用機序の薬剤開発は、HIV感染症治療の新たな選択肢に成り得る。
|
