Anti-Infectives Research

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



1) Flaviviral protease and fusion inhibitors (e.g. Dengue and West Nile Viruses)

2) Respiratory Syncytial Virus inhibitors (RSV)

   3) Human Immunodeficiency Virus inhibitors (HIV)

   4) Antimalarial and Antischistosomal (inhibitors of Plasmodium and Schistoma proteins (e.g. HDACs, proteases)

   5) Quorum Sensing Pheromones (Competence Stimulating Peptides)

   6) Bacterial Synthesis of Vitamins (T cell activation)

 

PUBLICATIONS:

BACTERIA & ANTIBACTERIALS

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(7500), 361-365. doi:10.1038/nature13160.

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.

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.

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 Commun. 2013, doi: 10.1038/ncomms3142.

Rv2969c, essential for optimal growth in Mycobacterium tuberculosis, is a DsbA-like enzyme that interacts with VKOR-derived peptides and has atypical features of DsbA-like disulfide oxidases. Premkumar L, Heras B, Duprez W, Walden P, Halili M, Kurth F, Fairlie DP, Martin JL. Acta Cryst Sect D 2013, D69, 1981–1994.

Comparative Sequence, Structure and Redox Analyses of Klebsiella pneumoniae DsbA Show That Anti-Virulence Target DsbA Enzymes Fall into Distinct Classes. Kurth F, Rimmer K, Premkumar L, Mohanty B, Duprez W, Halili MA, Shouldice SR, Heras B, Fairlie DP, Scanlon MJ, Martin JL. PLoS One, 2013, 8(11), e80210. 

Targeting quorum sensing and competence stimulation for antibacterial chemotherapy. Shepherd NE, Harrison RS, Fairlie DP. Curr Drug Targets. 2012, 13(11), 1348-1359.

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 2012, 491, 717-723.

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 A2010107, 11686-11691.

 

 

DENGUE AND WEST NILE VIRUSES

An interaction between the methyltransferase and RNA dependent RNA polymerase domains of the West Nile virus NS5 protein. Tan CS, Hobson-Peters JM, Stoermer MA, Fairlie DP, Khromykh AA, Hall RA. J Gen Virol 201394, 1961-1971. 

In silico screening of small molecule libraries using the dengue virus envelope E protein has identified compounds with antiviral activity against multiple flaviviruses. Kampmann T, Yennamalli R, Campbell P, Stoermer MJ, Fairlie DP, Kobe B, Young PR. Antiviral Res. 2009, 84, 234-241. 

Structure of West Nile virus NS3 protease: ligand stabilization of the catalytic conformation. Robin G, Chappell K, Stoermer MJ, Hu SH, Young PR, Fairlie DP, Martin JL. J Mol Biol. 2009, 385, 1568-1577.

Potent cationic inhibitors of West Nile virus NS2B/NS3 protease with serum stability, cell permeability and antiviral activity. Stoermer MJ, Chappell KJ, Liebscher S, Jensen CM, Gan CH, Gupta PK, Xu WJ, Young PR, Fairlie DP. J Med Chem. 2008, 51, 5714-5721.

Mutagenesis of the West Nile virus NS2B cofactor domain reveals two regions essential for protease activity. Chappell KJ, Stoermer MJ, Fairlie DP, Young PR. J Gen Virol. 2008, 89, 1010-1014.

A dual-purpose synthetic colloidal platform for protease mapping: substrate profiling for Dengue and West Nile virus proteases. Marcon L, Kozak D, Battersby BJ, Chappell KJ, Fairlie DP, Young P, Trau M. Anal Biochem. 2008, 376, 151-153.

West Nile Virus NS2B/NS3 protease as an antiviral target. Chappell KJ, Stoermer MJ, Fairlie DP, Young PR. Curr Med Chem. 2008, 15, 2771-2784.

Substrate specificity of recombinant dengue 2 virus NS2B-NS3 protease: influence of natural and unnatural basic amino acids on hydrolysis of synthetic fluorescent substrates. Gouvea IE, Izidoro MA, Judice WA, Cezari MH, Caliendo G, Santagada V, dos Santos CN, Queiroz MH, Juliano MA, Young PR, Fairlie DP, Juliano L. Arch Biochem Biophys. 2007, 457, 187-196.

Generation and characterization of proteolytically active and highly stable truncated and full-length recombinant West Nile virus NS3. Chappell KJ, Stoermer MJ, Fairlie DP, Young PR. Protein Expr Purif. 2007, 53, 87-96.

Insights to substrate binding and processing by West Nile Virus NS3 protease through combined modeling, protease mutagenesis, and kinetic studies. Chappell KJ, Stoermer MJ, Fairlie DP, Young PR. J Biol Chem. 2006, 281, 38448-38458.

Site-directed mutagenesis and kinetic studies of the West Nile Virus NS3 protease identify key enzyme-substrate interactions. Chappell KJ, Nall TA, Stoermer MJ, Fang NX, Tyndall JD, Fairlie DP, Young PR. J Biol Chem. 2005, 280, 2896-2903.

Enzymatic characterization and homology model of a catalytically active recombinant West Nile virus NS3 protease. Nall TA, Chappell KJ, Stoermer MJ, Fang NX, Tyndall JD, Young PR, Fairlie DP. J Biol Chem. 2004, 279, 48535-48542.

Catalytically active Dengue virus NS3 protease forms aggregates that are separable by size exclusion chromatography. Arakaki TL, Fang NX, Fairlie DP, Young PR, Martin JL. Protein Expr Purif. 2002, 25, 241-247.

Activity of recombinant dengue 2 virus NS3 protease in the presence of a truncated NS2B co-factor, small peptide substrates, and inhibitors. Leung D, Schroder K, White H, Fang NX, Stoermer MJ, Abbenante G, Martin JL, Young PR, Fairlie DP. J Biol Chem. 2001, 276, 45762-45771. [>100 citations]   

Homology model of the dengue 2 virus NS3 protease: putative interactions with both substrate and NS2B cofactor. Brinkworth RI, Fairlie DP, Leung D, Young PR. J Gen Virol. 1999, 80, 1167-1177.

 

    RESPIRATORY SYNCITIAL VIRUS

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.

Modular alpha-helical mimetics with antiviral activity against respiratory syncitial virus. Shepherd NE, Hoang HN, Desai VS, Letouze E, Young PR, Fairlie DP. J Am Chem Soc. 2006, 128, 13284-13289.

 

   HUMAN IMMUNODEFICIENCY VIRUS

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. Helical cyclic pentapeptides constrain HIV-1 Rev peptide for enhanced RNA binding. Tetrahedron 2014, 70, 7645-7650 [special issue on cyclic peptides].

Update 1 of: Proteases universally recognize beta strands in their active sites. Madala PK, Tyndall JD, Nall T, Fairlie DP. Chem Rev. 2010, 110(6), PR1-31. [>100 citations]   

Update 1 of: Beta-strand mimetics. Loughlin WA, Tyndall JD, Glenn MP, Hill TA, Fairlie DP. Chem Rev. 2010, 110(6), PR32-69. [>100 citations]  

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.

Crystal structures of highly constrained substrate and hydrolysis products bound to HIV-1 protease. Implications for the catalytic mechanism. Tyndall JD, Pattenden LK, Reid RC, Hu SH, Alewood D, Alewood PF, Walsh T, Fairlie DP, Martin JL. Biochemistry. 2008, 47, 3736-3744.

Potencies of human immunodeficiency virus protease inhibitors in vitro against Plasmodium falciparum and in vivo against murine malaria. Andrews KT, Fairlie DP, Madala PK, Ray J, Wyatt DM, Hilton PM, Melville LA, Beattie L, Gardiner DL, Reid RC, Stoermer MJ, Skinner-Adams T, Berry C, McCarthy JS. Antimicrob Agents Chemother. 2006, 50, 639-648.

Protease inhibitors in the clinic. Abbenante G, Fairlie DP. Med Chem. 2005, 1, 71-104. [>100 citations]   

Countering cooperative effects in protease inhibitors using constrained beta-strand-mimicking templates in focused combinatorial libraries. Reid RC, Pattenden LK, Tyndall JD, Martin JL, Walsh T, Fairlie DP. J Med Chem. 2004, 47, 1641-1651.

Conformational selection of inhibitors and substrates by proteolytic enzymes: implications for drug design and polypeptide processing. Fairlie DP, Tyndall JD, Reid RC, Wong AK, Abbenante G, Scanlon MJ, March DR, Bergman DA, Chai CL, Burkett BA. J Med Chem. 2000, 43, 1271-1281. [>100 citations]   

Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease. Tyndall JD, Reid RC, Tyssen DP, Jardine DK, Todd B, Passmore M, March DR, Pattenden LK, Bergman DA, Alewood D, Hu SH, Alewood PF, Birch CJ, Martin JL, Fairlie DP. J Med Chem. 2000, 43, 3495-3504. 

Protease inhibitors: current status and future prospects. Leung D, Abbenante G, Fairlie DP. J Med Chem. 2000, 43, 305-341. [>600 citations]   

Molecular recognition of macrocyclic peptidomimetic inhibitors by HIV-1 protease. Martin JL, Begun J, Schindeler A, Wickramasinghe WA, Alewood D, Alewood PF, Bergman DA, Brinkworth RI, Abbenante G, March DR, Reid RC, Fairlie DP. Biochemistry. 1999, 38, 7978-7988.

Substrate-Based Cyclic Peptidomimetics of Phe-Ile-Val That Inhibit HIV-1 Protease Using A Novel Enzyme-Binding Mode, March, D. R.; Abbenante, G.; Bergman, D. A.; Brinkworth, R. I.; Wickramasinghe, W. A.; Begun, J.; Martin, J. L.; Fairlie, D. P. J. Am. Chem. Soc.1996, 118, 3375-79.

A Novel Bicyclic Enzyme Inhibitor As A Consensus Peptidomimetic For The Receptor-Bound Conformations of Twelve Peptidic Inhibitors Of HIV-1 Protease, Reid, R. C.; March, D. R.; Dooley, M.; Bergman, D. A.; Abbenante, G.; Fairlie, D. P. J. Am. Chem. Soc. 1996, 118, 8511-8517.

Structure-Activity Relationships for Macrocyclic Inhibitors Of HIV-1 Protease, Abbenante, G.; Bergman, D. A.; Brinkworth, R. I.; March, D. R.; Reid, R. C.; Hunt, P. A.; James, I. W.; Dancer, R. J.; Garnham, B.; Stoermer, M. L. Fairlie DP. Bioorg. Med. Chem. Lett. 1996, 6, 2531-2536.

Regioselective Structural and Functional Mimicry of Peptides. Design of Hydrolytically Stable Cyclic Peptidomimetic Inhibitors of HIV-1 Protease,  Abbenante, G.; March, D. R.; Bergman, D. A.; Hunt, P. A.; Garnham, B.; Dancer, R. J.; Martin, J. L.; Fairlie, D. P. J. Am. Chem. Soc. 1995, 117, 10220-10226.

NMR solution structure of the RNA-binding peptide from human immunodeficiency virus (type 1) Rev. Scanlon MJ, Fairlie DP, Craik DJ, Englebretsen DR, West ML. Biochemistry. 1995, 34, 8242-8249.

Hydroxyquinones are competitive non-peptide inhibitors of HIV-1 proteinase. Brinkworth RI, Fairlie DP. Biochim Biophys Acta. 1995, 1253, 5-8.

Macrocyclic Peptidomimetics : Forcing Peptides into Bioactive Conformations, Fairlie, D. P.; Abbenante, G.; March, D. Curr. Med. Chem. 1995, 2, 672-705. [>100 citations]   

Targeting HIV-1 protease: a test of drug-design methodologies. West ML, Fairlie DP. Trends Pharmacol Sci. 1995, 16, 67-75. [>100 citations] 

 

MALARIA, SCHISTOSOMIASIS, HOOKWORMS

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.

Towards Histone Deacetylase Inhibitors as New Antimalarial Drugs. Andrews KT, Tran TN, Fairlie DP. Curr Pharm Des. 2012, 18, 3467-3479. 

Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939. Sumanadasa SD, Goodman CD, Lucke AJ, Skinner-Adams T, Sahama I, Haque A, Do TA, McFadden GI, Fairlie DP, Andrews KT. Antimicrob Agents Chemother. 2012, 56, 3849-3856.

Comparative gene expression profiling of P. falciparum malaria parasites exposed to three different histone deacetylase inhibitors. Andrews KT, Gupta AP, Tran TN, Fairlie DP, Gobert GN, Bozdech Z. PLoS One. 2012, 7(2), e31847.

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.

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. 2010, 20, 7080-7084.

Targeting histone deacetylase inhibitors for anti-malarial therapy. Andrews KT, Tran TN, Wheatley NC, Fairlie DP. Curr Top Med Chem. 2009, 9, 292-308.

Potent antimalarial activity of histone deacetylase inhibitor analogues. Andrews KT, Tran TN, Lucke AJ, Kahnberg P, Le GT, Boyle GM, Gardiner DL, Skinner-Adams TS, Fairlie DP. Antimicrob Agents Chemother. 2008, 52, 1454-1461.

Potencies of human immunodeficiency virus protease inhibitors in vitro against Plasmodium falciparum and in vivo against murine malaria. Andrews KT, Fairlie DP, Madala PK, Ray J, Wyatt DM, Hilton PM, Melville LA, Beattie L, Gardiner DL, Reid RC, Stoermer MJ, Skinner-Adams T, Berry C, McCarthy JS. Antimicrob Agents Chemother. 2006, 50, 639-648.

Hookworm aspartic protease, Na-APR-2, cleaves human hemoglobin and serum proteins in a host-specific fashion. Williamson AL, Brindley PJ, Abbenante G, Datu BJ, Prociv P, Berry C, Girdwood K, Pritchard DI, Fairlie DP, Hotez PJ, Zhan B, Loukas A. J Infect Dis. 2003, 187, 484-494.

Cleavage of hemoglobin by hookworm cathepsin D aspartic proteases and its potential contribution to host specificity. Williamson AL, Brindley PJ, Abbenante G, Prociv P, Berry C, Girdwood K, Pritchard DI, Fairlie DP, Hotez PJ, Dalton JP, Loukas A. FASEB J. 2002, 16, 1458-1460.

Proteolysis of human hemoglobin by schistosome cathepsin D. Brindley PJ, Kalinna BH, Wong JY, Bogitsh BJ, King LT, Smyth DJ, Verity CK, Abbenante G, Brinkworth RI, Fairlie DP, Smythe ML, Milburn PJ, Bielefeldt-Ohmann H, Zheng Y, McManus DP. Mol Biochem Parasitol. 2001, 112, 103-112.

Anti-malarial effect of histone deacetylation inhibitors and mammalian tumour cytodifferentiating agents.
Andrews KT, Walduck A, Kelso MJ, Fairlie DP, Saul A, Parsons PG. Int J Parasitol. 2000, 30, 761-768.