Bivalent ligands to understand dimerization of the mu opioid receptor and the chemokine receptor CCR5 in neurological disorders
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Publication Number
US-12643909-B2
Publication Date
2026-06-02
Expiration Date
Abstract
Bivalent ligands which bind to MOR-CCR5 heterodimers are provided. The bivalent ligands comprise two discrete pharmacophores, naltrexone and maraviroc, linked by a spacer and bind to MOR-CCR5 heterodimers, e.g. at the surface of a cell. The bivalent ligands are useful in assays to detect MOR-CCR5 heterodimers, as therapeutic agents to prevent and/or treat diseases characterized by the presence of MOR-CCR5 heterodimers.
Core Innovation
The described invention provides a family of bivalent ligands in which naltrexone and maraviroc are joined through a linker designated L, including compounds VZMC013, VZMC017, and VZMC019. Claim 1 defines a bivalent ligand having Formula I with specified linker structures, wherein the parameter n ranges from 0 to 12 and defined attachment points connect the linker to naltrexone and maraviroc. The ligands target cell-surface MOR–CCR5 heterodimers for detection and therapeutic application.
The reported results demonstrate that VZMC013 exhibits nanomolar MOR and CCR5 binding affinity, antagonist activity, and inhibition of CCL5-stimulated calcium mobilization. It displays concentration-dependent inhibition of HIV entry and reduces infection in MOR/CCR5-coexpressing cells and PBMCs, including opioid-accelerated infection. Molecular modeling shows the ligand spanning the MOR–CCR5 heterodimer, supporting its use as a chemical probe and candidate pharmacological agent against opioid-accelerated HIV entry.
Claims Coverage
The supplied claim information identifies one independent claim, claim 1, reciting one inventive feature.
Bivalent ligand linking naltrexone and maraviroc
Claim 1 recites a bivalent ligand having Formula I, wherein linker L is selected from specified linker structures, the parameter n ranges from 0 to 12, and defined attachment points connect the linker to naltrexone and maraviroc.
The independent claim covers a defined class of bivalent ligands linking naltrexone and maraviroc through specified linker structures across a stated range of n.
Stated Advantages
VZMC013 exhibits nanomolar MOR and CCR5 binding affinity and antagonist activity, and inhibits CCL5-stimulated calcium mobilization.
VZMC013 inhibits HIV-1BaL entry and reduces infection in MOR/CCR5-coexpressing cells and PBMCs, including opioid-enhanced and opioid-accelerated HIV entry.
The reported HIV-1BaL entry inhibition screening result for VZMC013 exhibits a therapeutic index greater than 1075.
The ligands enable preventing or decreasing opioid-accelerated HIV-1 entry into a cell through formation of a complex with MOR–CCR5 heterodimers.
Documented Applications
Use of VZMC013 as a chemical probe for MOR–CCR5 heterodimers.
Use as a candidate pharmacological agent for preventing or decreasing opioid-accelerated HIV-1 entry into a cell.
Detection of a MOR–CCR5 heterodimer by forming and detecting a complex with the bivalent ligand acting as a probe.
Prevention or treatment of neurological diseases or conditions including neuro-AIDS, dementia, neurodegradation, multiple sclerosis, neuropathic pain, chronic pain, and brain cancer.
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