Medicinal Chemistry

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


Medicinal Chemistry principles underpin much of the chemistry research and subsequent biological research performed in the Fairlie Labs at the University of Queensland, St. Lucia in Brisbane, Australia.

Medicinal chemists in our group develop expertise in medicinal and organic chemistry using solution and solid phase organic synthesis; structure determination through 2D NMR spectroscopy; computer-aided drug design; and study interactions between small molecules and proteins, DNA and RNA. Outcomes are new chemical reactions, new chemical mechanisms, novel organic compounds, chemical structures, enzyme inhibitors, protein agonists and antagonists, and structural mimics of protein surfaces, as new leads to drugs and diagnostics.

Recent Papers:

2018

Chemical Approaches To Modulating Complement-Mediated Diseases. Iyer A, Xu W, Reid RC, Fairlie DP. J Med Chem 201861, 3253-3276.

Bicyclic Helical Peptides as Dual Inhibitors Selective for Bcl2A1 and Mcl-1 Proteins. de Araujo AD, Lim J, Wu KC, Xiang Y, Good AC, Skerlj R, Fairlie DP. J Med Chem 201861, 2962-2972.

Glucuronic acid as a helix-inducing linker in short peptides. Wu C, Hoang HN, Liu L, Fairlie DP. Chemical Communications 201854, 2162-2165. 

Chemically diverse helix-constrained peptides using selenocysteine crosslinking. Dantas de Araujo A, Perry SR, Fairlie DP. Org Lett 201820, 1453-1456. 

Contiguous hydrophobic and charged surface patches in short helix-constrained peptides drive cell permeability. Perry SR, Hill TA, de Araujo AD, Hoang HN, Fairlie DP. Org Biomol Chem 201816, 367-371. 

 

2017

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.

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. 

Orally Absorbed Cyclic Peptides. Nielsen DS, Shepherd NE, Xu W, Lucke AJ, Stoermer MJ, Fairlie DP. Chem Rev 2017117, 8094-8128. 

Electrophilic helical peptides that bind covalently, irreversibly and selectively in a protein-protein interaction site. Dantas de Araujo A, Lim J, Good AC, Skerlj RT, Fairlie DP*. ACS Med Chem Lett 20178, 22−26.

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. 

Downsizing Proto-oncogene cFos to Short Helix-Constrained Peptides That Bind Jun. Baxter D, Perry SR, Hill TA, Kok WM, Zaccai NR, Brady RL, Fairlie DP, Mason JM. ACS Chem Biol 2017, 12, 2051-2061. 

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 2017127, 703-714.

Total synthesis of the Mycobacterium tuberculosis dideoxymycobactin-838 and stereoisomers: Diverse CD1a-restricted T cells display a common hierarchy of lipopeptide recognition. Cheng JMH, Liu L, Pellicci DG, Reddiex S, Cotton RN, Cheng T-Y, Young DC, Van Rhijn I, Moody DB, Rossjohn J, Fairlie DP, Godfrey DI, Williams SJ. Chem Eur J 201723, 1694 – 1701.

Europium-Labeled Synthetic C3a Protein as a Novel Fluorescent Probe for Human Complement C3a Receptor. de Araujo AD, Wu C, Wu K-C, Reid RC, Durek T, Lim J, Fairlie DP. Bioconjugate Chem 2017, 28, 1669-1676.

Quinazolinone derivatives as inhibitors of homologous recombinase RAD51. Ward A, Dong L, Harris JM, Khanna KK, Al-Ejeha F, Fairlie DP, Wiegmans AP, Liu L. Bioorg Med Chem Lett 2017, 27, 3096-3100. 

Alpha helix nucleation by a simple cyclic tetrapeptide. Hoang HN, Wu C, Beyer RL, Hill TA, Fairlie DP. Aust J Chem 201770, 213–219. 

 

2016

Helix nucleation by the smallest known alpha helix in water. Hoang HN, Driver RW, Beyer RL, Hill TA, de Araujo AD, Plisson F, Harrison RS, Goedecke L, Shepherd NE, Fairlie DP. Angew Chem Int Edit 201655, 8275-8279.

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 20167, 1179-1184. 

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.

Downsizing the BAD BH3 peptide to small constrained α-helices with improved ligand efficiency. Shepherd NE, Harrison RS, Ruiz-Gomez G, Abbenante G, Mason JM, Fairlie DP. Org Biomol Chem 201614, 10939-10945. [special issue on cyclic peptides]

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. doi: 10.1038/srep24575.

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.

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 2016, 60, 1521-1529.  

Protease activated receptor 2 (PAR2) modulators: a patent review (2010-2015). Yau MK, Lim J, Liu L, Fairlie DP. Expert Opinion on Therapeutic Patents 201626, 471-483. 

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 2016173, 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.      

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 2016360, 140-151. 

Truncated glucagon-like peptide-1 and exendin-4 α-conotoxin pl14a peptide chimeras maintain potency, α-helicity and reveal interactions vital for cAMP signaling in vitro. Swedberg JE, Schroeder CI, Mitchell J, Fairlie DP, Edmonds DJ, Griffith DA, Ruggeri RB, Derksen DR, Loria PM, Price DA, Liras S, Craik DJ. J Biol Chem 2016291, 15778-15787.

Development of cell-penetrating peptide-based drug leads to inhibit MDMX:p53 and MDM2:p53 interactions. Philippe G, Huang YH, Cheneval O, Lawrence N, Zhang Z, Fairlie DP, Craik DJ, de Araujo AD, Henriques ST. Biopolymers 2016, 106, 853-863.

Stapling peptides using cysteine crosslinking. Fairlie DP, de Araujo AD. Biopolymers 2016106, 843-852. 


2015

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 2015, 58, 4080-4085.

Peptide inhibitors of the Escherichia coli DsbA oxidative machinery essential for bacterial virulence. Duprez W, Premkumar L, Halili M, Lindahl F, Reid RC, Fairlie DP*, Martin JL*. J Med Chem 201558, 577-587.

Small molecule inhibitors of disulfide bond formation by the bacterial DsbA-DsbB dual enzyme system. Halili MA, Bachu P, Lindahl F, Bechara C, Mohanty B, Reid RC, Scanlon MJ, Robinson CV, Fairlie DP*, Martin JL*. ACS Chem Biol 2015, 10, 957-964.

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 2015, 97, 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 2015, 25, 5604-5608.

Flexibility versus Rigidity for Orally Bioavailable Cyclic Hexapeptides. Nielsen DS, Lohman RJ, Hoang HN, Hill TA, Jones A, Lucke AJ, Fairlie DP. Chembiochem 2015, 16, 2289-2293. 

Recognition of Vitamin B precursors and byproducts by Mucosal Associated Invariant T cells. Eckle SB, Corbett AJ, Keller A, Chen Z, Godfrey DI, Liu L, Mak JY, Fairlie DP, Rossjohn J, McCluskey J. J Biol Chem 2015, 290, 30204-30211.

Toward peptide-based inhibitors as therapies for Parkinson's disease. Mason JM, Fairlie DP. Future Med Chem 2015, 7, 2103-2105.

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. 

Comparing Sixteen Scoring Functions for Predicting Biological Activities of Ligands for Protein Targets. Xu W, Lucke AJ, Fairlie DP. J Mol Graphics Modelling 2015, 57, 76-88.

Three Homology Models of PAR2 Derived from Different Templates: Applications 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.

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.

Virtual Screening of Peptide and Peptidomimetic Fragments Targeted to Inhibit Bacterial Dithiol Oxidase DsbA. Duprez W, Bachu P, Stoermer MJ, Tay S, McMahon RM, Fairlie DP, Martin JL. PLoS One 2015, 10(7): e0133805.

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 2015, 5, 117-126.

 

2014

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 2014136, 11914-11917. Recommended by 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 201457, 8459-8470. 

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, Reantragoon R, Meehan B, Cao H, Williamson NA, Strugnell RA, Sinderen DV, Mak JYW, Fairlie DP*, Lars Kjer-Nielsen*, Rossjohn J*, McCluskey J*. Nature 2014, 509, 361-365. ISI Highly Cited.

Improving on Nature: Making a Cyclic Heptapeptide Orally Bioavailable. Nielsen DS, Hoang HN, Lohman RJ, Hill TA, Lucke AJ, Craik DJ, Edmonds DJ, Griffith DA, Rotter CJ, Ruggeri RB, Price DA, Liras S, Fairlie DP. Angew Chem Int Edit 2014, 53, 12059-12063.

Constraining Cyclic Peptides To Mimic Protein Structure Motifs. Hill TA, Shepherd NE, Diness F, Fairlie DP. Angew Chem Int Edit 2014, 53, 13020-13041.

Comparative Alpha Helicity of Cyclic Pentapeptides in Water. de Araujo AD, Hoang HN, Kok WM, Diness F, Gupta G, Hill TA, Driver RW, Price DA, Liras S, Fairlie DP. Angew Chem Int Edit 201453, 6965-6999.

Rational design and synthesis of orally bioavailable peptides guided by NMR amide temperature coefficients. Wang CK, Northfield SE, Colless B, Chaousis S, Hamernig I, Lohman RJ, Nielsen D, Schroeder CI, Liras S, Price D, Fairlie DP, Craik DJ. Proc Natl Acad Sci USA 2014, 111, 17504-17509.

Cyclic Penta- and Hexa- Leucine Peptides Without N-Methylation Are Orally AbsorbedHill TA, Lohman RJ, Hoang HN, Nielsen DS, Scully CCG, Kok WM, Liu L, Lucke AJ, Stoermer MJ, Schroeder CI, Chaousis S, Colless B, Bernhardt PV, Edmonds DJ, Griffith DA, Rotter CJ, Ruggeri RB, Price DA, Liras S, Craik DJ, Fairlie DP. ACS Med Chem Lett 2014, 5, 1148-1151. Recommended by Faculty1000Prime. 

Helical cyclic pentapeptides constrain HIV-1 Rev peptide for enhanced RNA binding. Harrison RS, Shepherd NE, Hoang HN, Beyer RL, Ruiz-Gómez G, Kelso MJ, WM Kok, TA Hill, Abbenante G, Fairlie DP. Tetrahedron 201470, 7645-7650. [special issue on cyclic peptides].

Crystal Structure of the Dithiol Oxidase DsbA Enzyme from Proteus Mirabilis Bound Non-Covalently to an Active Site Peptide Ligand.Kurth F, Duprez W, Premkumar L, Schembri M, Fairlie DP, Martin JL. J Biol Chem 2014, 289, 19810-19822.

Lysine acetylation in sexual stage malaria parasites is a target for antimalarial small molecules. Trenholme K, Marek L, Duffy S, Pradel G, Fisher G, Hansen FK, Skinner-Adams TS, Butterworth A, Julius Ngwa C, Moecking J, Goodman CD, McFadden GI, Sumanadasa SD, Fairlie DP, Avery VM, Kurz T, Andrews KT. Antimicrob Agents Chemother 2014, 58, 3666-3678.

 

2013

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

Downsizing a human inflammatory protein to a small molecule with equal potency and functionality. Reid RC, Yau MK, 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.

Recognition of vitamin B metabolites by mucosal-associated invariant T cells. Patel O, Kjer-Nielsen L, Nours JL, Eckle SBG, Bikinshaw R, Beddoe T, Corbett AJ, Liu L, Miles JJ, Mehan B, Reantragoon R, Sandoval-Romero ML, Sullivan LC, Brooks AG, Chen Z, Fairlie DP, McCluskey J, Rossjohn J. Nature Communications 2013, 4, 2142. doi: 10.1038/ncomms3142. 

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 201349, 2356-2358.

The Future of Peptide-based Drugs. Craik DJ, Fairlie DP, Liras S, Price D. Chem Biol Drug Des201381, 136-147. ISI Highly Cited. ISI Hot Paper.

Truncated and helix-constrained peptides with high affinity and specificity for the cFos coiled-coil of AP-1. Rao T, Ruiz-Gómez G, Hill TA, Hoang HN, Fairlie DP, Mason JM. PLoS One 2013, 8(3), e59415.

 

2012

Catalyst-Free N-arylation Using Unactivated Fluorobenzenes. Diness F, Fairlie DP. Angew. Chem. Int. Edit. 201251, 8012-8016.

MR1 presents microbial vitamin B metabolites to MAIT cells. Kjer-Nielsen L, Patel O, Nours JL, Meehan B, Corbett AJ, Liu L, Bhati M, Chen Z, Kostenko L, Reantragoon R, Williamson NA, Purcell AW, Dudek NL, McConville MJ, O’Hair RAJ, Khairallah GN, Godfrey DI, Fairlie DP, Rossjohn J, McCluskey J. Nature 2012491, 717-723. ISI Highly Cited.

Total Synthesis, Structure, and Oral Absorption of a Thiazole Cyclic Peptide, Sanguinamide A. Nielsen DS, Hoang HN, Lohman RJ, Diness F, Fairlie DP. Org Lett 201214, 5720–5723.

Folding pentapeptides into left and right handed alpha helices. Hoang, HN, Abbenante G, Hill TA, Ruiz-Gomez G, Fairlie DP. Tetrahedron, 201268, 4513–4516.

 

2011

Protein Alpha Turns Recreated in Structurally Stable Small Molecules. Hoang HN, Driver RW, Beyer RL, Malde AK, Le GT, Abbenante G, Mark AE, Fairlie DP. Angew Chem Int Ed Engl 201150, 11107-11111. 

VIP: Amyloid Formation from an α-Helix Peptide Bundle Is Seeded by 310-Helix Aggregates. Singh Y, Sharpe PC, Hoang HN, Lucke AJ, McDowall AW, Bottomley SP, Fairlie DP. Chem Eur J  2011,17, 151-160. 

Synthesis of the Thiazole-Thiazoline Fragment of Largazole Analogues. Diness F, Nielsen DS, Fairlie DP. J Org Chem 201176, 9845-9851. 

Ex Vivo Activity of Histone Deacetylase Inhibitors against Multidrug-Resistant Clinical Isolates of Plasmodium falciparum and P. vivax. Marfurt J, Chalfein F, Prayoga P, Wabiser F, Kenangalem E, Piera KA, Fairlie DP, Tjitra E, Anstey NM, Andrews KT, Price RN. Antimicrob Agents Chemother 2011, 55, 961-966. 

 

2010

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 agonists and antagonists for human protease activated receptor 2. Barry GD, Suen JY, Le GT, Cotterell A, Reid RC, Fairlie DP. J Med Chem 201053, 7428-7440. 

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 201053, 8400–8408. 

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 201053, 2651-2655. 

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, 4938-4948. 

Update 1 of: Over One Hundred Peptide-Activated G Protein-Coupled Receptors Recognize Ligands with Turn Structure. Gloria Ruiz-Gmez, Joel D. A. Tyndall, Bernhard Pfeiffer, Giovanni Abbenante and David P. Fairlie. Chemical Reviews2010110(4), PR1-PR41.

Update 1 of: Proteases Universally Recognize Beta Strands in their active sites. Madala PK, Tyndall JD, Nall T, Fairlie DP. Chemical Reviews 2010110(6), PR1-PR31.

Update 1 of: Beta-Strand Mimetics. Loughlin WA, Tyndall JD, Glenn MP, Hill TA, Fairlie DP. Chemical Reviews 2010110(6), PR32-PR69.

Inhibitors Selective For HDAC6 In Enzymes and Cells. Gupta PK, Reid RC, Liu L, Lucke AJ, Broomfield SA, Andrews MR, Sweet MJ, Fairlie DP. Bioorg Med Chem Lett 201020, 7067-7070. 

Antimalarial Histone Deacetylase Inhibitors Containing Cinnamate or NSAID Components. Wheatley NC, Andrews KT, Tran TL, Lucke AJ, Reid RC, Fairlie DP. Bioorg Med Chem Lett 201020, 7080-7084.