Molecular Glues: A New Approach to Modulating GPCR Signaling Bias DOI Creative Commons

Jamie Kushnir,

Ryan H. Gumpper

Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

G-protein-coupled receptors (GPCRs) transmit an extracellular chemical/biological signal across the cell membrane, stimulating array of intracellular signaling cascades. Canonically, these molecules bind to endogenous ligand pocket (orthosteric pocket), which stabilizes either active or inactive conformational ensemble receptor. However, recent structural evidence indicates that small can mediate protein–protein interactions between GPCR and their transducers. These are reminiscent molecular glues be powerful tools for modulating bias. In this Perspective, we will investigate current information available on how they modulate We also examine prospects drug/probe design.

Language: Английский

Designer cannabinoids could be the key to pain relief without adverse effects. DOI
Iain R. Greig, Ruth A. Ross

PubMed, Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

Language: Английский

Citations

1
Biased allosteric activation of ketone body receptor HCAR2 suppresses inflammation DOI Creative Commons
Chang Zhao, Heli Wang, Ying Liu

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(17), P. 3171 - 3187.e7

Published: Aug. 18, 2023

Language: Английский

Citations

21
IUPHAR themed review: Opioid efficacy, bias, and selectivity DOI Creative Commons
Nokomis Ramos‐Gonzalez,

Barnali Paul,

Susruta Majumdar

et al.

Pharmacological Research, Journal Year: 2023, Volume and Issue: 197, P. 106961 - 106961

Published: Oct. 14, 2023

Drugs acting at the opioid receptor family are clinically used to treat chronic and acute pain, though they represent second line of treatment behind GABA analogs, antidepressants SSRI's. Within mu kappa commonly targeted. However, activation has side effects constipation, tolerance, dependence, euphoria, respiratory depression; leads dysphoria sedation. The have led drugs being widely abused with great overdose risk. For these reasons, newer safer analgesics in high demand. many years a focus within field was finding that activated G protein pathway receptor, without activating β-arrestin pathway, known as biased agonism. Recent advances shown this may not be way forward develop there is still some promise receptor. Here we discuss recent novel approaches including efficacy vs bias fine-tuning by targeting sub-pockets orthosteric site, explore works on structural basis bias, put suggestion Gα subtype selectivity an exciting new area interest.

Language: Английский

Citations

18
ASD2023: towards the integrating landscapes of allosteric knowledgebase DOI Creative Commons
Jixiao He, Xinyi Liu,

Chunhao Zhu

et al.

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 52(D1), P. D376 - D383

Published: Oct. 23, 2023

Abstract Allosteric regulation, induced by perturbations at an allosteric site topographically distinct from the orthosteric site, is one of most direct and efficient ways to fine-tune macromolecular function. The Database (ASD; accessible online http://mdl.shsmu.edu.cn/ASD) has been systematically developed since 2009 provide comprehensive information on regulation. In recent years, allostery seen sustained growth wide-ranging applications in life sciences, basic research new therapeutics development, while also elucidating emerging obstacles across stages. To overcome these challenges maintain high-quality data center services, novel features were curated ASD2023 update: (i) 66 589 potential sites, covering > 80% human proteome constituting pocketome; (ii) 748 protein–protein interaction (PPI) modulators with clear mechanisms, aiding protein machine studies PPI-targeted drug discovery; (iii) ‘Allosteric Hit-to-Lead,’ a pioneering dataset providing panoramic views 87 well-defined hits 6565 leads (iv) 456 dualsteric for exploring simultaneous regulation sites. Meanwhile, maintains significant foundational data. Based efforts, knowledgebase progressively evolving towards integrated landscape, facilitating advancements target identification, mechanistic exploration discovery.

Language: Английский

Citations

18
Highly biased agonism for GPCR ligands via nanobody tethering DOI Creative Commons
Shivani Sachdev,

Brendan A. Creemer,

Thomas J. Gardella

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 1, 2024

Abstract Ligand-induced activation of G protein-coupled receptors (GPCRs) can initiate signaling through multiple distinct pathways with differing biological and physiological outcomes. There is intense interest in understanding how variation GPCR ligand structure be used to promote pathway selective (“biased agonism”) the goal promoting desirable responses avoiding deleterious side effects. Here we present an approach which a conventional peptide for type 1 parathyroid hormone receptor (PTHR1) converted from agonist induces all relevant compound that highly single pathway. This achieved not core agonist, but rather by linking it nanobody tethering agent binds high affinity separate site on involved signal transduction. The resulting conjugate represents most biased PTHR1 reported date. holds promise facile generation ligands other GPCRs.

Language: Английский

Citations

6
Structural basis of μ-opioid receptor targeting by a nanobody antagonist DOI Creative Commons
Jun Yu,

Amit Kumar,

Xuefeng Zhang

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Oct. 9, 2024

The μ-opioid receptor (μOR), a prototypical G protein-coupled (GPCR), is the target of opioid analgesics such as morphine and fentanyl. Due to severe side effects current drugs, there considerable interest in developing novel modulators μOR function. Most GPCR ligands today are small molecules, however biologics, including antibodies nanobodies, represent alternative therapeutics with clear advantages affinity selectivity. Here, we describe nanobody NbE, which selectively binds acts an antagonist. We functionally characterize NbE extracellular genetically encoded ligand uncover molecular basis for antagonism by determining cryo-EM structure NbE-μOR complex. displays unique binding mode achieves selectivity interactions orthosteric pocket loops. Based on β-hairpin loop formed that deeply protrudes into μOR, design linear cyclic peptide analogs recapitulate NbE's antagonism. work illustrates potential nanobodies uniquely engage GPCRs describes lower weight can serve therapeutic developments.

Language: Английский

Citations

6
Carfentanil is a β‐arrestin‐biased agonist at the μ opioid receptor DOI Creative Commons
Nokomis Ramos‐Gonzalez,

Sam Groom,

Katy J. Sutcliffe

et al.

British Journal of Pharmacology, Journal Year: 2023, Volume and Issue: 180(18), P. 2341 - 2360

Published: April 3, 2023

Abstract Background and Purpose The illicit use of fentanyl‐like drugs (fentanyls), which are μ opioid receptor agonists, the many overdose deaths that result, has become a major problem. Fentanyls very potent in vivo, leading to respiratory depression death. However, efficacy possible signalling bias different fentanyls is not clearly known. Here, we compared relative series fentanyls. Experimental Approach For agonist measurements, Bioluminescence Resonance Energy Transfer experiments were undertaken HEK293T cells transiently transfected with receptors, assess Gi protein activation β‐arrestin 2 recruitment. Agonist‐induced cell surface loss was assessed using an enzyme‐linked immunosorbent assay, whilst agonist‐induced G protein‐coupled inwardly rectifying potassium channel current measured electrophysiologically from rat locus coeruleus slices. Ligand poses determined silico molecular dynamics simulations. Key Results Relative reference ligand DAMGO, carfentanil β‐arrestin‐biased, whereas fentanyl, sufentanil alfentanil did display bias. Carfentanil induced extensive loss, marked desensitisation currents continued presence neurones prevented by GRK2/3 inhibitor. Molecular simulations suggested unique interactions orthosteric site could underlie Conclusions Implications β‐arrestin‐biased drug at receptor. It uncertain how such influences vivo effects other

Language: Английский

Citations

15
Structure-based identification of a G protein–biased allosteric modulator of cannabinoid receptor CB1 DOI Creative Commons
Siyuan Shen, Chao Wu, Guifeng Lin

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(24)

Published: June 3, 2024

Cannabis sativa is known for its therapeutic benefit in various diseases including pain relief by targeting cannabinoid receptors. The primary component of cannabis, Δ9-tetrahydrocannabinol (THC), and other agonists engage the orthosteric site CB1, activating both Gi β-arrestin signaling pathways. activation diverse pathways could result on-target side effects cannabis addiction, which may hinder potential. A significant challenge pharmacology design a ligand that can modulate specific CB1. By leveraging insights from structure–function selectivity relationship (SFSR), we have identified signaling–biased agonist-allosteric modulators (ago-BAMs). Further, two cryoelectron microscopy (cryo-EM) structures reveal binding mode ago-BAM at extrahelical allosteric Combining mutagenesis pharmacological studies, elucidated detailed mechanism ago-BAM-mediated biased signaling. Notably, CB-05 demonstrated analgesic efficacy with fewer effects, minimal drug toxicity no addiction mouse models. In summary, our finding not only suggests ago-BAMs CB1 provide potential nonopioid strategy management but also sheds light on BAM identification GPCRs.

Language: Английский

Citations

5
Molecular glues as potential GPCR therapeutics DOI
Bryan L. Roth, B. Krumm

Biochemical Pharmacology, Journal Year: 2024, Volume and Issue: 228, P. 116402 - 116402

Published: June 28, 2024

Language: Английский

Citations

5
Signaling Modulation Mediated by Ligand Water Interactions with the Sodium Site at μOR DOI Creative Commons
Rohini S. Ople, Nokomis Ramos‐Gonzalez, Qiongyu Li

et al.

ACS Central Science, Journal Year: 2024, Volume and Issue: 10(8), P. 1490 - 1503

Published: July 17, 2024

The mu opioid receptor (μOR) is a target for clinically used analgesics. However, adverse effects, such as respiratory depression and physical dependence, necessitate the development of alternative treatments. Recently we reported novel strategy to design functionally selective opioids by targeting sodium binding allosteric site in μOR with supraspinally active analgesic named C6guano. Presently, improve systemic activity this ligand, structure-based design, identifying new ligand RO76 where flexible alkyl linker polar guanidine guano group swapped benzyl alcohol, targeted indirectly through waters. A cryoEM structure bound μOR-Gi complex confirmed that interacts residues water molecule, unlike C6guano which engages directly. Signaling assays coupled APEX based proximity labeling show pocket modulates efficacy trafficking. In mice, was systemically tail withdrawal showed reduced liabilities compared those morphine. summary, molecules may be an avenue modulate signaling properties opioids, potentially extended other G-protein receptors conserved.

Language: Английский

Citations

5