Toward Drugs for Protease-Activated Receptor 2 (PAR2)

Yau, Mei-Kwan; Liu, Ligong; Fairlie, David P.

doi:10.1021/jm400638v

Cited by 75 publications

(86 citation statements)

References 192 publications

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“…Regulates Both mRNA and MicroRNA Expression-Numerous studies have shown that PAR-2 activation induces G␣-mediated signaling, mobilizing intracellular calcium and Nf-B signaling, and leading to increased expression of pro-inflammatory mRNAs (11)(12)(13)(14)(15). To determine whether PAR-2 activation in OSCC cell lines induces expression of candidate mRNAs known to be associated with inflammation in OSCC, expression of three pro-inflammatory genes known to be regulated downstream of PAR-2 activation was evaluated (27,39,40).…”

Section: Par-2 Activationmentioning

confidence: 99%

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Protease-activated Receptor-2 (PAR-2)-mediated Nf-κB Activation Suppresses Inflammation-associated Tumor Suppressor MicroRNAs in Oral Squamous Cell Carcinoma

Johnson

Miller

Jiang

et al. 2016

Journal of Biological Chemistry

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Oral cancer is the sixth most common cause of death from cancer with an estimated 400,000 deaths worldwide and a low (50%) 5-year survival rate. The most common form of oral cancer is oral squamous cell carcinoma (OSCC). OSCC is highly inflammatory and invasive, and the degree of inflammation correlates with tumor aggressiveness. The G protein-coupled receptor protease-activated receptor-2 (PAR-2) plays a key role in inflammation. PAR-2 is activated via proteolytic cleavage by trypsin-like serine proteases, including kallikrein-5 (KLK5), or by treatment with activating peptides. PAR-2 activation induces G protein-␣-mediated signaling, mobilizing intracellular calcium and Nf-B signaling, leading to the increased expression of pro-inflammatory mRNAs. Little is known, however, about PAR-2 regulation of inflammation-related microRNAs. Here, we assess PAR-2 expression and function in OSCC cell lines and tissues. Stimulation of PAR-2 activates Nf-B signaling, resulting in RelA nuclear translocation and enhanced expression of pro-inflammatory mRNAs. Concomitantly, suppression of the anti-inflammatory tumor suppressor microRNAs let-7d, miR-23b, and miR-200c was observed following PAR-2 stimulation. Analysis of orthotopic oral tumors generated by cells with reduced KLK5 expression showed smaller, less aggressive lesions with reduced inflammatory infiltrate relative to tumors generated by KLK5-expressing control cells. Together, these data support a model wherein KLK5-mediated PAR-2 activation regulates the expression of inflammation-associated mRNAs and microRNAs, thereby modulating progression of oral tumors. Squamous cell carcinoma of the oral cavity (OSCC)2 is a highly inflammatory disease that ranks as the 6th most frequently diagnosed cancer worldwide, with a poor 5-year survival rate of about 50% (1). Early diagnosis of OSCC is challenging, predominantly because early oral cancers and premalignant lesions are often subtle and asymptomatic. Although many patients present for diagnosis with stage III or IV disease, premalignant lesions in the oral mucosa often precede invasive OSCC (2). Furthermore, unlike most solid tumors that are monoclonal in origin, multiple distinct foci of dysplastic cells may be present in the oral mucosa. These epithelial dysplasia are categorized as mild, moderate, severe, or carcinoma in situ based on the histologic abnormalities present in the oral epithelium (3). Studies show that ϳ12-36% of epithelial dysplasia progress to carcinoma (4, 5); however, current approaches do not enable accurate identification of premalignant lesions likely to undergo malignant transformation.The link between inflammation and cancer is now well established, and inflammatory mediators are present in the microenvironment of virtually all solid tumors (6 -10). Many studies have associated proteinase-activated receptor-2 (PAR-2) with both inflammation and tumor progression (11-15); however, the expression of PAR-2 in OSCC has not been evaluated. PAR-2 is a G protein-coupled receptor that is activated by trypsin-...

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Section: Par-2 Activationmentioning

confidence: 99%

“…Many studies have associated proteinase-activated receptor-2 (PAR-2) with both inflammation and tumor progression (11)(12)(13)(14)(15); however, the expression of PAR-2 in OSCC has not been evaluated. PAR-2 is a G protein-coupled receptor that is activated by trypsin-like serine proteinases.…”

mentioning

confidence: 99%

Protease-activated Receptor-2 (PAR-2)-mediated Nf-κB Activation Suppresses Inflammation-associated Tumor Suppressor MicroRNAs in Oral Squamous Cell Carcinoma

Johnson

Miller

Jiang

et al. 2016

Journal of Biological Chemistry

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“…However, no improvement was observed. 182 Instead, this peptide (8) had similar potency to 2f-LIGRLI-NH 2 (7,EC 50 0.2 μM) in iCa 2+ release assay on HT29 cells. 182 In the same paper, a series of heterocycles and aromatic substitutents (9) were substituted for the serine residue of SLIGRLI-NH 2 (3), with 4-(2-methyloxazolyl), 5-isoxazolyl, 2-pyrazoyl, 2-pyridoyl, 3-pyridoyl, 2-benzofuranoyl, 2-naphthoyl, 2-benzothienyl, and others, all producing potent agonists with EC 50 0.1−0.3 μM (iCa 2+ , HT29 cells).…”

Section: ■ Par2 Agonistsmentioning

confidence: 83%

“…182 Instead, this peptide (8) had similar potency to 2f-LIGRLI-NH 2 (7,EC 50 0.2 μM) in iCa 2+ release assay on HT29 cells. 182 In the same paper, a series of heterocycles and aromatic substitutents (9) were substituted for the serine residue of SLIGRLI-NH 2 (3), with 4-(2-methyloxazolyl), 5-isoxazolyl, 2-pyrazoyl, 2-pyridoyl, 3-pyridoyl, 2-benzofuranoyl, 2-naphthoyl, 2-benzothienyl, and others, all producing potent agonists with EC 50 0.1−0.3 μM (iCa 2+ , HT29 cells). 182 Recently, the serine of SLIGRL-NH 2 was similarly replaced with closely related heterocycles, 2-aminothiazol-4-oyl (2-at) and 6-aminonicotinoyl (6-an), to also produce agonist analogues of 2f-LIGRLO-NH 2 (2), activating both Ca 2+ and MAPK signaling with comparable potency to the above.…”

Section: ■ Par2 Agonistsmentioning

confidence: 83%

“…180 This peptide remains one of the most potent PAR2 agonists reported to date for cells (EC 50 0.2 μM), as measured by iCa 2+ mobilization. 171,180,181 It has also been reported that addition of a seventh residue, such as isoleucine (3), to the C-terminus of SLIGRL-NH 2 increased potency by ∼6-fold 182,183 and that replacing the sixth residue leucine with aromatic groups, such as tyrosine (4), 4-nitrophenylalanine (5), or 3,4-dichlorophenylalanine (6), increased potency further (Table 3). 182 Therefore, it was expected that substituting the sixth residue leucine of 2f-LIGRLI-NH 2 peptide (7) with a 4-nitrophenylalanine group (8) could also improve agonist potency.…”

Section: ■ Par2 Agonistsmentioning

confidence: 94%

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Novel agonists & antagonists for protease-activated receptor 2 and C3a receptor

Yau¹

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About 30-40% of all drugs currently in the market place target G-protein coupled receptors, however of the 900 plus GPCRs predicted to exist only about 30 are targeted by approved drugs. Two novel human GPCRs were investigated in this thesis, namely protease-activated receptor 2 (PAR2) and C3a receptor (C3aR). These membranebound receptors are implicated in a variety of diseases in which inflammation is a common component, making them attractive targets for drugs that can treat such disorders. This thesis describes the rational design, synthesis and in vitro assay of ligands targeting these two GPCRs and they will become useful probes for investigating the pathology of inflammatory disorders and may lead to possible future treatments.Chapter 1 of this thesis summarises peptidic and non-peptidic ligands for proteaseactivated receptor and C3a receptor reported in the literature to date, together with their known physiological effects.Chapter 2 examines structure-activity relationships for analogues of the only known potent PAR2 antagonist (GB88) discovered at IMB. The chemical features of GB88 were investigated separately by dividing the molecule into fragments, which were independently varied to study the effect of structure on agonist/antagonist function of the ligands. A potent and selective PAR2 agonist (132) was developed with EC 50 of 0.4 µM in calcium release assays on HT29 cells. Agonist 132 has comparable agonist potency and better ligand efficiency to 2f-LIGRLO-NH 2 , which was previously the most potent PAR2 agonist prior to these studies. In addition, a new PAR2 antagonist was developed (167), which was 2-fold more potent than GB88 in the calcium mobilisation assay.Chapter 3 describes the non-peptidic PAR2 agonist (GB110) and SAR studies for the truncation of this compound that led to the development of new PAR2 antagonists (192, 209, 211, 212). These ligands inhibited the activation of PAR2 induced by 1 µM 2f-LIGRLO-NH 2 with IC 50 0.4-0.6 µM in the calcium release assay.Chapter 4 evaluates the anti-inflammatory properties of newly developed PAR2antagonists (133, 159, 167, 192 -from Chapters 2 & 3) in both in vivo and in vitro experiments. The most potent PAR2 antagonists (167 and 192) were stable in rat plasma and rat liver homogenates and were able to inhibit PAR2 activation induced by peptide agonist 2f-LIGRLO-NH 2 as well as the endogenous activator, trypsin. These iv antagonists have been demonstrated to be anti-inflammatory agents, inhibiting proinflammatory cytokine release (IL6 and TNF-α) and were effective in relieving joint inflammation in rat models of arthritis.Chapter 5 explores various aromatic heterocycles that confer a turn conformation to ligands and this mimics the turn conformation observed for the C-terminus of C3a in its crystal structure. The study investigates how the hydrogen bonding capabilities of heteroatoms in each heterocycle affect the binding and functions of the ligands.Increasing the hydrogen bond acceptor properties of the heterocycle improves binding affinity...

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Pain pathways and potential new targets for pain relief

Thyagarajan

2020

Biotech and App Biochem

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Pain is an unpleasant sensory and emotional experience that affects a sizable percentage of people on a daily basis. Sensory neurons known as nociceptors built specifically to detect damaging stimuli can be found throughout the body. They transmit information about noxious stimuli from mechanical, thermal, and chemical sources to the central nervous system and higher brain centers via electrical signals. Nociceptors express various channels and receptors such as voltage-gated sodium and calcium channels, transient receptor potential channels, and opioid receptors that allow them to respond in a highly specific manner to noxious stimuli. Attenuating the pain response can be achieved by inhibiting or altering the expression of these pain targets. Achieving a deeper understanding of how these receptors can be affected at the molecular level can lead to the development of novel pain therapies. This review will discuss the mechanisms of pain, introduce the various receptors that are responsible for detecting pain, and future directions in pharmacological therapies.

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Toward Drugs for Protease-Activated Receptor 2 (PAR2)

Cited by 75 publications

References 192 publications

Protease-activated Receptor-2 (PAR-2)-mediated Nf-κB Activation Suppresses Inflammation-associated Tumor Suppressor MicroRNAs in Oral Squamous Cell Carcinoma

Protease-activated Receptor-2 (PAR-2)-mediated Nf-κB Activation Suppresses Inflammation-associated Tumor Suppressor MicroRNAs in Oral Squamous Cell Carcinoma

Novel agonists & antagonists for protease-activated receptor 2 and C3a receptor

Pain pathways and potential new targets for pain relief

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