Enzyme Regulation


We use computer-assisted methods to design small organic compounds that can bind to enzymes in substrate-binding grooves (competitive inhibitors) or at more remote sites (non-competitive inhibitors) thereby preventing or down-regulating enzyme activity in vitro and in animal models of disease. We are experts in developing inhibitors of enzymes, including proteases, histone deacetylases, phospholipases, complement enzymes, viral and inflammatory enzymes. Some examples are inhibitors of :

1) NS2B-NS3 proteases from Flaviviruses such as Dengue and West Nile Viruses.

2) Aspartyl proteases (e.g. HIV protease, Schistosomal Cathepsin D, Plasmepsins).

3) Complement serine proteases such as C2, C3 convertase, Factor B.

4) Cysteine proteases (e.g. Caspase 1 (ICE), Caspases 3, 8, Cathepsins B,K and S).

5) Histone deacetylases (e.g. HDAC6, HDAC7).

6) Phosphlipases A2 (e.g. pla2g2a, pla2g5).

Figure. Inhibitors of Proteases: (Left) : Antiviral protease inhibitor (Ki 9 nM) of the heterodimeric NS2B-NS3 protease from West Nile Virus docked (GOLD) into the active site of the protease (Stoermer et. al, 2008) . (Right) Non-covalent Inhibitor of Caspase-1 that blocks formation of interleukin 1 beta.


General Enzyme Inhibitors

Proteases Universally Recognize Beta Strands In Their Active Sites. Tyndall, J. D. A.; Nall, T.; Fairlie, D. P. Chem. Reviews  2005, 105, 973-1000. [>100 citations]                    

Protease Inhibitors in the Clinic. Abbenante, G.; Fairlie, D. P. Medicinal Chemistry 2005, 1, 71-104. [>100 citations]

Conformational Selection Of Inhibitors and Substrates By Proteolytic Enzymes : Implications for Drug Design and Polypeptide Processing. Fairlie, D. P.; Tyndall, J. D. A.; Reid, R. C.; Wong, A. K.; Abbenante, G.; Scanlon, M. J.; March, D. R.; Bergman, D. A.;  Chai, C. L. L.; Burkett, B. A. J. Med. Chem. 2000, 43, 1271-1281. [> 100 citations] 

Protease Inhibitors: Current Status and Future Prospects. Leung D, Abbenante G, Fairlie DP. J. Med. Chem. 2000, 43, 305-341. [>600 citations]

Conformational Homogeneity In Molecular Recognition By Proteolytic Enzymes. Tyndall, J.; Fairlie, D. P. J. Molecular Recognition 1999, 12, 363-370.

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

Aspartic Protease Inhibitors

Crystal Structures of Highly Constrained Substrate and Hydrolysis Products Bound to HIV-1 Protease. Implications for Catalytic Mechanism. Tyndall, J. D. A.; Pattenden, L. K.; Reid, R. C.; Hu, S.-H.; Alewood, D.; Alewood, P. F.; Walsh, T.; Fairlie, D. P.; Martin, J. L. Biochemistry 2008, 47, 3736-44.

Countering cooperative effects in protease inhibitors using constrained beta strand-mimicking templates in focussed combinatorial libraries. Reid, R. C.; Pattenden, L. K.; Tyndall, J. D. A.; Martin, J. L.; Walsh, T.; Fairlie, D. P. J. Med. Chem. 2004, 47, 1641-51.                              

Beta strand mimicking macrocyclic amino acids. Templates for protease inhibitors with antiviral activity. Glenn, M. P.; Pattenden, L. K.; Reid, R. C.; Tyssen, D. P.; Tyndall, J. D. A.; Birch, C. J.; Fairlie, D. P. J. Med. Chem. 2002, 45, 371-381. 

Synthesis, Stability, Antiviral Activity, and Protease-Bound Structures of Substrate-Mimicking Constrained Macrocyclic Inhibitors of HIV-1 Protease. Tyndall, J. D. A.; Reid, R. C.; Tyssen, D. P.; Jardine, D. K.; Todd, B.; Passmore , M.; March, D. R.; Pattenden, L. K.; Bergman, D. A.; Alewood, D.; Hu, S-H.; Alewood, P. F.; Birch, C. J.; Martin, J. L.; Fairlie, D. P.  J. Med. Chem. 2000, 43, 3495-3504. 

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, 7978-88.

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, 3375-3379.

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, DP.  J. Am. Chem. Soc. 1995, 117, 10220-10226.

Serine Protease Inhibitors

Complement Factor C2, Inhibiting A Latent Serine Protease In The Classical Pathway Of Complement Activation. Halili MA, Ruiz-Gómez G, Le GT, Abbenante G, Fairlie DP. Biochemistry 2009, 48, 8466–8472. 

Structure activity relationships for substrate based inhibitors of human complement factor B. Ruiz-Gómez, G.; Lim, J.; Halili, MA; Le, GT; Madala, PK; Abbenante G.; Fairlie DP J Med Chem 2009, 52, 6042-6052. 

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, 5714-21. 

Profiling the enzymatic properties and inhibition of human complement factor B. Le, G.T.; Abbenante, G.; Fairlie, D.P. J. Biol. Chem. 2007, 282, 34809-34816. 

Insights to Substrate Binding and Processing by West Nile Virus NS3 Protease :through Combined Modelling, Protease Mutagenesis, and Kinetic Studies. Chappell, K. J.; Stoermer, M. J.; Fairlie, D. P.; Young, P.R. J. Biol. Chem. 2006, 281, 38448-58. 

Site-directed Mutagenesis and Kinetic Studies of the West Nile Virus NS3 Protease Identify Key Enzyme-Substrate Interactions. Chappell,  K. J.; Nall, T.; Stoermer, M.J.; Fang, N.-X.; Tyndall, J.D.A.; Fairlie, D.P.; Young, P.Y. J. Biol. Chem. 2005, 280, 2896-2903.

Activity Of Recombinant Dengue 2 Virus NS3 Protease In The Presence Of NS2B Cofactor, Small Peptide Substrates, And Inhibitors. Leung, D.; Schroder, K.; White, H.; Fang, N.-X.; Stoermer, M. J.; Abbenante, G.; Martin, J. L.; Young, P.; Fairlie, D. P. J. Biol. Chem. 2001, 276, 45762-45771. [>100 citations]   

Cysteine Protease Inhibitors

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. 

Organic azide inhibitors of cysteine proteases. Le, G.T.; Abbenante,G.; Madala, P.K.; Hoang, H.N.; Fairlie, D.P. J. Am. Chem. Soc. 2006, 128, 12396-12397.

Phospholipase A2 Inhibitors

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. 

Gregory LS, Kelly WL, Reid RC, Fairlie DP, Forwood MR. Inhibitors of cyclooxygenase-2 and phospho-lipase A2  preserve bone architecture following ovariectomy in adult rats Bone 2006, 39, 134-142.

Levick S, Loch D, Rolfe B, Reid RC, Fairlie DP, Taylo SM, Brown L. Anti-fibrotic activity of a group IIa secretory phospholipase A2 inhibitor in a rat model of cardiac fibrosis. J. Immunol. 2006, 176, 7000-7.

Arumugam TV, Arnold N, Proctor LM, Newman M, Reid RC, Hansford KA, Fairlie DP, Shiels IA, Taylor SM. Comparative protection against rat intestinal reperfusion injury by a new inhibitor of sPLA2, COX-1 and COX-2 selective inhibitors, and an LTC4 receptor antagonist. Br. J. Pharmacol. 2003, 140, 71-80.

D-Tyrosine As A Chiral Precursor To Potent Inhibitors Of Human Non-Pancreatic Secretory Phospholipase A2 (IIa) With Anti-Inflammatory Activity. Hansford, K. A.; Reid, R. C.; Clark, C. I.; Tyndall, J. D. A.; Whitehouse, M. W.; Guthrie, T.; McGeary, R. P.; Schafer, K.; Martin, J. L.; Fairlie D. P. ChemBioChem. 2003, 4, 181-185. 

Kinase Inhibitors

Identification and characterization of bi-thiazole-2,2'-diamines as kinase inhibitory scaffolds. Ngoei KR, Ng DC, Gooley PR, Fairlie DP, Stoermer MJ, Bogoyevitch MA. Biochim Biophys Acta2013, 1834,1077-1088.

A new paradigm for protein kinase inhibition : Blocking phosphorylation without targeting ATP binding. Bogoyevitch, M.A.; Fairlie, D.P. Drug Discovery Today 2007, 12, 622-633. [>100 citations]    

Histone Deacetylase Inhibitors

Towards isozyme-selective HDAC inhibitors for interrogating disease. Gupta P, Reid RC, Iyer A, Sweet MJ, Fairlie DP. Curr Top Med Chem. 2012, 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.

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 20127, e31847. 

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.

HDAC inhibitors: modulating leukocyte differentiation, survival, proliferation and inflammation. Sweet MJ, Shakespear MR, Kamal NA, Fairlie DP. Immunol Cell Biol. 2012, 90, 14-22. 

Histone deacetylases as regulators of inflammation and immunity. Shakespear MR, Halili MA, Irvine KM, Fairlie DP, Sweet MJ. Trends Immunol. 2011, 32, 335-343. 

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, 3233-3241.

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, 961-6. 

Synthesis of the Thiazole-Thiazoline Fragment of Largazole Analogues. Diness F, Nielsen DS, Fairlie DP. J Org Chem. 2011, 76, 9845-51. 

Antifibrotic activity of an inhibitor of histone deacetylases in DOCA-salt hypertensive rats. Iyer A, Fenning A, Lim J, Le GT, Reid RC, Halili MA, Fairlie DP, Brown L. Br. J. Pharmacol. 2010, 159, 1408-1417.

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.

Differential effects of selective HDAC inhibitors on macrophage inflammatory responses to the Toll-like receptor 4 agonist LPS. Halili MA, Andrews MR, Labzin LI, Schroder K, Matthias G, Cao C, Lovelace E, Reid RC, Le GT, Hume DA, Irvine KM, Matthias P, Fairlie DP, Sweet MJ. J Leukoc Biol. 2010, 87, 1103-1114. 

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.

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. 2010, 20, 7067-7070. 

Histone deacetylase inhibitors in inflammatory disease. Halili MA, Andrews MR, Sweet MJ, Fairlie DP. Curr. Top. Med. Chem. 20099, 309-319. 

Potent new antimalarial agents that cause histone hyperacetylation in Plasmodium falciparum. Andrews, K.T.; Tran, T.N.; Lucke, A.J.; Kahnberg, P.; Le, G.T.; Boyle, G.M.; Gardiner, D.L.; Skinner-Adams, T. S.; Fairlie, D.P. Antimicrobial Antiinfectives Chemother. 2008, 52, 1454-1461.

Design, Synthesis, Potency and Cytoselectivity Of Anticancer Agents Derived By Parallel Synthesis From alpha-Aminosuberic Acid. Kahnberg, P.; Lucke, A.J.; Glenn, M.P.; Boyle, G.M.; Tyndall, J.D.A.; Parsons, P.G.; Fairlie, D. P. J. Med. Chem. 2006, 49, 7611-7622. 

Anti-Proliferative And Phenotype-Transforming Antitumor Agents  Derived From Cysteine. Glenn, M. P.; Kahnberg, P.; Boyle, G. M.; Hansford, K. A.; Hans, D.; Martyn, A. C.; Parsons, G. P.; Fairlie, D. P. J. Med. Chem. 2004, 47, 2984-2994.

Other Enzyme Inhibitors

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.