Identification and characterization of a new type of inhibitor against the human immunodeficiency virus type-1 nucleocapsid protein

Retrovirology

Ji Chang You²  Eun Soo Lee²  Byung Soo Kim¹  Soo In Jang²  Kyung Lee Yu²  Jung Ae Park¹  Seon Hee Kim²  Min-Jung Kim¹ 

[1] Avixgen Inc., Seoul 137-701, Korea;National Research Laboratory of Molecular Virology, Department of Pathology, School of Medicine, The Catholic University of Korea, Seoul 137-701, Korea

关键词: Core uncoating;    Gag processing;    Noninfectious virus;    Psi RNA dimerization;    NC inhibitor;    HIV-1;   

Others  :  1230905
DOI  :  10.1186/s12977-015-0218-9

 received in 2015-02-26, accepted in 2015-10-22,  发布年份 2015

【 摘 要 】

Background

The human immunodeficiency virus type-1 (HIV-1) nucleocapsid protein (NC) is an essential and multifunctional protein involved in multiple stages of the viral life cycle such as reverse transcription, integration of proviral DNA, and especially genome RNA packaging. For this reason, it has been considered as an attractive target for the development of new anti-HIV drugs. Although a number of inhibitors of NC have been reported thus far, the search for NC-specific and functional inhibitor(s) with a good antiviral activity continues.

Results

In this study, we report the identification of A1752, a small molecule with inhibitory action against HIV-1 NC, which shows a strong antiviral efficacy and an IC ₅₀around 1 μM. A1752 binds directly to HIV-1 NC, thereby inhibiting specific chaperone functions of NC including Psi RNA dimerization and complementary trans-activation response element (cTAR) DNA destabilization, and it also disrupts the proper Gag processing. Further analysis of the mechanisms of action of A1752 also showed that it generates noninfectious viral particles with defects in uncoating and reverse transcription in the infected cells.

Conclusions

These results demonstrate that A1752 is a specific and functional inhibitor of NC with a novel mode of action and good antiviral efficacy. Thus, this agent provides a new type of anti-HIV NC inhibitor candidate for further drug development.

【 授权许可】

   
2015 kim et al.

【 图 表 】

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