Small Molecular Compounds Inhibit HIV-1 Replication through Specifically Stabilizing APOBEC3G

Cen, Shan; Peng, Zong–Gen; Li, Xiaoyü; Li, Zhuorong; Ma, Jing; Wang, Yueming; Fan, Bo; You, Xuefu; Wang, Yuping; Liu, Fei; Shao, Rong‐Guang; Zhao, Lu; Yu, Liyan; Jiang, Jian‐Dong

doi:10.1074/jbc.m109.085308

Cited by 98 publications

(86 citation statements)

References 20 publications

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“…Small molecules that inhibit HIV-1 Vif function in vitro have recently been identified, but these compounds do not inhibit the Vif-A3G interaction (50 -53). Another study identified two compounds, IMB-26 and IMB-35, as specific inhibitors of Vifdependent degradation of huA3G via stabilization of A3G (54). Although this study demonstrated a Vif-dependent effect on inhibition, a mechanistic explanation for the specific inhibition was unknown, and compound activity was not characterized in physiologically relevant target cells.…”

Section: Apobec3g (A3g) Is a Cellular Cytidine Deaminase That Restricmentioning

confidence: 99%

Identification of a Novel HIV-1 Inhibitor Targeting Vif-dependent Degradation of Human APOBEC3G Protein

Pery

Sheehy

Nebane

et al. 2015

Journal of Biological Chemistry

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Background:The interaction between HIV Vif protein and innate antiviral factor APOBEC3G represents a potential therapeutic target. Results: Screening for inhibitors of Vif-APOBEC3G interaction identified a small molecule, N.41, that protects APOBEC3G from Vif-mediated degradation and exhibits antiviral activity. Conclusion: N.41 is a lead for further development as an antiviral. Significance: These findings suggest new strategies for developing anti-HIV therapeutics.

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Section: Apobec3g (A3g) Is a Cellular Cytidine Deaminase That Restricmentioning

confidence: 99%

Identification of a Novel HIV-1 Inhibitor Targeting Vif-dependent Degradation of Human APOBEC3G Protein

Pery

Sheehy

Nebane

et al. 2015

Journal of Biological Chemistry

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“…Recent reports have described several small molecules that inhibit HIV-1 infectivity by degrading Vif in an A3G-dependent manner (7) or suppressing the Vif/A3G interaction (8,9). In particular, the inhibitor TPEN removes zinc from the zinc binding motif of Vif that contributes to the interaction with A3G (9).…”

Section: Introductionmentioning

confidence: 99%

An anti-HIV-1 compound that increases steady-state expression of apoplipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G

Ejima

Hirota²,

Mizukami

et al. 2011

Int J Mol Med

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Abstract. Human apoplipoprotein B mRNA-editing enzymecatalytic polypeptide-like (APOBEC) 3G (A3G) is an antiviral protein that blocks HIV-1 replication. However, the antiviral activity of A3G is overcome by the HIV-1 protein Vif. This inhibitory function of Vif is related to its ability to degrade A3G in the proteasome. This finding prompted us to examine the activities of �- (SN-2) and SN-3. We found that 5 µM SN-2 increases the expression of A3G to a level much higher than that observed in the absence of Vif, without affecting the level of Vif expression. The proteasome inhibitor MG-132 increased the level of both A3G and Vif expression. These results demonstrate that A3G is ubiquitinated and degraded in the proteasome by a factor other than Vif, and that SN-2 selectively inhibits these processes. Furthermore, 5 µM SN-2 significantly inhibited the MAGI cell infectivity of wild-type HIV-1. These findings may contribute to the development of a novel anti-HIV-1 drug.

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“…Importantly, no cellular toxicity could be observed, not even with a 200-fold higher concentration than required for an efficient antiviral response. Moreover, doses up to 1 g/kg injected intraperitoneally into mice do not cause significant weight loss or toxicity in any of the tested organs (liver, kidney, heart and lungs) [44].…”

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confidence: 99%

Protein-protein Interactions: Network Analysis and Applications in Drug Discovery

Bultinck¹,

Lievens²,

Tavernier

2012

CPD

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Physical interactions among proteins constitute the backbone of cellular function, making them an attractive source of therapeutic targets. Although the challenges associated with targeting proteinprotein interactions (PPIs) -in particular with small molecules -are considerable, a growing number of functional PPI modulators is being reported and clinically evaluated. An essential starting point for PPI inhibitor screening or design projects is the generation of a detailed map of the human interactome and the interactions between human and pathogen proteins. Different routes to produce these biological networks are being combined, including literature curation and computational methods. Experimental approaches to map PPIs mainly rely on the yeast two-hybrid (Y2H) technology, which have recently shown to produce reliable protein networks. However, other genetic and biochemical methods will be essential to increase both coverage and resolution of current protein networks in order to increase their utility towards the identification of novel disease-related proteins and PPIs, and their potential use as therapeutic targets.

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Small Molecular Compounds Inhibit HIV-1 Replication through Specifically Stabilizing APOBEC3G

Cited by 98 publications

References 20 publications

Identification of a Novel HIV-1 Inhibitor Targeting Vif-dependent Degradation of Human APOBEC3G Protein

Identification of a Novel HIV-1 Inhibitor Targeting Vif-dependent Degradation of Human APOBEC3G Protein

An anti-HIV-1 compound that increases steady-state expression of apoplipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G

Protein-protein Interactions: Network Analysis and Applications in Drug Discovery

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