Key aspects of modern GPCR drug discovery

Addis, Phil; Bali, Utsav; Baron, Frank; Campbell, Adrian; Harborne, Steven; Jagger, Liz; Milne, Gavin; Pearce, Martin; Rosethorne, Elizabeth M; Satchell, Rupert; Swift, Denise; Young, Barbara; Unitt, John F

doi:10.1016/j.slasd.2023.08.007

Cited by 6 publications

(7 citation statements)

References 138 publications

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“…GPCR signaling via Gαi is commonly associated with the inhibition of adenylyl cyclases, thus interfering with de novo cAMP generation by other cellular stimuli. Our comparative analysis of FPR signaling in FPR-transfected HEK293 cells, a classical model in GPCR-based drug discovery [19], and PMNs as the FPR natural environment [35]- [37], revealed different outcomes based on the distinct cellular context.…”

Section: Discussionmentioning

confidence: 97%

Physiological bias governs neutrophil inflammatory threat perception

Pajonczyk,

Pauli,

Pünt

et al. 2024

Preprint

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The functional GPCR unit consists of an agonist acting on a receptor that is coupled to a G protein that transduces the signals to effectors within a complex cellular environment. While much attention is given to GPCR-agonist or GPCR-transducer relationships, the contribution of the cell environment is less well investigated. Here, we compared the signals transmitted upon activation of two pattern recognition receptors, Formyl peptide receptor 1 and Formyl peptide receptor 2 in a recombinant cell model with the FPR-mediated signaling texture in the physiological neutrophilic environment. We observed that agonist activation lead to substantial differences in de novo cAMP generation, depending on the cell context, whereas MAPK activation was similar in both systems. The physiological bias was conserved across species. Thus, a generic signal provided by different receptors leads to discrete responses that depend on the specific identity of the signal-receiving cell, thus highlighting the cellular context as a decisive component in GPCR-mediated signal transduction.

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Section: Discussionmentioning

confidence: 97%

Physiological bias governs neutrophil inflammatory threat perception

Pajonczyk,

Pauli,

Pünt

et al. 2024

Preprint

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“…These receptors interact with a diverse array of ligands, including photons, ions, hormones, and neurotransmitters to rapidly adapt cellular functions to shifting environmental conditions. The omnipresence of their cellular signaling in the regulation of mammalian physiology, coupled with a high 'druggability', has long made GPCRs a therapeutic target of choice for the treatment of many human diseases [1][2][3]. Pharmacological modulation of GPCR signaling is particularly relevant to the cardiovascular system, for which many GPCR agonists and antagonists have become the standard of care for several acute and chronic conditions such as hypertension, coronary artery disease, and heart failure [4].…”

Section: Introductionmentioning

confidence: 99%

Role of Ectopic Olfactory Receptors in the Regulation of the Cardiovascular–Kidney–Metabolic Axis

Beito,

Ashraf,

Odogwu

et al. 2024

Life

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Olfactory receptors (ORs) represent one of the largest yet least investigated families of G protein-coupled receptors in mammals. While initially believed to be functionally restricted to the detection and integration of odors at the olfactory epithelium, accumulating evidence points to a critical role for ectopically expressed ORs in the regulation of cellular homeostasis in extranasal tissues. This review aims to summarize the current state of knowledge on the expression and physiological functions of ectopic ORs in the cardiovascular system, kidneys, and primary metabolic organs and emphasizes how altered ectopic OR signaling in those tissues may impact cardiovascular–kidney–metabolic health.

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“…According to statistics, GPCR proteins account for 12% of the drug targets of proteins in the human body; among small molecule drugs, 33% are targeted at GPCR protein family. At the same time, they classified and summarized the approved drugs up to 2015 (without distinguishing small molecule drugs and biological drugs) for the four most popular targets of GPCR, nuclear receptor, ion channel and kinase, and found that the number of drugs developed based on GPCR targets was as many as 370, accounting for the largest proportion; and the ratio of the number of approved drugs in recent 5 years to the total number of approved drugs was also high, showing a rapid growth [1,2]. The above data show that GPCR, as a class of proteins that play an important role in the physiological and pathological processes of the human body, has always been one of the main targets of drug development.…”

Section: Introductionmentioning

confidence: 99%

Preparation scheme and research progress of GPCR antibody drugs

Yikai

2023

TNS

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As a class of proteins that play crucial roles in physiological and pathological processes within the human body, G protein-coupled receptors (GPCRs) have emerged as prominent targets for drug development. However, there is still ample room for improvement and replacement of currently developed drugs due to their inherent toxicity and associated side effects. In recent years, the attention has shifted towards antibody-based therapeutics targeting GPCRs, owing to their exceptional specificity and low plasma clearance rate. This review provides an overview of the fundamental preparation process and existing challenges encountered in developing GPCR antibody drugs, along with an introduction to several strategies employed in their formulation.

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Key aspects of modern GPCR drug discovery

Cited by 6 publications

References 138 publications

Physiological bias governs neutrophil inflammatory threat perception

Physiological bias governs neutrophil inflammatory threat perception

Role of Ectopic Olfactory Receptors in the Regulation of the Cardiovascular–Kidney–Metabolic Axis

Preparation scheme and research progress of GPCR antibody drugs

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