Targeting cryptic allosteric sites of G protein-coupled receptors as a novel strategy for biased drug discovery

Pharmacological Research, Год журнала: 2025, Номер 212, С. 107574 - 107574

Опубликована: Янв. 2, 2025

G protein-coupled receptors (GPCRs) represent the largest family of membrane and are highly effective targets for therapeutic drugs. GPCRs couple different downstream effectors, including proteins (such as Gi/o, Gs, G12, Gq) β-arrestins β-arrestin 1 2) to mediate diverse cellular physiological responses. Biased signaling allows specific activation certain pathways from full range receptors' capabilities. Targeting more variable allosteric sites, which spatially conserved orthosteric represents a novel approach in biased GPCR drug discovery, leading innovative strategies targeting GPCRs. Notably, emergence cryptic sites on has expanded repertoire available improved receptor subtype selectivity. Here, we conduct summary recent progress structural determination elucidate mechanisms induced by modulators. Additionally, discuss means identify design modulators based through structure-based design, is an advanced pharmacotherapeutic treating GPCR-associated diseases.

Язык: Английский

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GPCR drug discovery: new agents, targets and indications

Nature Reviews Drug Discovery, Год журнала: 2025, Номер unknown

Опубликована: Март 3, 2025

Язык: Английский

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Research article for 1st revision to the Chemico-Biological InteractionModulatory roles of capsaicin on thermogenesis in C2C12 myoblasts and the skeletal muscle of mice

Chemico-Biological Interactions, Год журнала: 2025, Номер unknown, С. 111380 - 111380

Опубликована: Янв. 1, 2025

Язык: Английский

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Precision Psychobiotics for Gut–Brain Axis Health: Advancing the Discovery Pipelines to Deliver Mechanistic Pathways and Proven Health Efficacy

Microbial Biotechnology, Год журнала: 2025, Номер 18(1)

Опубликована: Янв. 1, 2025

ABSTRACT Advancing microbiome–gut–brain axis science requires systematic, rational and translational approaches to bridge the critical knowledge gaps currently preventing full exploitation of gut microbiome as a tractable therapeutic target for gastrointestinal, mental brain health. Current research is still marked by many open questions that undermine widespread application humans. For example, lack mechanistic understanding probiotic effects means it remains unclear why even apparently closely related strains exhibit different in vivo. live microbial psychobiotics, consensus on their adjunct treatments conventional neuromodulators, use unmedicated populations or at‐risk cohorts with sub‐clinical symptomatology warranted. This missing information both sides equation when treating central nervous system (CNS) conditions makes psychobiotic challenging, especially compared other pharmaceutical functional food approaches. Expediting transition from positive preclinical data proven benefits humans includes interpreting promises pitfalls animal behavioural assays, well navigating mechanism‐informed decision making select right microbe(s) job. In this review, we consider how these decisions can be supported light accrued range clinical studies across healthy, pathological study populations, where specific have been evaluated context gastrointestinal physiology, function behaviour. Examples successful, partial unsuccessful translation bench bedside are considered. We also discuss developments silico analyses enhanced our moved towards pinpointing host–microbe interactions most important optimal gut–brain function. Combining assays vitro ex vivo domains incorporating model organisms prime discovery pipelines promising rationally selected candidates.

Язык: Английский

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Cannabinoid receptor 1 ligands: Biased signaling mechanisms driving functionally selective drug discovery

Pharmacology & Therapeutics, Год журнала: 2025, Номер unknown, С. 108795 - 108795

Опубликована: Янв. 1, 2025

Язык: Английский

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Raptin, a sleep-induced hypothalamic hormone, suppresses appetite and obesity

Cell Research, Год журнала: 2025, Номер unknown

Опубликована: Янв. 29, 2025

Abstract Sleep deficiency is associated with obesity, but the mechanisms underlying this connection remain unclear. Here, we identify a sleep-inducible hypothalamic protein hormone in humans and mice that suppresses obesity. This cleaved from reticulocalbin-2 (RCN2), name it Raptin. Raptin release timed by circuit vasopressin-expressing neurons suprachiasmatic nucleus to RCN2-positive paraventricular nucleus. levels peak during sleep, which blunted sleep deficiency. binds glutamate metabotropic receptor 3 (GRM3) of hypothalamus stomach inhibit appetite gastric emptying, respectively. Raptin-GRM3 signaling mediates anorexigenic effects via PI3K-AKT signaling. Of note, verify connections between deficiencies sleeping state, impaired release, obesity patients Moreover, carrying an RCN2 nonsense variant present night eating syndrome These data define unique food intake prevents

Язык: Английский

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Direct effect of membrane environment on the activation of mGluR2 revealed by single-molecule FRET

Structure, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

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De novodesign of miniprotein agonists and antagonists targeting G protein-coupled receptors

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 23, 2025

Abstract G protein-coupled receptors (GPCRs) play key roles in physiology and are central targets for drug discovery development, yet the design of protein agonists antagonists has been challenging as GPCRs integral membrane proteins conformationally dynamic. Here we describe computational de novo methods a high throughput “receptor diversion” microscopy based screen generating GPCR binding miniproteins with affinity, potency selectivity, use these to generate MRGPRX1 CXCR4, GLP1R, GIPR, GCGR CGRPR antagonists. Cryo-electron data reveals atomic-level agreement between designed experimentally determined structures CGRPR-bound MRGPRX1-bound agonists, confirming precise conformational control receptor function. Our screening approach opens new frontiers development.

Язык: Английский

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Genome-wide pan-GPCR cell libraries accelerate drug discovery

Acta Pharmaceutica Sinica B, Год журнала: 2024, Номер 14(10), С. 4296 - 4311

Опубликована: Июнь 26, 2024

G protein-coupled receptors (GPCRs) are pivotal in mediating diverse physiological and pathological processes, rendering them promising targets for drug discovery. GPCRs account about 40% of FDA-approved drugs, representing the most successful targets. However, only approximately 15% 800 human targeted by market leaving numerous opportunities discovery among remaining receptors. Cell expression systems play crucial roles GPCR field, including novel target identification, structural functional characterization, potential ligand screening, signal pathway elucidation, safety evaluation. Here, we discuss principles, applications, limitations widely used cell GPCR-targeted discovery, function investigation, pharmacological property studies. We also propose three strategies constructing genome-wide pan-GPCR libraries, which will provide a powerful platform facilitate study mechanisms evaluation, ultimately accelerating process

Язык: Английский

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AlphaFold3 versus experimental structures: assessment of the accuracy in ligand-bound G protein-coupled receptors

Acta Pharmacologica Sinica, Год журнала: 2024, Номер unknown

Опубликована: Дек. 6, 2024

Язык: Английский

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