Small molecules targeting heterotrimeric G proteins

Ayoub, Mohammed Akli

doi:10.1016/j.ejphar.2018.03.003

Cited by 18 publications

(19 citation statements)

References 77 publications

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“…Given that YM-254890 at nano-mole level inhibited multiple Gs-coupled receptors' signaling to cAMP and the ERK1/2 pathways without affecting forskolin-induced cAMP generation, it is reasonable to conclude that in addition to the Gq proteins, the Gs proteins may be a previously unrecognized target for YM-254890. Although our finding challenged the view of YM-254890 as a selective Gq protein inhibitor, it should be noted that as of today there is no potent Gs protein inhibitor available on the market except for Cholera toxin acting as a permanent activator of Gs proteins (20) and few suramin analogs unselectively blocking Gs proteins at >10 µM (21,22). From this point of view, YM-254890 may be a good parental molecule to be used for further synthesis of highly selective and potent Gs protein blocker for research and maybe clinical use as well.…”

Section: Discussioncontrasting

confidence: 76%

Functional evidence for biased inhibition of G protein signaling by YM-254890 in human coronary artery endothelial cells

Peng

Alqahtani

Nasrullah

et al. 2021

European Journal of Pharmacology

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G protein-coupled receptor (GPCR) has been the primary therapeutic targets for many diseases. Agonists and antagonists of various GPCR are estimated to occupy approximately 35% of the drug market (1). Extracellular signals perceived by GPCR are transmitted via G proteins and trigger intracellular signaling cascades resulting in a plethora of physiological responses. G proteins usually are categorized into four main classical subfamilies according to their α subunits: Gαq/11, Gαs, Gαi/o, Gα12/13 (2). Main subunits Gαq/11, Gαs, Gαi/o and G12/13 are commonly thought to be coupled with phospholipase C (PLC), adenylyl cyclase activation, adenylyl cyclase inactivation, and other small GTPase families, respectively (3). Gαq/11 activates phospholipase Cβ pathway leading to intracellular Ca 2+ mobilization. Gαs and Gαi/o proteins regulate adenylyl cyclase activation and inhibition, respectively, which control intracellular cAMP level. Thus, G proteins are important signal transducing molecules for various cellular responses. Malfunction of GPCR signaling pathways are involved in many diseases, such as diabetes, cardiovascular diseases, and certain forms of cancers (4).

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Section: Discussioncontrasting

confidence: 76%

Functional evidence for biased inhibition of G protein signaling by YM-254890 in human coronary artery endothelial cells

Peng

Alqahtani

Nasrullah

et al. 2021

European Journal of Pharmacology

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“…G protein coupled receptors are the most common molecular targets of clinically-relevant drug therapies – at this moment nearly 50% of all therapies are directed at the heterotrimeric G protein signaling GPCR states ( Ayoub, 2018 ). However, it is now clear that the seven-transmembrane receptors can signal through β-arrestins in a clinically-relevant manner.…”

Section: Discussionmentioning

confidence: 99%

β-Arrestin Based Receptor Signaling Paradigms: Potential Therapeutic Targets for Complex Age-Related Disorders

et al. 2018

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G protein coupled receptors (GPCRs) were first characterized as signal transducers that elicit downstream effects through modulation of guanine (G) nucleotide-binding proteins. The pharmacotherapeutic exploitation of this signaling paradigm has created a drug-based field covering nearly 50% of the current pharmacopeia. Since the groundbreaking discoveries of the late 1990s to the present day, it is now clear however that GPCRs can also generate productive signaling cascades through the modulation of β-arrestin functionality. β-Arrestins were first thought to only regulate receptor desensitization and internalization – exemplified by the action of visual arrestin with respect to rhodopsin desensitization. Nearly 20 years ago, it was found that rather than controlling GPCR signal termination, productive β-arrestin dependent GPCR signaling paradigms were highly dependent on multi-protein complex formation and generated long-lasting cellular effects, in contrast to G protein signaling which is transient and functions through soluble second messenger systems. β-Arrestin signaling was then first shown to activate mitogen activated protein kinase signaling in a G protein-independent manner and eventually initiate protein transcription – thus controlling expression patterns of downstream proteins. While the possibility of developing β-arrestin biased or functionally selective ligands is now being investigated, no additional research has been performed on its possible contextual specificity in treating age-related disorders. The ability of β-arrestin-dependent signaling to control complex and multidimensional protein expression patterns makes this therapeutic strategy feasible, as treating complex age-related disorders will likely require therapeutics that can exert network-level efficacy profiles. It is our understanding that therapeutically targeting G protein-independent effectors such as β-arrestin will aid in the development of precision medicines with tailored efficacy profiles for disease/age-specific contextualities.

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“…Arrestins and G proteins have different nonoverlapping functions and play important roles in GPCRs signaling [29]. G protein dependent mechanism result in GDP to GTP exchange on the Gαi subunit and triggers the activation of second messenger signaling and multiple intracellular pathways such a cyclic adenosine 3', 5' monophosphate (cAMP), inositol triphosphate (IP3), Ca 2+ , diacylglycerol (DAG), mitogen-activated protein kinase (MAP kinase) and Rho/Rac [30]. Whereas arrestins mechanism involve the GPCRs phosphorylation by GPCR kinases (GRK), which trigger the recruitment of β-arrestins causing GPCR desensitization and internalization, initiating a G-protein independent wave of downstream signaling [31].…”

Section: Discussionmentioning

confidence: 99%

Amino Terminal Recognition by a CCR6 Chemokine Receptor Antibody Blocks CCL20 Signaling and IL-17 Expression via β-arrestin

Gómez-Melero¹,

Garcı́a-Maceira²,

García-Maceira³

et al. 2021

Preprint

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Background: CCR6 chemokine receptor is an important target in inflammatory diseases. Th17 cells express CCR6 and a number of inflammatory cytokines, including IL-17 and IL-22, which are involved in the propagation of inflammatory immune responses. CCR6 antagonist would be a potential treatment for inflammatory diseases such as psoriasis or rheumatoid arthritis. The aim of this study is to develop an antagonistic monoclonal antibody (mAb) against human CCR6 receptor (hCCR6).Results: We generate monoclonal antibodies against hCCR6 immunizing Balb/c mice with hCCR6 overexpressing cells. The antibodies were tested by flow cytometry for specific binding to hCCR6, cloned by limiting dilution and resulted in the isolation and purification monoclonal antibody 1C6. By ELISA and flow cytometry, was determined that the antibody obtained binds to hCCR6 N-terminal domain. The ability of 1C6 to neutralize hCCR6 signaling was tested and we determined that 1C6 antibody were able to block response in β-arrestin recruitment assay with IC50 10.23 nM, but did not inhibit calcium mobilization. In addition, we found in a chemotaxis assay that 1C6 reduces the migration of hCCR6 cells to their ligand CCL20. Finally, we determined by RT-qPCR that the expression of IL-17A in Th17 cells treated with 1C6 was inhibited.Conclusions: In the present study, we applied whole cell immunization for successfully obtain an antibody that is capable to neutralize hCCR6 signaling and to reduce hCCR6 cells migration and IL-17 expression. These results provide an efficient approach to obtain therapeutic potential antibodies in the treatment of CCR6-mediated inflammatory diseases.

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Small molecules targeting heterotrimeric G proteins

Cited by 18 publications

References 77 publications

Functional evidence for biased inhibition of G protein signaling by YM-254890 in human coronary artery endothelial cells

Functional evidence for biased inhibition of G protein signaling by YM-254890 in human coronary artery endothelial cells

β-Arrestin Based Receptor Signaling Paradigms: Potential Therapeutic Targets for Complex Age-Related Disorders

Amino Terminal Recognition by a CCR6 Chemokine Receptor Antibody Blocks CCL20 Signaling and IL-17 Expression via β-arrestin

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