2018 Fiscal Year Final Research Report
Designing novel protease inhibitors based on the interference of mouse APOBEC3 with retroviral Gag-Pol autocatalysis
| Project/Area Number |
16H05199
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Virology
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| Research Institution | Kindai University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
博多 義之 近畿大学, 医学部, 講師 (30344500)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | レトロウイルス / 宿主因子 / 複製阻害 / プロテアーゼ / APOBEC3 / 粒子成熟 / Gag-Pol前駆体 |
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| Outline of Final Research Achievements |
Mouse APOBEC3 (mA3) inhibits murine leukemia virus (MuLV) replication through a deamination-independent mechanism in which the reverse transcription is considered the prime target process. However, other steps in virus replication can also be targeted by mA3. We have investigated the possible effect of mA3 on viral protease-mediated processes. We found that mA3 directly bound both mature viral protease and Pr180gag-pol precursor. Furthermore, the autoprocessing of Pr180gag-pol was impeded by mA3, resulting in reduced production of mature viral protease. Exon 5-containing and -lacking isoforms of mA3 equally exhibited this antiviral activity, and physiologically expressed levels of mA3 impeded Pr180gag-pol autocatalysis and Pr65gag processing. This blockade was independent of the deaminase activity and required the C-terminal half of mA3. These results suggest that Pr180gag-pol autoprocessing can be a critical step for mA3 to exert its deaminase-independent antiretroviral activity.
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| Free Research Field |
ウイルス学
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| Academic Significance and Societal Importance of the Research Achievements |
抗レトロウイルス薬の多剤併用により、先進国ではHIV-1感染者の生命予後が非感染者のそれに近付いているとされる。しかし、現在用いられている抗レトロウイルス薬では耐性株出現が不可避であり、若年感染者が短期間に治療を必要とするようになる現状からも、新たな作用機序を持つ抗HIV薬開発が喫緊の課題である。プロテアーゼ阻害薬は、活性部位への結合や二量体化の抑制を指標に開発されて来た。我々の研究成果を基礎に、Gag-Pol前駆体からのプロテアーゼ切り出しを阻害する薬物のシーズを宿主因子の分子構造から探ることにより、有効でかつ副作用の少ない新規抗レトロウイルス薬の開発に貢献できる可能性がある。
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