Bridge protein-mediated viral targeting of cells expressing endogenous μ-opioid G protein-coupled receptors in the mouse and monkey brain.

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Tác giả: Ken-Ichi Amemori, Satoko Amemori, Riki Kamaguchi, Fumitaka Osakada

Ngôn ngữ: eng

Ký hiệu phân loại: 668.43 Protein plastics

Thông tin xuất bản: Ireland : Neuroscience research , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 117698

Targeting specific cell types is essential for understanding their functional roles in the brain. Although genetic approaches enable cell-type-specific targeting in animals, their application to higher mammalian species, such as nonhuman primates, remains challenging. Here, we developed a nontransgenic method using bridge proteins to direct viral vectors to cells endogenously expressing μ-opioid receptors (MORs), a G protein-coupled receptor. The bridge protein comprises the avian viral receptor TVB, the MOR ligand β-endorphin (βed), and an interdomain linker. EnvB-enveloped viruses bind to the TVB component, followed by the interaction of βed with MORs, triggering viral infection in MOR-expressing cells. We optimized the secretion signals, domain arrangements, and interdomain linkers of the bridge proteins to maximize viral targeting efficiency and specificity. Alternative configurations incorporating different ligands and viral receptors also induced viral infection in MOR-expressing cells. The optimized βed-f2-TVB bridge protein with EnvB-pseudotyped lentiviruses induced infection in MOR-expressing cells in the striatum of mice and monkeys. An intersectional approach combining βed-f2-TVB with a neuron-specific promoter refined cell-type specificity. This study establishes the foundation for the rational bridge protein design and the feasibility of targeting G protein-coupled receptors beyond tyrosine kinase receptors, thereby expanding targetable cell types in the brain and throughout the body.
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