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Updated: Jan 29, 2026
Low Molecular Weight Protein Enrichment on Mesoporous Silica Thin Films for Biomarker Discovery
Published on: April 17, 2012
Design, synthesis and biological evaluation of low molecular weight CXCR4 ligands
Maxwell M Sakyiamah1, Takuya Kobayakawa2, Masayuki Fujino3
1Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan; Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8150, Japan.
Abstract:
The chemokine receptor CXCR4/stromal cell-derived factor-1 (SDF-1: CXCL12) signaling axis represents a crucial drug target due to its relevance to several diseases such as HIV-1 infection, cancer, leukemia, and rheumatoid arthritis. With the aim of enhancing the binding affinity and anti-HIV activity of a potent CXCR4 ligand as a lead, 23 low molecular weight compounds containing dipicolylamine (Dpa) and cyclam cationic moieties with varying spacers and spatial positioning were designed, synthesized and biologically evaluated. All of the synthesized compounds screened at 1.0 μM in the NanoBRET assay system exhibited >70% inhibition of the binding of a competitive probe TAMRA-Ac-TZ14011 (10 nM) to CXCR4 in the presence of zinc (II) ion. Furthermore, selected compounds 3, 8, 9, 19 and 21 with spatial distances between the next carbon to Dpa and the next carbon to cyclam within the range of 6.5-7.5 Å showed potent binding affinity selective for CXCR4 with IC50 values of 1.6, 7.9, 5.7, 3.5 and 4.5 nM, respectively, with corresponding high anti-HIV activity with EC50s of 28, 13, 21, 28 and 61 nM, respectively, in the presence of zinc (II) ion. Some compounds with remarkably more potent CXCR4-binding affinity than that of an initial lead were obtained. These compounds interact with different but overlapping amino acid residues of CXCR4. The present studies have developed new low molecular weight CXCR4 ligands with high CXCR4-binding and anti-HIV activities, which open avenue into the development of more potent CXCR4 ligands.
Insights
Researchers developed new low molecular weight compounds targeting the CXCR4 receptor, showing enhanced binding affinity and potent anti-HIV activity. These findings offer new avenues for developing more effective CXCR4-targeting therapeutics for various diseases.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Pharmacology
Background:
- The chemokine receptor CXCR4 and its ligand SDF-1 (CXCL12) signaling pathway is implicated in diseases like HIV-1, cancer, and rheumatoid arthritis.
- Targeting the CXCR4 pathway is a significant strategy for therapeutic intervention in these conditions.
Purpose of the Study:
- To design, synthesize, and evaluate novel low molecular weight compounds with enhanced binding affinity and anti-HIV activity against CXCR4.
- To explore the structure-activity relationships of dipicolylamine (Dpa) and cyclam moieties in CXCR4 ligand development.
Main Methods:
- Synthesis of 23 novel compounds incorporating Dpa and cyclam cationic moieties with varied spacers.
- Biological evaluation using NanoBRET assay to assess inhibition of probe binding to CXCR4.
- Determination of IC50 and EC50 values for selected potent compounds.
Main Results:
- All synthesized compounds showed >70% inhibition of probe binding to CXCR4 at 1.0 μM.
- Compounds 3, 8, 9, 19, and 21 exhibited potent and selective CXCR4 binding (IC50 values 1.6–7.9 nM) and high anti-HIV activity (EC50 values 13–61 nM).
- Several compounds demonstrated superior binding affinity compared to the initial lead compound.
Conclusions:
- New low molecular weight CXCR4 ligands with significant binding affinity and anti-HIV activity have been developed.
- These compounds interact with distinct yet overlapping amino acid residues within CXCR4.
- The study opens pathways for the development of more potent CXCR4-targeting drugs.
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