Anti-Inflammatory Research

CHEMISTRY, BIOCHEMISTRY, PHARMACOLOGY, PROTEIN SURFACE MIMETICS, GPCR REGULATION, ENZYME REGULATION, ANTI-INFLAMMATORY RESEARCH, ANTI-INFECTIVES RESEARCH, ANTI-CANCER RESEARCH, NEURODEGENERATIVE RESEARCH, CARDIOVASCULAR RESEARCH


We target many proteins involved in inflammatory pathways; including secreted proteins from cells, GPCRs at the cell surface, signaling proteins in the cytoplasm, and enzymes in blood, in the cytoplasm, and in the cell nucleus. We are especially interested in selective regulation of intracellular signaling pathways and biased ligands for GPCRs. Some examples are:

1) Proteins involved in complement activation

2) Proteases and their targets in inflammatory events

3) Lipases and phospholipases

4) Histone deacetylases (especially class II HDACs)

5) GPCRs (including PAR2, C5aR, C5L2, C3aR, ORL-1)

  6) Targeting T cells, mast cells, neutrophils, macrophages

 

RECENT PUBLICATIONS (INFLAMMATION) :

2017

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.

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 201712, 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 A, He Y, Yau MK, Hooper JD, Fairlie DP. Pharmacol Res 2017117, 328-342.

Stabilising short-lived Schiff base derivatives of 5-aminouracils that activate mucosal-associated invariant T cells. Mak JYW, Xu W, Reid RC, Corbett AJ, Meehan B, Wang H, Chen Z, Rossjohn J, McCluskey J, Liu L*, Fairlie* DP. Nature Commun 20178, 14599.

Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells.  Keller AN, Eckle SBG, Xu W, Liu L, Hughes VA, Mak JYW, Meehan B, Pediongco T, Birkinshaw RW, Chen Z, Wang H, D’Souza C, Kjer-Nielsen L, Gheradin NA, Godfrey DI, Kostenko L, Corbett AJ, Purcell AW, Fairlie DP*, McCluskey J*, Rossjohn J*. Nature Immunol 201718, 402-411. 

Mucosal-associated invariant T cell activation and accumulation after in vivo infection depends on microbial riboflavin synthesis and co-stimulatory signals. Chen Z, Wang H, D’Souza C, Sun S, Kostenko L, Eckle SBG, Meehan BS, Jackson DC, Strugnell RA, Cao H, Wang N, Fairlie DP, Liu L, Godfrey DI, Rossjohn J, McCluskey J, Corbett AJ. Mucosal Immunology 201710, 58-68.

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.

An HDAC6 inhibitor confers protection and selectively inhibits B-cell infiltration in DSS-induced colitis in mice. Do A, Reid RC, Lohman RJ, Sweet MJ, Fairlie DP*, Iyer A*.  J Pharm Exp Ther 2017360, 140-151.

Histone deacetylases (HDAC) in physiological and pathological bone remodelling. Cantley MD, Zannettino AC, Bartold PM, Fairlie DP, Haynes DR. Bone 201795, 162-174.

 

2016

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.

Differential anti-inflammatory activity of low versus high dose HDAC inhibitors in human macrophages and collagen induced arthritis in rats. Lohman RJ, Iyer A, Fairlie TJ, Cotterell A, Gupta P, Reid RC, Vesey DA, Sweet MJ, Fairlie DP. J Pharmacol Exp Ther 2016356, 387-396. 

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.

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.

Histone deacetylase inhibitors promote mitochondrial reactive oxygen species production and bacterial clearance by human macrophages. Ariffin JK, das Gupta K, Kapetanovic R, Iyer A, Reid RC, Fairlie DP, Sweet MJ. Antimicrob Agents Chemother 201660, 1521-1529.

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.

Diversity of T Cells Restricted by the MHC Class I-Related Molecule MR1 Facilitates Differential Antigen Recognition. Gherardin NA, Keller AN, Woolley RE, Le Nours J, Ritchie DS, Neeson PJ, Birkinshaw RW, Eckle SB, Waddington JN, Liu L, Fairlie DP, Uldrich AP, Pellicci DG, McCluskey J, Godfrey DI, Rossjohn J. Immunity 201644, 32-45. ISI Highly Cited.

The intracellular pathway for the presentation of vitamin B-related antigens by the antigen-presenting molecule MR1. McWilliam HEG, Eckle SBG, Theodossis A, Liu L, Chen Z, Wubben JM, Fairlie DP, Strugnell RA, Mintern JD, McCluskey J, Rossjohn J, Villadangos JA. Nature Immunol 201617, 531-537.

A three-stage intrathymic development pathway for the mucosal-associated invariant T cell lineage. Koay HF, Gherardin NA, Enders A, Loh L, Mackay LK, Almeida CF, Russ BE, Nold-Petry CA, Nold MF, Bedoui S, Chen Z, Corbett AJ, Eckle SB, Meehan B, d'Udekem Y, Konstantinov IE, Lappas M, Liu L, Goodnow CC, Fairlie DP, Rossjohn J, Chong MM, Kedzierska K, Berzins SP, Belz GT, McCluskey J, Uldrich AP, Godfrey DI, Pellicci DG. Nature Immunol 2016, 17, 1300-1311. 

Human mucosal-associated invariant T cells contribute to antiviral influenza immunity via IL-18-dependent activation. Loh L, Wang Z, Sant S, Koutsakos M, Jegaskanda S, Corbett AJ, Liu L, Fairlie DP, Crowe J, Rossjohn J, Xu J, Doherty PC, McCluskey J, Kedzierska K. Proc Natl Acad Sci USA 2016113, 10133-10138. 

Histone deacetylases in monocyte/macrophage development, activation and metabolism: refining HDAC targets for inflammatory and infectious diseases. Das Gupta K, Shakespear MR, Iyer A, Fairlie DP, Sweet MJ. Clin Transl Immunology 20165(1), e62. 

 

2015

Nutrient And Immune Sensing Are Obligate Pathways In Metabolism, Immunity And Disease. Iyer A, Brown L, Whitehead JP, Prins JB, Fairlie DP. FASEB J 201529, 3612-3625.  

Inhibiting Histone Deacetylase 1 (HDAC 1) Suppresses both Inflammation and Bone Loss in Arthritis. Cantley MD, Fairlie DP, Bartold PM, Marino V, Gupta PK, Haynes DR. Rheumatology 201554, 1713-1723.

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 DP. J Med Chem 201558, 4080-4085.

Helix-constrained nociceptin peptides are potent agonists and antagonists of ORL-1 and nociception. Lohman RJ, Harrison RS, Ruiz-Gomez G, Hoang HN, Shepherd NE, Chow S, Hill TA, Madala PK, Fairlie DP. Vitamins and Hormones 201597, 1-55. 

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.

Functional heterogeneity and anti-mycobacterial effects of mouse mucosal associated invariant T (MAIT) cells specific for riboflavin metabolites. Sakala IG, Kjer-Nielsen L, Eickhoff CS, Wang X, Blazevic A, Liu L, Fairlie DP, Rossjohn J, McCluskey J, Hansen TH, Hoft DF.  J Immunol 2015195, 587-601. 

Identification of phenotypically and functionally heterogeneous mouse Mucosal Associated Invariant T cells using MR1 tetramers. Rahimpour A, Koay HF, Enders A, Clanchy R, Eckle SB, Meehan B, Chen Z, Whittle B, Liu L, Fairlie DP, Goodnow C, McCluskey J, Rossjohn J, Uldrich AP, Pellicci DG, Godfrey DI. J Exp Med 2015212, 1095-1108.

Flexibility versus Rigidity for Orally Bioavailable Cyclic Hexapeptides. Nielsen DS, Lohman RJ, Hoang HN, Hill TA, Jones A, Lucke AJ, Fairlie DP. Chembiochem 201516, 2289-2293. 

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 2015103, 175-184. 

Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites. Engel JA, Jones AJ, Avery VM, Sumanadasa SD, Ng SS, Fairlie DP, Adams TS, Andrews KT. Int J Parasitol Drugs Drug Resist 20155, 117-126.


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. 2014171, 1180-1194.

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 2014171, 4112-4124.

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 201474, 3454-3465.

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.

T cell activation by transitory neo-antigens derived from distinct microbial pathways. Corbett AJ, Eckle SBG, Birkinshaw RW, Liu L, Patel O, Mahony J, Chen Z, Reantra-goon R, Meehan B, Cao H, Williamson NA, Strugnell RA, Sinderen DV, Mak JYW, Fairlie DP*, Lars Kjer-Nielsen*, Rossjohn J*, McCluskey J*. Nature 2014, doi:10.1038/nature13160

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.

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.

A Molecular Basis Underpinning the T Cell Heterogeneity of Mucosal Associated Invariant T Cells. Eckle SBG, Birkinshaw RW, Kostenko L, Corbett AJ, McWilliam HEG, Reantragoon R, Chen Z, Gherardin NA, Beddoe T, Liu L, Patel O, Meehan B, Fairlie DP, Villadangos JA, Godfrey DI, Kjer-Nielsen L, McCluskey J, Rossjohn J. J Exp Med 2014, 211, 1585-1600.

 

Towards Drugs for Protease-Activated Receptor 2 (PAR2). Yau MK, Liu L, Fairlie DP. J Med Chem 2013, 56, 7477–7497.

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 20134, 2802. doi: 10.1038/ncomms3802.

Histone deacetylase 7 promotes Toll-like receptor 4-dependent pro-inflammatory gene expression in macrophages. Shakespear MR, Hohenhaus DM, Kelly GM, Kamal NA, Gupta P, Labzin LI, Schroder K, Garceau V, Barbero S, Iyer A, Hume DA, Reid RC, Irvine KM, Fairlie DP, Sweet MJ. J Biol Chem 2013, 288, 25362-25374.

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 2013, 27, 4757-4767. 

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.  Immunobiology2013, 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. 

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.

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, F737-750. 

An inhibitor of pla2g2a modulates adipocyte signaling and protects against diet-induced metabolic syndrome in rats. Iyer A, Lim J, Poudyal H, Reid RC, Suen JY, Webster J, Prins JB, Whitehead JP, Fairlie DP*, Brown L*. Diabetes 2012, 61, 2320-2329.

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.

HDACs and their inhibitors in immunology: teaching anticancer drugs new tricks. Fairlie DP, Sweet MJ. Immunol Cell Biol. 2012, 90, 3-5.

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 Ther. 2012, 340, 256-65.

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. 2012, 14, 30-9.

Towards isozyme-selective HDAC inhibitors for interrogating disease. Gupta P, Reid RC, Iyer A, Sweet MJ, Fairlie DP. Curr Top Med Chem2012, 12, 1479-1499.

HDAC inhibitors: modulating leukocyte differentiation, survival, proliferation and inflammation. Sweet MJ, Shakespear MR, Kamal NA, Fairlie DP. Immunol Cell Biol. 201290, 14-22.

Histone deacetylases as regulators of inflammation and immunity. Shakespear MR, Halili MA, Irvine KM, Fairlie DP, Sweet MJ. Trends Immunol. 2011, 32, 335-43.

Inhibitors of histone deacetylases in class I and class II suppress human osteoclasts in vitro. Cantley MD, Fairlie DP, Bartold PM, Rainsford KD, Le GT, Lucke AJ, Holding CA, Haynes DR. J Cell Physiol. 2011, 226, 3233-41.

Inflammatory lipid mediators in adipocyte function and obesity. Iyer, A.; Fairlie, D. P.; Prins J.; Hammock B. D.; Brown, L. Nature Reviews Endocrinology 20106, 71-82.

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 A. 2010, 107, 11686-11691. 

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. 

Novel agonists and antagonists for human protease activated receptor 2. Barry GD, Suen JY, Le GT, Cotterell A, Reid RC, Fairlie DP. J Med Chem. 2010, 53, 7428-40.

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. 2010, 53, 4938-48.

Non-covalent tripeptidylbenzyl and cyclohexyl amine inhibitors of the cysteine protease caspase-1. Löser R, Abbenante G, Madala PK, Halili M, Le GT, Fairlie DP. J. Med. Chem. 2010, 53, 2651-2655. 

Histone deacetylase inhibitors in inflammatory disease. Halili MA, Andrews MR, Sweet MJ, Fairlie DP. Curr Top Med Chem. 2009, 9, 309-19.

Intravenous immunoglobulin (IVIG) protects the brain against experimental stroke by preventing complement-mediated neuronal cell death. Arumugam TV, Tang S-C, Lathia JD, Cheng A, Mughal MR, Chigurupati S, Magnus T, Chan SL, Jo D-G, Ouyang X, Fairlie DP, Granger DN, Vortmeyer A, Basta M, Mattson MP. Proc. Natl. Acad. Sci. (USA)  2007, 104, 14104-14109.

Function, structure and therapeutic potential of complement C5a receptors. Monk PN, Scola AM, Madala P, Fairlie DP. Br J Pharmacol. 2007, 152, 429-48. [>100 citations]    

Nonpeptide ligands that target peptide-activated GPCRs in inflammation. Blakeney JS, Fairlie DP. Curr Med Chem. 2005, 12, 3027-42.

Therapeutic targets in inflammatory disease. Hume DA, Fairlie DP. Curr Med Chem. 2005, 12, 2925-9.