Chemically Induced Dimerization via Nanobody Binding Facilitates in Situ Ligand Assembly and On-Demand GPCR Activation DOI Creative Commons

Shubhra Jyoti Saha,

Ross W. Cheloha

JACS Au, Год журнала: 2024, Номер 4(12), С. 4780 - 4789

Опубликована: Ноя. 25, 2024

Methods that enable the on-demand synthesis of biologically active molecules offer potential for a high degree control over timing and context target activation; however, such approaches often require extensive engineering to implement. Tools restrict localization assembly also remain limited. Here we present new approach stimulus-induced ligand helps address these challenges. This methodology relies on affinity specificity recognition exhibited by antibody fragments (nanobodies, Nbs). By using Nbs recognize short peptide epitopes create semisynthetic conjugates, develop bioengineering platform termed epitope dimerization (PED) in which addition heterodimeric composed two Nb stimulates proximity-induced functional parathyroid hormone receptor-1, G protein-coupled receptor. We further demonstrate efficiency can be achieved cell surface via Nb-based delivery template. opens door generation bioactive receptor ligands preferentially at desired biological niche.

Язык: Английский

Matchmaking at the cell surface using bispecifics to put cells on their best behavior DOI Creative Commons
C. Driscoll, Mark Howarth

Current Opinion in Biotechnology, Год журнала: 2025, Номер 92, С. 103267 - 103267

Опубликована: Фев. 5, 2025

Язык: Английский

Процитировано

0
Generation of Site‐Specifically Labeled Affinity Reagents via Use of a Self‐Labeling Single Domain Antibody DOI Creative Commons
Stanley Fayn, Swarnali Roy, Chino C. Cabalteja

и другие.

Advanced Science, Год журнала: 2025, Номер unknown

Опубликована: Фев. 18, 2025

Abstract Several chemical and enzymatic methods have been used to link antibodies moieties that facilitate visualization of cognate targets. Emerging evidence suggests the extent labeling, dictated by type chemistry used, has a substantial impact on performance, especially in context for tumors vivo. These effects are particularly pronounced studies using small antibody fragments, such as single‐domain antibodies, or nanobodies. Here, we leverage new variety conjugation chemistry, based nanobody forms crosslink with specialized high‐affinity epitope analogue, label target‐specific constructs functionalities choice, including fluorophores, chelators, click handles. Using heterodimeric conjugates, comprised an antigen recognition module self‐labeling module, enables us attach desired functional group at location distal site recognition. Constructs generated this approach bound antigens expressed xenograft murine models liver cancer allowed non‐invasive diagnostic imaging. The modularity our offers novel method site‐specific functionalization biomolecules can be extended other applications which covalent labeling is required.

Язык: Английский

Процитировано

0
Induced proximity at the cell surface DOI
Nicholas A. Till,

Muthukumar Ramanathan,

Carolyn R. Bertozzi

и другие.

Nature Biotechnology, Год журнала: 2025, Номер unknown

Опубликована: Март 26, 2025

Язык: Английский

Процитировано

0
Tumor Cell-Specific Signal Processing Platform Controlled by ATP for Non-invasive Modulation of Cellular Behavior DOI
Guo‐Fang Zhang, Shuzhen Yue,

Hongyan Geng

и другие.

Nano Letters, Год журнала: 2024, Номер 24(46), С. 14829 - 14837

Опубликована: Ноя. 11, 2024

Regulating the spatial distribution of membrane receptors can artificially reprogram cellular behaviors, which play a critical biological role in various physiological and pathological processes. Herein, we construct tumor cell-specific signal processing platform (TCS-SPP) for controlled promotion/inhibition cellular-mesenchymal epithelial transition factor (c-Met) receptor dimerization to noninvasively modulate behaviors. Upon dual-aptamer recognition upstream input circuit (UISC) discriminate target cancer cells, membrane-anchored DNA processor (DSP) is activated amplification via rolling circle (RCA) followed by working an ATP molecular switch conversion, achieving modulation downstream output (DOSC). Benefiting from rigid structure DSP, protective effect, confinement effect RCA products, this TCS-SPP has demonstrated good performance accurately modulating behavior such as cell migration, invasion, proliferation, showing great potential targeted therapy biomedical engineering applications.

Язык: Английский

Процитировано

1
Design of allosteric modulators that change GPCR G protein subtype selectivity DOI Creative Commons
Madelyn Moore, Kelsey L. Person,

Abigail Alwin

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 21, 2024

G protein-coupled receptors (GPCRs), the largest family of drug targets, can signal through 16 subtypes Gα proteins. Biased compounds that selectively activate therapy-relevant pathways promise to be safer, more effective medications. The determinants bias are poorly understood, however, and rationally-designed, protein-subtype-selective lacking. Here, using prototypical class A GPCR neurotensin receptor 1 (NTSR1), we find small molecules binding intracellular GPCR-transducer interface change protein coupling by subtype-specific predictable mechanisms, enabling rational design. We demonstrate compound SBI-553 switches NTSR1 preference acting both as a molecular bumper glue. Structurally, occludes on NTSR1, promoting association with select for which an alternative, shallow-binding conformation is energetically favorable. Minor modifications scaffold produce allosteric modulators distinct subtype selectivity profiles. Selectivity profiles probe-independent, conserved across species, translate differences in

Язык: Английский

Процитировано

0
Chemically Induced Dimerization via Nanobody Binding Facilitates in Situ Ligand Assembly and On-Demand GPCR Activation DOI Creative Commons

Shubhra Jyoti Saha,

Ross W. Cheloha

JACS Au, Год журнала: 2024, Номер 4(12), С. 4780 - 4789

Опубликована: Ноя. 25, 2024

Methods that enable the on-demand synthesis of biologically active molecules offer potential for a high degree control over timing and context target activation; however, such approaches often require extensive engineering to implement. Tools restrict localization assembly also remain limited. Here we present new approach stimulus-induced ligand helps address these challenges. This methodology relies on affinity specificity recognition exhibited by antibody fragments (nanobodies, Nbs). By using Nbs recognize short peptide epitopes create semisynthetic conjugates, develop bioengineering platform termed epitope dimerization (PED) in which addition heterodimeric composed two Nb stimulates proximity-induced functional parathyroid hormone receptor-1, G protein-coupled receptor. We further demonstrate efficiency can be achieved cell surface via Nb-based delivery template. opens door generation bioactive receptor ligands preferentially at desired biological niche.

Язык: Английский

Процитировано

0