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Abstract
BackgroundThe 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.ResultsIn 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 IC50 around 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-015-0218-9) contains supplementary material, which is available to authorized users.
Highlights
The human immunodeficiency virus type-1 (HIV-1) nucleocapsid protein (NC) is an essential and multi‐ functional protein involved in multiple stages of the viral life cycle such as reverse transcription, integration of proviral DNA, and especially genome RNA packaging
Identification of A1752, a new HIV‐1 inhibitor To assess the antiviral efficacy of a newly identified small molecule inhibitor designated as A1752 (Fig. 1a) against HIV-1, we used an HIV-1 NL4-3 isolate derivative harboring enhanced green fluorescent protein (NL4-3/ EGFP)
Virions generated in the presence of A1752 are defective in synthesis of the viral early reverse transcriptase (RT) product in the virus‐infected cells To further characterize the inhibition and loss of viral infectivity induced by the A1752, we examined the synthesis of RT products in the virion-infected cells
Summary
The human immunodeficiency virus type-1 (HIV-1) nucleocapsid protein (NC) is an essential and multi‐ functional 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. DIBA, Dithiane, and SAMT have shown similar effects by inducing intermolecular cross-links between cysteins in the zinc fingers of NC in Gag protein This action causes modification and aggregation of the NC and Gag protein, which results in disturbance of Gag processing [15, 16, 20]. There are other types of NC-zinc ejectors reported such as N,N’-bis(4-ethoxycarbonyl-1,2,3-thiadiazol-5-yl)benzene-1,2-diamine (NV038) and 2-methyl-3-phenyl-2H[1, 2, 4] thiadiazol-5-ylideneamine (WDO-217), which have not shown covalent bonds in NC [23, 24] unlike the aforementioned inhibitors
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