Small molecule inhibitors of the HIV-1 virulence factor, Nef

Smithgall, Thomas E.; Thomas, Gary

doi:10.1016/j.ddtec.2013.07.002

Cited by 31 publications

(26 citation statements)

References 43 publications

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“…Of note, an alanine at residue 84, located in Nef alpha helix 2, appears to be essential for the proper expression of HIV-1 Nef. The importance of residue 84 in Nef biology provides an additional molecular target for disrupting Nef function, an anti-HIV-1 approach that has gained interest in both the cure and treatment fields (52, 53). …”

Section: Discussionmentioning

confidence: 99%

A Highly Conserved Residue in HIV-1 Nef Alpha Helix 2 Modulates Protein Expression

Johnson

Dirk

Coutu

et al. 2016

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The HIV-1 Nef protein has been established as a key pathogenic determinant of HIV/AIDS, but there is little knowledge of how the extensive genetic diversity of HIV-1 affects Nef function. Upon compiling a set of subtype-specific reference strains, we identified a subtype C reference strain, C.BR92025, that contained natural polymorphisms at otherwise highly conserved residues 13, 84, and 92. Interestingly, strain C.BR92025 Nef displayed impaired Nef function and had decreased protein expression. We have demonstrated that strain C.BR92025 Nef has a higher rate of protein turnover than highly expressed Nef proteins and that this higher rate of protein turnover is due to an alanine-to-valine substitution at Nef residue 84. These findings highlight residue A84 as a major determinant of HIV-1 Nef expression.

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Section: Discussionmentioning

confidence: 99%

A Highly Conserved Residue in HIV-1 Nef Alpha Helix 2 Modulates Protein Expression

Johnson

Dirk

Coutu

et al. 2016

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“…As Nef P 72 xxP 75 is well conserved across various Nef alleles and plays an important role in pathogenicity, it has become the target of a number of inhibitors (reviewed in [62]). Betzi et al [63] were the first to target the Nef-SFK interaction using in silico modeling to identify two small molecules that block the Nef-Hck interaction.…”

Section: Signaling Molecules: Sfksmentioning

confidence: 99%

HIV-1 Nef: a master manipulator of the membrane trafficking machinery mediating immune evasion

Pawlak

Dikeakos

2015

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…Nef-mediated activation of Hck in HIV-1 target cells contributes to enhanced viral replication 10,11 as well as MHC-1 downregulation 12,13 , which is important for immune escape of HIV-infected cells. Several classes of small molecule inhibitors of Nef-dependent Hck activation have been discovered, and represent promising therapeutic leads for antiretroviral drug development 14–16 .…”

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confidence: 99%

Subtle Dynamic Changes Accompany Hck Activation by HIV-1 Nef and are Reversed by an Antiretroviral Kinase Inhibitor

et al. 2015

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The HIV-1 virulence factor Nef interacts with the macrophage Src-family kinase Hck, resulting in constitutive kinase activation that contributes to viral replication and immune escape. Previous chemical library screens identified the diphenylfuranopyrimdine kinase inhibitor DFP-4AB, which selectively inhibits Nef-dependent Hck activity in biochemical assays and potently blocks HIV replication in vitro. In the present study, hydrogen exchange mass spectrometry (HX MS) was used to study conformational changes in downregulated Hck that result from Nef binding, as well as the impact of DFP-4AB on these changes. Remarkably, interaction with Nef induced only subtle changes in deuterium uptake by Hck, with the most significant changes in the N-lobe of the kinase domain adjacent to the docking site for Nef on the SH3 domain. No changes in hydrogen exchange were observed in the Hck SH2 domain or C-terminal tail, indicating that this regulatory interaction is unaffected by Nef binding. When HX MS was performed in the presence of DFP-4AB, the effect of Nef on Hck N-lobe dynamics was completely reversed. These results show that constitutive activation of Hck by HIV-1 Nef requires only modest changes to the conformational dynamics of the overall kinase structure. DFP-4AB reverses these effects, consistent with its activity against this Nef-induced signaling event in HIV-infected cells.

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Small molecule inhibitors of the HIV-1 virulence factor, Nef

Cited by 31 publications

References 43 publications

A Highly Conserved Residue in HIV-1 Nef Alpha Helix 2 Modulates Protein Expression

A Highly Conserved Residue in HIV-1 Nef Alpha Helix 2 Modulates Protein Expression

HIV-1 Nef: a master manipulator of the membrane trafficking machinery mediating immune evasion

Subtle Dynamic Changes Accompany Hck Activation by HIV-1 Nef and are Reversed by an Antiretroviral Kinase Inhibitor

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