Lipopeptide Pepducins as Therapeutic Agents

Michael, Emily; Covic, Lidija; Kuliopulos, Athan

doi:10.1007/978-1-0716-1752-6_21

Cited by 11 publications

(7 citation statements)

References 125 publications

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“…It remains to be determined if blockade of PAR2 translates into superior glycemic control and better clinical outcomes in patients as indicated by significant drops in HbA1c in severely diabetic mice that received a PAR2 pepducin inhibitor. Given the multipronged beneficial effects of the liver‐homing pepducin on glucose homeostasis, fibrosis, and steatosis, PZ‐235 and its derivatives will be explored for therapeutic purposes [ 21 ] and may offer certain advantages over current monotherapies, especially in the diabetic NASH population.…”

Section: Discussionmentioning

confidence: 99%

PAR2 promotes impaired glucose uptake and insulin resistance in NAFLD through GLUT2 and Akt interference

et al. 2022

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Background and Aims: Insulin resistance and poor glycemic control are key drivers of the development of NAFLD and have recently been shown to be associated with fibrosis progression in NASH. However, the underlying mechanisms involving dysfunctional glucose metabolism and relationship with NAFLD/NASH progression remain poorly understood. We set out to determine whether protease-activated receptor 2 (PAR2), a sensor of extracellular inflammatory and coagulation proteases, links NAFLD and NASH with liver glucose metabolism. Approach and Results:Here, we demonstrate that hepatic expression of PAR2 increases in patients and mice with diabetes and NAFLD/NASH. Mechanistic studies using whole-body and liver-specific PAR2-knockout mice reveal that hepatic PAR2 plays an unexpected role in suppressing glucose internalization, glycogen storage, and insulin signaling through a bifurcating G q -dependent mechanism. PAR2 activation downregulates the major glucose transporter of liver, GLUT2, through G q -MAPK-FoxA3 and inhibits insulin-Akt signaling through G q -calcium-CaMKK2 pathways. Therapeutic dosing with a liver-homing pepducin, PZ-235, blocked PAR2-G q signaling and afforded significant improvements in glycemic indices and HbA1c levels in severely diabetic mice. Conclusions:This work provides evidence that PAR2 is a major regulator of liver glucose homeostasis and a potential target for the treatment of diabetes and NASH.

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Section: Discussionmentioning

confidence: 99%

PAR2 promotes impaired glucose uptake and insulin resistance in NAFLD through GLUT2 and Akt interference

et al. 2022

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“…The greatest success in the creation of allosteric regulators of PAR1, PAR2, and PAR4 is due to the development of pepducins, which are lipidated derivatives of their ICLs [ 246 , 274 , 275 , 276 , 277 , 278 , 279 , 280 ] ( Figure 3 ).…”

Section: Allosteric Regulators Of Proteinase-activated Receptorsmentioning

confidence: 99%

“…PZ-128 did not affect bleeding, coagulation, biochemical and metabolic parameters, and electrocardiogram parameters and the drug was well tolerated when administered intravenously at a dose of 0.5 mg/kg. Currently, PZ-128 has successfully completed clinical trials (phase 2) in patients with cardiovascular disease demonstrating safety and efficacy in the suppression of myonecrosis and arterial thrombosis [ 280 ].…”

Section: Allosteric Regulators Of Proteinase-activated Receptorsmentioning

confidence: 99%

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

2023

IJMS

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Allosteric regulation is critical for the functioning of G protein-coupled receptors (GPCRs) and their signaling pathways. Endogenous allosteric regulators of GPCRs are simple ions, various biomolecules, and protein components of GPCR signaling (G proteins and β-arrestins). The stability and functional activity of GPCR complexes is also due to multicenter allosteric interactions between protomers. The complexity of allosteric effects caused by numerous regulators differing in structure, availability, and mechanisms of action predetermines the multiplicity and different topology of allosteric sites in GPCRs. These sites can be localized in extracellular loops; inside the transmembrane tunnel and in its upper and lower vestibules; in cytoplasmic loops; and on the outer, membrane-contacting surface of the transmembrane domain. They are involved in the regulation of basal and orthosteric agonist-stimulated receptor activity, biased agonism, GPCR-complex formation, and endocytosis. They are targets for a large number of synthetic allosteric regulators and modulators, including those constructed using molecular docking. The review is devoted to the principles and mechanisms of GPCRs allosteric regulation, the multiplicity of allosteric sites and their topology, and the endogenous and synthetic allosteric regulators, including autoantibodies and pepducins. The allosteric regulation of chemokine receptors, proteinase-activated receptors, thyroid-stimulating and luteinizing hormone receptors, and beta-adrenergic receptors are described in more detail.

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“…Its effect required the presence of both PAR1 and PAR2, which indicates that the target of pepducin is the PAR1-PAR2 complex. This complex is also a target for Palm-RSSAMDENSEKKRKSAIK [270][271][272][273][274][275][276][277][278][279][280][281][282][283][284][285][286][287] (P2pal-18S), an ICL3 derivative of PAR2 that inhibits migration of neutrophils and cholangiocarcinoma cells stimulated by both trypsin (PAR1-agonist) and selective PAR2-agonists [286,287].…”

Section: -277] (Figure 2)mentioning

confidence: 99%

“…PZ-128 did not affect bleeding, coagulation, biochemical and metabolic parameters, electrocardiogram parameters, and the drug was well tolerated when administered intravenously at a dose of 0.5 mg/kg. Currently, PZ-128 has successfully completed clinical trials (phase 2) in patients with cardiovascular disease, demonstrating safety and efficacy in the suppression of myonecrosis and arterial thrombosis[277].The longer pepducin Pal-RCLSSSAVANRSKKSRALF (P1pal-19), in contrast to P1pal-12 and P1pal-7, demonstrated full PAR1-agonist activity and stimulated Gq/11-and Gi/o-proteins, similar to selective PAR1-agonists[271,281]. This indicates that the modification of the structure of PAR-pepducins not only affects the efficiency and selectivity of their action, but also changes their pharmacological profile.A significant progress has been made in the development of PAR1-pepducins with antitumor activity[242,276].…”

mentioning

confidence: 99%

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

Ao¹

2023

Preprint

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A separate group consists of compounds that are able to simultaneously interact with both orthosteric and allosteric sites, which are classified as bitopic GPCR ligands [74, 76-81]. They have two pharmacophores, one of which binds with high affinity to the orthosteric site, while the other, with lower affinity, binds to the allosteric site. If these sites are spatially separated in the receptor, then the pharmacophores in the bitopic ligand must be connected with a flexible linker, the length of which exactly corresponds to the distance between the orthosteric and allosteric sites. At the same time, it is important that the linker does not significantly affect the conformational rearrangements in the receptor caused by its activation by orthosteric and (or) allosteric agonists [74, 79].

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Lipopeptide Pepducins as Therapeutic Agents

Cited by 11 publications

References 125 publications

PAR2 promotes impaired glucose uptake and insulin resistance in NAFLD through GLUT2 and Akt interference

PAR2 promotes impaired glucose uptake and insulin resistance in NAFLD through GLUT2 and Akt interference

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

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