An <i>o</i>-Aminoanilide Analogue of 1α,25-Dihydroxyvitamin D<sub>3</sub> Functions as a Strong Vitamin D Receptor Antagonist

Lamblin, Marc; Spingarn, Russell; Wang, Tiantian; Burger, Melanie; Dabbas, Basel; Moitessier, Nicolas; White, John H.; Gleason, James L.

doi:10.1021/jm1007159

Cited by 23 publications

(10 citation statements)

References 32 publications

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“…To further test if the observed enhanced pneumococcal killing induced by vitamin D was dependent on VDR, we employed the iVDR ZK159222 [25] . Inhibition of VDR blocked vitamin D-induced neutrophil killing of pneumococci in a dose-dependent manner ( Fig.…”

Section: Vitamin D and S Pneumoniae Induce The Vdr And The Convertasmentioning

confidence: 99%

Vitamin D Promotes Pneumococcal Killing and Modulates Inflammatory Responses in Primary Human Neutrophils

2017

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Streptococcus pneumoniae is a major human pathogen and a leading cause of pneumonia, septicemia, and meningitis worldwide. Despite clinical studies linking vitamin D deficiency and pneumonia, molecular mechanisms behind these observations remain unclear. In particular, the effects of vitamin D on neutrophil responses remain unknown. Using pneumococcal strains, primary neutrophils isolated from human blood, and sera from patients with frequent respiratory tract infections (RTIs), we investigated the effects of vitamin D on neutrophil bactericidal and inflammatory responses, including pattern recognition receptors, antimicrobial peptides, and cytokine regulation. We found that vitamin D upregulated pattern recognition receptors, TLR2, and NOD2, and induced the antimicrobial human neutrophil peptides (HNP1-3) and LL-37, resulting in increased killing of pneumococci in a vitamin D receptor-dependent manner. Antibodies targeting HNP1-3 inhibited bacterial killing. Vitamin D supplementation of serum from patients with bacterial RTIs enhanced neutrophil killing. Moreover, vitamin D lowered inflammatory cytokine production by infected neutrophils via IL-4 production and the induction of suppressor of cytokine signaling (SOCS) proteins SOCS-1 and SOCS-3, leading to the suppression of NF-κB signaling. Thus, vitamin D enhances neutrophil killing of S. pneumoniae while dampening excessive inflammatory responses and apoptosis, suggesting that vitamin D could be used alongside antibiotics when treating pneumococcal infections.

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Section: Vitamin D and S Pneumoniae Induce The Vdr And The Convertasmentioning

confidence: 99%

Vitamin D Promotes Pneumococcal Killing and Modulates Inflammatory Responses in Primary Human Neutrophils

2017

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“…However, in vitro studies have confirmed interactions between VDR and corepressors (Meyer and Pike, 2013). When bound to VDR, antagonist ML 3-452 decreased SRC3 binding to CYP24A1 promoter-bound VDR and increased the recruitment of corepressor NCoR (Lamblin et al, 2010). The conformational change of VDR helix 12 was confirmed by hydrogen/deuterium exchange experiments when bound to antagonists/partial agonists (Zhang et al, 2010).…”

Section: The Vdr Corepressor Binding Sitementioning

confidence: 92%

Alternative binding sites at the vitamin D receptor and their ligands

Mutchie

Milo

et al. 2019

Molecular and Cellular Endocrinology

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In recent decades, the majority of ligands developed for the vitamin D receptor (VDR) bind at its deeply buried genomic ligand binding pocket. Theses ligands can be categorized into agonists and partial agonists/antagonists. A limited number of ligands, most of them peptides, bind the VDRcoactivator binding site that is formed in the presence of an agonist and inhibit coactivator recruitment, and therefore transcription. Another solvent exposed VDR-ligand binding pocket was identified for lithocholic acid, improving the overall stability of the VDR complex. Additional proposed interactions with VDR are discussed herein that include the alternative VDR-ligand binding pocket that may mediate both non-genomic cellular responses and binding function 3 that was identified for the androgen receptor. Many VDR ligands increase blood calcium levels at therapeutic concentrations in vivo, thus the identification of alternative VDR-ligand binding pockets might be crucial to develop non-calcemic and potent ligands for VDR to treat cancer and inflammatory disease.

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“…ML-3-452 binds VDR with an EC 50 of 107 nM (Figure 13) (145). In CCS25 cells, ML-3-452 did not increase the expression of CYP24A1 and TSLP but reduced their expression in the presence of 1,25-(OH) 2 D 3 .…”

Section: Vdr Antagonists or Allosteric Inhibition Of The Vdr–coregmentioning

confidence: 99%

Inhibitors for the Vitamin D Receptor–Coregulator Interaction

Teske

2016

Vitamin D Hormone

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The vitamin D receptor (VDR) belongs to the superfamily of nuclear receptors and is activated by the endogenous ligand 1,25-dihydroxyvitamin D3. The genomic effects mediated by VDR consist of the activation and repression of gene transcription, which includes the formation of multi-protein complexes with coregulator proteins. Coregulators bind many nuclear receptors and can be categorized according their role as coactivators (gene activation) or corepressors (gene repression). Herein, different approaches to develop compounds that modulate the interaction between VDR and coregulators are summarized. This include coregulator peptides that were identified by creating phage display libraries. Subsequent modification of these peptides including the introduction of a tether or non-hydrolysable bonds resulted in the first direct VDR–coregulator inhibitors. Later, small molecules that inhibit VDR–coregulator inhibitors were identified using rational drug design and high throughput screening. Early on, allosteric inhibition of VDR–coregulator interactions was achieved with VDR antagonists that change the conformation of VDR and modulate the interactions with coregulators. A detailed discussion of their dual agonist/antagonist effects is given as well as a summary of their biological effects in cell-based assays and in vivo studies.

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An o-Aminoanilide Analogue of 1α,25-Dihydroxyvitamin D₃ Functions as a Strong Vitamin D Receptor Antagonist

Cited by 23 publications

References 32 publications

Vitamin D Promotes Pneumococcal Killing and Modulates Inflammatory Responses in Primary Human Neutrophils

Vitamin D Promotes Pneumococcal Killing and Modulates Inflammatory Responses in Primary Human Neutrophils

Alternative binding sites at the vitamin D receptor and their ligands

Inhibitors for the Vitamin D Receptor–Coregulator Interaction

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An o-Aminoanilide Analogue of 1α,25-Dihydroxyvitamin D3 Functions as a Strong Vitamin D Receptor Antagonist

Cited by 23 publications

References 32 publications

Vitamin D Promotes Pneumococcal Killing and Modulates Inflammatory Responses in Primary Human Neutrophils

Vitamin D Promotes Pneumococcal Killing and Modulates Inflammatory Responses in Primary Human Neutrophils

Alternative binding sites at the vitamin D receptor and their ligands

Inhibitors for the Vitamin D Receptor–Coregulator Interaction

Contact Info

Product

Resources

About

An o-Aminoanilide Analogue of 1α,25-Dihydroxyvitamin D₃ Functions as a Strong Vitamin D Receptor Antagonist