G Protein Coupled Receptors



We are especially interested in small molecule drugs that can modulate G protein-coupled receptors (GPCR) activated by proteins and peptides (e.g. Tyndall et al, Chem. Rev. 2005). Our chemistry researchers design and develop potent and selective non-peptide agonists and antagonists and study the molecular basis for agonist and antagonist activities. Our pharmacologists investigate the effects of our novel compounds on intracellular signaling pathways and in animal models of inflammatory, metabolic, cardiovascular and other diseases. We design biased ligands and harness their properties to obtain greater control over therapeutic profiles (e.g. Blakeney et al, Chem. Rev. 2007).


GPCRs in General: Selected Publications

Crystal Structures of Protein-Bound Cyclic Peptides. Malde AK, Hill TA, Iyer A, Fairlie DP. Chem Rev 2019, 119, 9861-9914.

Orally Absorbed Cyclic Peptides. Nielsen DS, Shepherd NE, Xu W, Lucke AJ, Stoermer MJ, Fairlie DP. Chem Rev2017117, 8094-8128.

Matching Cavities in G Protein-Coupled Receptors to Infer Ligand-Binding Sites. Madala PK, Fairlie DP, Bodén M. J Chem Inf Model 2012, 52, 1401-1410.

Update 1 of: Over one hundred peptide-activated G protein-coupled receptors recognize ligands with turn structure. Ruiz-Gómez G, Tyndall JD, Pfeiffer B, Abbenante G, Fairlie DP. Chem Rev2010110(4), PR1-41.

Nonpeptidic ligands for peptide-activated G protein-coupled receptors. Blakeney JS, Reid RC, Le GT, Fairlie DP. Chem Rev2007107(7), 2960-3041.

Nonpeptide ligands that target peptide-activated GPCRs in inflammation. Blakeney JS, Fairlie DP. Curr Med Chem. 2005, 12(25), 3027-3042.

Over one hundred peptide-activated G protein-coupled receptors recognize ligands with turn structure. Tyndall JD, Pfeiffer B, Abbenante G, Fairlie DP. Chem Rev. 2005, 105(3), 793-826. [>100 citations]


Complement GPCRs: Recent Publications

Potent thiophene antagonists of human complement C3a receptor with anti-inflammatory activity. Rowley JA, Reid RC, Poon EKY, Wu KC, Lim J, Lohman RJ, Hamidon JK, Yau MK, Halili MA, Durek T, Iyer A, Fairlie DP. J Med Chem 2020, 63, 529-541. 

Complement C3a and C5a receptors promote GVHD by suppressing mitophagy in recipient dendritic cells. Nguyen H, Kuril S, Bastian D, Kim J, Zhang M, Vaena SG, Dany M, Dai M, Heinrichs JL, Daenthanasanmak A, Iamsawat S, Schutt S, Fu J, Wu Y, Fairlie DP, Atkinson C, Ogretmen B, Tomlinson S, Yu XZ. JCI Insight 2018, 3(24). pii: 121697. 

Chemical Approaches To Modulating Complement-Mediated Diseases. Iyer A, Xu W, Reid RC, Fairlie DP. J Med Chem 2018, 61, 3253-3276.

The ribosomal protein S19 suppresses antitumor immune responses via the complement C5a receptor 1. Vadrevu SK, Sharma SK, Chintala NK, Cho J-H, Patel J, Patel B, Fairlie DP, Paterson Y, Astrinidis A, Karbowniczek M, Markiewski MM. J Immunol 2017, 198, 2989-2999.

Exploiting a novel conformational switch to control innate immunity mediated by complement protein C3a. Lohman R-J, Hamidon JK, Reid RC, Rowley JA, Yau M-K, Halili MA, Nielsen DS, Lim J, Wu K-C, Loh Z, Do A, Suen JY, Iyer A, Fairlie DP. Nature Commun 20178, 351.

Europium-Labeled Synthetic C3a Protein as a Novel Fluorescent Probe for Human Complement C3a Receptor. Dantas de Araujo A, Wu C, Wu KC, Reid RC, Durek T, Lim J, Fairlie DP. Bioconjug Chem 201728, 1669-1676.

Receptor residence time trumps drug-likeness and oral bioavailability in determining efficacy of complement C5a antagonists. Seow V, Lim J, Cotterell AJ, Yau MK, Xu W, Lohman RJ, Kok WM, Stoermer MJ, Sweet MJ, Reid RC, Suen JY, Fairlie DP. Science Reports 20166, 24575.

Potent complement C3a receptor agonists derived from oxazole amino acids: Structure-activity relationships. Singh R, Reed AN, Chu P, Scully CC, Yau MK, Suen JY, Durek T, Reid RC, Fairlie DP. Bioorg Med Chem Lett 201525, 5604-5608.

Stereoelectronic effects dictate molecular conformation and biological function of heterocyclic amides. Reid RC, Yau MK, Singh R, Lim J, Fairlie DP. J Am Chem Soc 2014, 136, 11914-11917. Faculty1000Prime.

Potent Heterocyclic Ligands for Human Complement C3a Receptor Reid RC, Yau M-K, Singh R, Hamidon JK, Lim J, Stoermer MJ, Fairlie DP. J Med Chem 2014, 57, 8459-8470. 

Complement C5a receptor facilitates cancer metastasis by altering T cell responses in the metastatic niche. Vadrevu SK, Chintala NK, Sharma SK, Sharma P, Cleveland C, Riediger L, Manne S, Fairlie DP, Gorczyca W, Almanza O, Karbowniczek M, Markiewski MM. Cancer Research 2014, 74, 3454-3465.

C5aR and C5L2 act in concert to balance immunometabolism in adipose tissue. Poursharifi P, Lapointe M, Fisette A, Lu H, Roy C, Munkonda MN, Fairlie DP, Cianflone K. Molecular and Cellular Endocrinology 2014, 382, 325-333.

Downsizing a Human Inflammatory Protein to a Small Molecule with Equal Potency and Functionality. Reid RC, Yau M-K, Singh R, Hamidon JK, Reed AN, Chu P, Suen JY, Stoermer MJ, Blakeney JS, Lim J, Faber JM, Fairlie DP. Nature Communications 2013, 4, 2802. doi: 10.1038/ncomms3802.

C5aR and C3aR antagonists each inhibit diet-induced obesity, metabolic dysfunction, and adipocyte and macrophage signaling. Lim J, Iyer A, Suen JY, Seow V, Reid RC, Brown L, Fairlie DP. FASEB J. 201327, 822-831.

An mRNA atlas of G protein-coupled receptor expression during primary human monocyte/macrophage differentiation and lipopolysaccharide-mediated activation identifies targetable candidate regulators of inflammation. Hohenhaus DM, Schaale K, Le Cao KA, Seow V, Iyer A, Fairlie DP, Sweet MJ.  Immunobiology. 2013, 218, 1345-1353. 

Inflammatory responses induced by lipopolysaccharide are amplified in primary human monocytes but suppressed in macrophages by complement protein C5a. Seow V, Lim J, Iyer A, Suen JY, Ariffin JK, Hohenhaus DM, Sweet MJ, Fairlie DP. J Immunol 2013, 191, 4308-4316.

Efficient chemical synthesis of human complement protein C3a. Ghassemian A, Wang CI, Yau MK, Reid RC, Lewis RJ, Fairlie DP, Alerwood PF, Durek T. Chem Commun 2013, 49, 2356-2358.

C5a receptor (CD88) inhibition improves hypothermia-induced neuroprotection in an in vitro ischemic model. Thundyil J, Pavlovski D, Hsieh YH, Gelderblom M, Magnus T, Fairlie DP, Arumugam TV. Neuromolecular Med. 201214(1), 30-39.

Selective hexapeptide agonists and antagonists for human complement C3a receptor. Scully CC, Blakeney JS, Singh R, Hoang HN, Abbenante G, Reid RC, Fairlie DP. J Med Chem. 201053(13), 4938-4948.

Function, structure and therapeutic potential of complement C5a receptors. Monk PN, Scola AM, Madala P, Fairlie DP. Br J Pharmacol.2007152(4), 429-448. [>100 citations]   

Intravenous immunoglobulin (IVIG) protects the brain against experimental stroke by preventing complement-mediated neuronal cell death. Arumugam TV, Tang SC, Lathia JD, Cheng A, Mughal MR, Chigurupati S, Magnus T, Chan SL, Jo DG, Ouyang X,Fairlie DP, Granger DN, Vortmeyer A, Basta M, Mattson MP. Proc Natl Acad Sci U S A. 2007104(35), 14104-14109. [>100 citations] 

The role of the N-terminal domain of the complement fragment receptor C5L2 in ligand binding. Scola AM, Higginbottom A, Partridge LJ, Reid RC, Woodruff T, Taylor SM, Fairlie DP, Monk PN. J Biol Chem. 2007, 282(6), 3664-3371.

Comparative agonist/antagonist responses in mutant human C5a receptors define the ligand binding site. Higginbottom A, Cain SA, Woodruff TM, Proctor LM, Madala PK, Tyndall JD, Taylor SM, Fairlie DP, Monk PN. J Biol Chem. 2005, 280(18), 17831-17840.

Potent cyclic antagonists of the complement C5a receptor on human polymorphonuclear leukocytes. Relationships between structures and activity. March DR, Proctor LM, Stoermer MJ, Sbaglia R, Abbenante G, Reid RC, Woodruff TM, Wadi K, Paczkowski N, Tyndall JD, Taylor SM, Fairlie DP. Mol Pharmacol. 200465(4), 868-879.


Protease Activated Receptor 2: Recent Publications 

PAR2 induces ovarian cancer cell motility by merging three signalling pathways to transactivate EGFR. Jiang Y, Lim J, Wu KC, Xu W, Suen JY, Fairlie DP. Br J Pharmacol 2021, 178, 913-932.

Activation of protease‐activated receptor 2 is associated with blood pressure regulation and proteinuria reduction in metabolic syndromeMaruyama‐Fumoto K, McGuire JJ, Fairlie DP, Shinozuka K, Kagota S. Clin Exp Pharmacol Physiol 2021, 48, 211-220.

PAR2 activation on human kidney tubular epithelial cells induces tissue factor synthesis that enhances blood clotting.Iyer A, Humphries TLR, Owens EP, Zhao K, Masci P, Johnson DW, Nikolic-Paterson D, Gobe G, Fairlie DP, Vesey DA. Frontiers in Physiology, Renal and Epithelial Physiology 2021, 12, 615428. 

Protease-activated receptor-2 ligands reveal orthosteric and allosteric mechanisms of receptor inhibition.Kennedy AJ, Sundström L, Geschwindner S, Poon EKY, Jiang Y, Chen R, Cooke R, Johnstone S, Madin A, Lim J, Liu Q, Lohman RJ, Nordqvist A, Fridén-Saxin M, Yang W, Brown DG, Fairlie DP, Dekker N. Commun Biol 2020, 3(1), 782. 

Pharmacological inhibition of protease-activated receptor-2 reduces crescent formation in rat nephrotoxic serum nephritis. Han Y, Tian L, Ma F, Tesch G, Vesey DA, Gobe GC, Lohman RJ, Morais C, Suen JY, Fairlie DP, Nikolic-Paterson DJ. Clin Exp Pharmacol Physiol 2019, 46, 456-464. 

Protease-activated receptor 2 does not contribute to renal inflammation or fibrosis in the obstructed kidney. Ma FY, Han Y, Ozols E, Chew P, Vesey DA, Gobe GC, Morais C, Lohman RJ, Suen JY, Johnson DW, Fairlie DP, Nikolic-Paterson DJ. Nephrology (Carlton) 201924, 983-991. 

A potent antagonist of protease-activated receptor 2 that inhibits multiple signaling functions in human cancer cells. Jiang Y, Yau MK, Lim J, Wu KC, Xu W, Suen JY, Fairlie DP. J Pharmacol Exp Ther 2018, 364, 246-257.

Protease activated receptor 2 controls myelin development, resiliency and repair. Yoon H, Radulovic M, Walters G, Paulsen AR, Drucker K, Starski P, Wu J, Fairlie DP, Scarisbrick IA. Glia 2017, 65, 2070-2086. 

Biased signaling by agonists of protease activated receptor 2. Jiang Y, Yau M-K, Kok WM, Lim J, Wu K-C, Liu L, Hill TA, Suen JY, Fairlie DP. ACS Chem Biol 2017, 12, 1217-1226. 

Mapping transmembrane residues of proteinase activated receptor 2 (PAR2) that influence ligand-modulated calcium signaling. Suen JY, Adams MN, Lim J, Madala PK, Xu W, Cotterell AJ, He Y, Yau MK, Hooper JD, Fairlie DP. Pharmacol Research 2017, 117, 328-342.

PAR2 modulators derived from GB88. Yau MK, Liu L, Suen JY, Lim J, Lohman RJ, Cotterell AJ, Barry GD, Mak JYC, Vesey DA, Reid RC, Fairlie DP. ACS Med Chem Lett 2016, 7, 1179-1184.

Antagonism of the proinflammatory and pronociceptive actions of canonical and biased agonists of protease-activated receptor-2. Lieu T, Savage E, Zhao P, Edgington-Mitchell L, Barlow N, Bron R, Poole DP, McLean P, Lohman RJ, Fairlie DP, Bunnett NW. Br J Pharmacol 2016, 173, 2752-2765. 

Inhibition of membrane-anchored serine protease matriptase reduces experimental pulmonary fibrosis. Bardou O, François C, Menou A, Jvon der Thüsen J, Borie R, Castier Y, Sage E, Liu L, Fairlie DP, Königshoff M, Crestani B, Borensztajn K. American Journal of Respiratory and Critical Care Medicine2016193, 847-860.

Potent Small Agonists Of Protease Activated Receptor 2. Yau MK, Suen JY, Xu W, Lim J, Liu L, Adams MN, He Y, Hooper JD, Reid RC, Fairlie DP. ACS Med Chem Lett 20167, 105–110.

Benzylamide antagonists of protease activated receptor 2 with anti-inflammatory activity. Yau MK, Liu L, Lim J, Lohman RJ, Cotterell AJ, Suen JY, Vesey DA, Reid RC, Fairlie DP. Bioorg Med Chem Lett 201626, 986-991.

Protease activated receptor 2 (PAR2) modulators: a patent review (2010-2015). Yau MK, Lim J, Liu L, Fairlie DP. Expert Opin Ther Pat. 2016, 26, 471-483.

Repurposing Registered Drugs as Antagonists for Protease-Activated Receptor 2. Xu W, Lim J, Goh CY, Suen JY, Jiang Y, Yau MK, Wu KC, Liu L, Fairlie DP. J Chem Inf Model. 2015, 55, 2079-2084.  

Three Homology Models of PAR2 Derived from Different Templates: Application to Antagonist Discovery.Perry SR, Xu W, Wirija A, Lim J, Yau MK, Stoermer MJ, Lucke AJ, Fairlie DP. J Chem Inf Model. 2015, 55, 1181-1191.

Pathway Selective Antagonism Of Proteinase Activated Receptor 2. Suen JY, Cotterell A, Lohman RJ, Han A, Yau MK, Liu L, Cooper MA, Vesey DA, Fairlie DP. Br J Pharmacol 2014, 171, 4112-4124. 

Biased Signalling and Proteinase-Activated Receptors (PARs): Targeting Inflammatory Disease.Hollenberg MD, Mihara K, Polley D, Suen JY, Han A, Fairlie DP, Ramachandran R. Br J Pharmacol. 2014,  171, 1180-94.

Diet-Induced Obesity, Adipose Tissue Inflammation And Metabolic Dysfunction Correlating With PAR2 Expression Are Attenuated By A PAR2 Antagonist. Lim J, Iyer A, Suen JY, Liu L, Lohman RJ, Seow V, Yau MK, Brown L, Fairlie DP. FASEB J 201327, 4757-4767.

Towards Drugs for Protease-Activated Receptor 2 (PAR2). Yau MK, Liu L, Fairlie DP. J Med Chem 201356, 7477–7497.

PAR2-induced inflammatory responses in human kidney tubular epithelial cells. Vesey DA, Suen JY, Seow V, Lohman RJ, Liu L, Gobe GC, Johnson DW, Fairlie DP. Am J Physiol Renal Physiol. 2013, 304(6), F737-F750. 

An antagonist of human protease activated receptor-2 attenuates PAR2 signaling, macrophage activation, mast cell degranulation, and collagen-induced arthritis in rats. Lohman RJ, Cotterell AJ, Barry GD, Liu L, Suen JY, Vesey DA, Fairlie DP. FASEB J. 201226, 2877-2887.

Structures of peptide agonists for human protease activated receptor 2. Stoermer MJ, Flanagan B, Beyer RL, Madala PK, Fairlie DP. Bioorg Med Chem Lett2012, 22(2), 916-919.

Antagonism of protease-activated receptor 2 protects against experimental colitis. Lohman RJ, Cotterell AJ, Suen J, Liu L, Do AT, Vesey DA, Fairlie DP. J Pharmacol Exp Ther2012, 340(2), 256-265.

Modulating human proteinase activated receptor 2 with a novel antagonist (GB88) and agonist (GB110). Suen JY, Barry GD, Lohman RJ, Halili MA, Cotterell AJ, Le GT, Fairlie DP. Br J Pharmacol. 2012,165(5), 1413-1423.

Structure, function and pathophysiology of protease activated receptors. Adams MN, Ramachandran R, Yau MK, Suen JY, Fairlie DP, Hollenberg MD, Hooper JD. Pharmacol Ther2011, 130(3), 248-282.

Profiling gene expression induced by protease-activated receptor 2 (PAR2) activation in human kidney cells. Suen JY, Gardiner B, Grimmond S, Fairlie DP. PLoS One20105(11), e13809.

Novel agonists and antagonists for human protease activated receptor 2. Barry GD, Suen JY, Le GT, Cotterell A, Reid RC, Fairlie DP. J Med Chem2010, 53(20), 7428-7440.

A refined agonist pharmacophore for protease activated receptor 2. Barry GD, Suen JY, Low HB, Pfeiffer B, Flanagan B, Halili M, Le GT, Fairlie DP. Bioorg Med Chem Lett2007, 17(20), 5552-5557.

Protease-activated receptor-2 peptides activate neurokinin-1 receptors in the mouse isolated trachea. Abey HT, Fairlie DP, Moffatt JD, Balzary RW, Cocks TM. J Pharmacol Exp Ther2006317(2), 598-605.

Agonists and antagonists of protease activated receptors (PARs). Barry GD, Le GT, Fairlie DP. Curr Med Chem. 2006, 13(3), 243-265.


Opioid Receptor Like Receptor: Recent Publications

Helix-Constrained Nociceptin Peptides Are Potent Agonists and Antagonists of ORL-1 and Nociception. Lohman RJ, Harrison RS, Ruiz-Gómez GG, Hoang HN, Shepherd NE, Chow S, Hill TA, Madala PK, Fairlie DP. Vitamins and Hormones201597, 1–55.

Novel Helix-Constrained Nociceptin Derivatives Are Potent Agonists and Antagonists of ERK Phosphorylation and Thermal Analgesia in Mice. Harrison RS, Ruiz-Gómez G, Hill TA, Chow SY, Shepherd NE, Lohman RJ, Abbenante G, Hoang HN, Fairlie DP. J Med Chem. 2010, 53, 8400–8408. 

Downsizing human, bacterial, and viral proteins to short water-stable alpha helices that maintain biological potency. Harrison RS, Shepherd NE, Hoang HN, Ruiz-Gómez G, Hill TA, Driver RW, Desai VS, Young PR, Abbenante G, Fairlie DP. Proc Natl Acad Sci U S A2010, 107(26), 11686-11691.

Glucagon Like Peptide Receptor 1: Recent Publications 

Helix-constraints and amino acid substitution in GLP-1 increase cAMP and insulin secretion but not beta arrestin 2 signalling. Plisson F, Hill TA, Mitchell JM, Hoang HN, de Araujo AD, Xu W, Cotterell A, Edmonds DJ, Stanton RV, Derksen DR, Loria PM, Griffith DA, Price DA, Liras S, Fairlie DP*. Eur J Med Chem 2017, 127, 703-714.

Truncated Glucagon-like Peptide-1 and Exendin-4 α-Conotoxin pl14a Peptide Chimeras Maintain Potency and α-Helicity and Reveal Interactions Vital for cAMP Signaling in Vitro. Swedberg JE, Schroeder CI, Mitchell JM, Fairlie DP, Edmonds DJ, Griffith DA, Ruggeri RB, Derksen DR, Loria PM, Price DA, Liras S, Craik DJ. J Biol Chem 2016291, 15778-15787.

Cyclic alpha-conotoxin peptidomimetic chimeras as potent GLP-1R agonists. Swedberg JE, Schroeder CI, Mitchell JM, Durek T, Fairlie DP, Edmonds DJ, Griffith DA, Ruggeri RB, Derksen DR, Loria PM, Liras S, Price DA, Craik DJ. Eur J Med Chem 2015, 103, 175-184.

Short Hydrophobic Peptides with Cyclic Constraints Are Potent Glucagon-like Peptide-1 Receptor (GLP-1R) Agonists. Hoang HN, Song K, Hill TA, Derksen DR, Edmonds DJ, Kok WM, Limberakis C, Liras S, Loria PM, Mascitti V, Mathiowetz AM, Mitchell JM, Piotrowski DW, Price DA, Stanton RV, Suen JY, Withka JM, Griffith DA, Fairlie DPJ Med Chem. 2015, 58, 4080-4085.