Oligoarginine-Conjugated Peptide Foldamers Inhibiting Vitamin D Receptor-Mediated Transcription
Mami Takyo1,2, Yumi Sato1,2, Naoya Hirata1
1National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki, Kanagawa 210-9501, Japan.
Abstract:
The vitamin D receptor (VDR) is a nuclear receptor, which is involved in several physiological processes, including differentiation and bone homeostasis. The VDR is a promising target for the development of drugs against cancer and bone-related diseases. To date, several VDR antagonists, which bind to the ligand binding domain of the VDR and compete with the endogenous agonist 1α,25(OH)D3, have been reported. However, these ligands contain a secosteroidal skeleton, which is chemically unstable and complicated to synthesize. A few VDR antagonists with a nonsecosteroidal skeleton have been reported. Alternative inhibitors against VDR transactivation that act via different mechanisms are desirable. Here, we developed peptide-based VDR inhibitors capable of disrupting the VDR-coactivator interaction. It was reported that helical SRC2-3 peptides strongly bound to the VDR and competed with the coactivator in vitro. Therefore, we designed and synthesized a series of SRC2-3 derivatives by the introduction of nonproteinogenic amino acids, such as β-amino acids, and by side-chain stapling to stabilize helical structures and provide resistance against digestive enzymes. In addition, conjugation with a cell-penetrating peptide increased the cell membrane permeability and was a promising strategy for intracellular VDR inhibition. The nona-arginine-conjugated peptides 24 with side-chain stapling and 25 with cyclic β-amino acids showed strong intracellular VDR inhibitory activity, resulting in suppression of the target gene expression and inhibition of the cell differentiation of HL-60 cells. Herein, the peptide design, structure-activity relationship (SAR) study, and biological evaluation of the peptides are described.
Insights
New peptide inhibitors target the vitamin D receptor (VDR) by disrupting VDR-coactivator interactions. These novel VDR inhibitors show promise for treating cancer and bone diseases.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- The vitamin D receptor (VDR) is crucial for differentiation and bone homeostasis, making it a therapeutic target for cancer and bone diseases.
- Existing VDR antagonists often have unstable, complex secosteroidal structures, necessitating alternative approaches.
- There is a need for VDR inhibitors that utilize different mechanisms, such as disrupting VDR-coactivator interactions.
Purpose of the Study:
- To design and synthesize novel peptide-based VDR inhibitors.
- To develop VDR inhibitors that target the VDR-coactivator interaction.
- To create stable, cell-permeable VDR inhibitors for intracellular application.
Main Methods:
- Designed and synthesized SRC2-3 peptide derivatives incorporating nonproteinogenic amino acids (e.g., β-amino acids) and side-chain stapling for stability.
- Conjugated peptides with cell-penetrating peptides (e.g., nona-arginine) to enhance cell membrane permeability.
- Evaluated intracellular VDR inhibitory activity, target gene expression, and cell differentiation in HL-60 cells.
Main Results:
- Peptide derivatives with side-chain stapling and cyclic β-amino acids demonstrated potent intracellular VDR inhibitory activity.
- These peptide inhibitors effectively suppressed target gene expression.
- The developed peptides inhibited cell differentiation in HL-60 cells, indicating biological efficacy.
Conclusions:
- Peptide-based VDR inhibitors disrupting VDR-coactivator interactions represent a promising new therapeutic strategy.
- Stabilized helical peptides, particularly those conjugated with cell-penetrating moieties, offer enhanced intracellular VDR inhibition.
- These findings support the potential of peptide inhibitors for treating VDR-related diseases like cancer and bone disorders.
More Related Videos
08:18Author Spotlight: Unraveling Vitamin A Transport Mechanisms — Linking Liver Receptors to Vision Health Through RBPR2 and RBP4 Interactions
Published on: October 4, 2024
10:33Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
Published on: October 26, 2015
Related Concept Videos
01:23Role of Skin in Vitamin D Synthesis
The solar UV B rays (290-315 nm) are absorbed by the skin, and 7-dehydrocholesterol (provitamin D3) photolyzes it to previtamin D3, which undergoes a rapid transformation to vitamin...
01:16TGF - β Signaling Pathway
01:52Eukaryotic Transcription Inhibitors
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
01:31Transducer Mechanism: Nuclear Receptors
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
01:23Dipeptidyl Peptidase 4 Inhibitors
01:16Calmodulin-dependent Signaling
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...