The pharmacological landscape and therapeutic potential of serine hydrolases

Nature Reviews Drug Discovery

Volumn 11, Issue 1, 2012, Pages 52-68

  Bachovchin, Daniel A ^a   Cravatt, Benjamin F ^a  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

7 PHENYL 1 [5 (2 PYRIDINYL) 2 OXAZOLYL] 1 HEPTANONE; ALOGLIPTIN; ANTIVITAMIN K; ARGATROBAN; BETA LACTAM ANTIBIOTIC; BOCEPREVIR; CYCLOHEXYLCARBAMIC ACID 3' CARBAMOYLBIPHENYL 3 YL ESTER; DABIGATRAN; DABIGATRAN ETEXILATE; DARAPLADIB; DONEPEZIL; FONDAPARINUX; GALANTAMINE; HIRUDIN; HIRULOG; HYDROLASE; LINAGLIPTIN; RIVAROXABAN; RIVASTIGMINE; SAXAGLIPTIN; SERINE HYDROLASE; SITAGLIPTIN; SIVELESTAT; TACRINE; TELAPREVIR; TETRAHYDROLIPSTATIN; UNCLASSIFIED DRUG; UNINDEXED DRUG; VILDAGLIPTIN; WARFARIN; XIMELAGATRAN; ZOMELIS;

ANALGESIC ACTIVITY; ANTICOAGULATION; ANTIINFLAMMATORY ACTIVITY; BLOOD CLOTTING; CORONARY ARTERY ATHEROSCLEROSIS; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG PROTEIN BINDING; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG TARGETING; ENZYME INHIBITION; HUMAN; LIVER TOXICITY; NEUROPATHIC PAIN; NONHUMAN; PAIN; PRIORITY JOURNAL; REVIEW; UNSPECIFIED SIDE EFFECT;

ALZHEIMER DISEASE; ANIMALS; DIABETES MELLITUS, TYPE 2; DRUG DISCOVERY; HUMANS; PROTEASE INHIBITORS; SERINE ENDOPEPTIDASES;

EID: 84855414065     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd3620     Document Type: Review

References (217)

1. Long, J. Z. & Cravatt, B. F. The metabolic serine hydrolases and their functions in mammalian physiology and disease. Chem. Rev. 111, 6022-6063 (2011).
2. Davie, E. W. & Ratnoff, O. D. Waterfall sequence for intrinsic blood clotting. Science 145, 1310-1312 (1964).
3. Whitcomb, D. C. & Lowe, M. E. Human pancreatic digestive enzymes. Dig. Dis. Sci. 52, 1-17 (2007).
4. Lane, R. M., Potkin, S. G. & Enz, A. Targeting acetylcholinesterase and butyrylcholinesterase in dementia. Int. J. Neuropsychopharmacol. 9, 101-124 (2006). (Pubitemid 43068340)
5. Bonventre, J. V. et al. Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2. Nature 390, 622-625 (1997). (Pubitemid 28016198)
6. Menendez, J. A. & Lupu, R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nature Rev. Cancer 7, 763-777 (2007). (Pubitemid 47469806)
7. Simon, G. M. & Cravatt, B. F. Activity-based proteomics of enzyme superfamilies: serine hydrolases as a case study. J. Biol. Chem. 285, 11051-11055 (2010).
8. Nomura, D. K. et al. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell 140, 49-61 (2010).
9. Steuber, H. & Hilgenfeld, R. Recent advances in targeting viral proteases for the discovery of novel antivirals. Curr. Top. Med. Chem. 10, 323-345 (2010).
10. White, M. J. et al. The HtrA-like serine protease PepD interacts with and modulates the Mycobacterium tuberculosis 35-kDa antigen outer envelope protein. PLoS ONE 6, e18175 (2011).
11. Damblon, C. et al. The catalytic mechanism of β-lactamases: NMR titration of an active-site lysine residue of the TEM-1 enzyme. Proc. Natl Acad. Sci. USA 93, 1747-1752 (1996). (Pubitemid 26079828)
12. Bachovchin, D. A. et al. Superfamily-wide portrait of serine hydrolase inhibition achieved by library-versus-library screening. Proc. Natl Acad. Sci. USA 107, 20941-20946 (2010).
13. Li, W., Blankman, J. L. & Cravatt, B. F. A functional proteomic strategy to discover inhibitors for uncharacterized hydrolases. J. Am. Chem. Soc. 129, 9594-9595 (2007). (Pubitemid 47237463)
14. Johnson, D. S. et al. Discovery of PF-04457845: a highly potent, orally bioavailable, and selective urea FAAH inhibitor. ACS Med. Chem. Lett. 2, 91-96 (2011).
15. Adibekian, A. et al. Click-generated triazole ureas as ultrapotent in vivo-active serine hydrolase inhibitors. Nature Chem. Biol. 7, 469-478 (2011).
16. Leung, D., Hardouin, C., Boger, D. L. & Cravatt, B. F. Discovering potent and selective reversible inhibitors of enzymes in complex proteomes. Nature Biotech. 21, 687-691 (2003). (Pubitemid 36638097)
17. Hoover, H. S., Blankman, J. L., Niessen, S. & Cravatt, B. F. Selectivity of inhibitors of endocannabinoid biosynthesis evaluated by activity-based protein profiling. Bioorg. Med. Chem. Lett. 18, 5838-5841 (2008).
18. Tew, D. G., Boyd, H. F., Ashman, S., Theobald, C. & Leach, C. A. Mechanism of inhibition of LDL phospholipase A2 by monocyclic-β-lactams. Burst kinetics and the effect of stereochemistry. Biochemistry 37, 10087-10093 (1998). (Pubitemid 28366362)
19. Stedman, E. & Barger, G. J. Physostigmine (eserine). Part III. J. Chem. Soc. 127, 247-258 (1925).
20. Weibel, E. K., Hadvary, P., Hochuli, E., Kupfer, E. & Lengsfeld, H. Lipstatin, an inhibitor of pancreatic lipase, produced by Streptomyces toxytricini. I. Producing organism, fermentation, isolation and biological activity. J. Antibiot. 40, 1081-1085 (1987). (Pubitemid 17141406)
21. Li, J., Wilk, E. & Wilk, S. Aminoacylpyrrolidine-2-nitriles: potent and stable inhibitors of dipeptidyl-peptidase IV (CD 26). Arch. Biochem. Biophys. 323, 148-154 (1995).
22. Flentke, G. R. et al. Inhibition of dipeptidyl aminopeptidase IV (DP-IV) by Xaa-boroPro dipeptides and use of these inhibitors to examine the role of DP-IV in T-cell function. Proc. Natl Acad. Sci. USA 88, 1556-1559 (1991). (Pubitemid 21916264)
23. Perona, J. J. & Craik, C. S. Structural basis of substrate specificity in the serine proteases. Protein Sci. 4, 337-360 (1995).
24. Yousef, G. M., Kopolovic, A. D., Elliott, M. B. & Diamandis, E. P. Genomic overview of serine proteases. Biochem. Biophys. Res. Commun. 305, 28-36 (2003). (Pubitemid 36535405)
25. Holmes, R. S. et al. Recommended nomenclature for five mammalian carboxylesterase gene families: human, mouse, and rat genes and proteins. Mamm. Genome 21, 427-441 (2010).
26. Kienesberger, P. C., Oberer, M., Lass, A. & Zechner, R. Mammalian patatin domain containing proteins: a family with diverse lipolytic activities involved in multiple biological functions. J. Lipid Res. 50, S63-S68 (2009).
27. Shin, S. et al. Structure of malonamidase E2 reveals a novel Ser-cisSer-Lys catalytic triad in a new serine hydrolase fold that is prevalent in nature. EMBO J. 21, 2509-2516 (2002). (Pubitemid 34619367)
28. Bracey, M. H., Hanson, M. A., Masuda, K. R., Stevens, R. C. & Cravatt, B. F. Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling. Science 298, 1793-1796 (2002). (Pubitemid 35404124)
29. Shi, Y. & Burn, P. Lipid metabolic enzymes: emerging drug targets for the treatment of obesity. Nature Rev. Drug Discov. 3, 695-710 (2004). (Pubitemid 39173510)
30. Singh, J., Petter, R. C., Baillie, T. A. & Whitty, A. The resurgence of covalent drugs. Nature Rev. Drug Discov. 10, 307-317 (2011).
31. Bar-On, P. et al. Kinetic and structural studies on the interaction of cholinesterases with the anti-Alzheimer drug rivastigmine. Biochemistry 41, 3555-3564 (2002). (Pubitemid 34224667)
32. Metzler, W. J. et al. Involvement of DPP-IV catalytic residues in enzyme-saxagliptin complex formation. Protein Sci. 17, 240-250 (2008). (Pubitemid 351171836)
33. Villhauer, E. B. et al. 1-[[(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano- (S)-pyrrolidine: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J. Med. Chem. 46, 2774-2789 (2003). (Pubitemid 36702545)
34. Hadvary, P., Sidler, W., Meister, W., Vetter, W. & Wolfer, H. The lipase inhibitor tetrahydrolipstatin binds covalently to the putative active site serine of pancreatic lipase. J. Biol. Chem. 266, 2021-2027 (1991). (Pubitemid 21909023)
35. Kawabata, K. et al. ONO-5046, a novel inhibitor of human neutrophil elastase. Biochem. Biophys. Res. Commun. 177, 814-820 (1991).
36. Nakayama, Y. et al. Clarification of mechanism of human sputum elastase inhibition by a new inhibitor, ONO-5046, using electrospray ionization mass spectrometry. Bioorg. Med. Chem. Lett. 12, 2349-2353 (2002). (Pubitemid 34879864)
37. Silver, L. L. Multi-targeting by monotherapeutic antibacterials. Nature Rev. Drug Discov. 6, 41-55 (2007). (Pubitemid 46020285)
38. Flores, M. V., Strawbridge, J., Ciaramella, G. & Corbau, R. HCV-NS3 inhibitors: determination of their kinetic parameters and mechanism. Biochim. Biophys. Acta 1794, 1441-1448 (2009).
39. Papp-Wallace, K. M., Endimiani, A., Taracila, M. A. & Bonomo, R. A. Carbapenems: past, present, and future. Antimicrob. Agents Chemother. 55, 4943-4960 (2011).
40. Llarrull, L. I., Testero, S. A., Fisher, J. F. & Mobashery, S. The future of the β-lactams. Curr. Opin. Microbiol. 13, 551-557 (2010).
41. Schlutter, J. Therapeutics: new drugs hit the target. Nature 474, S5-S7 (2011).
42. Mackman, N. Triggers, targets and treatments for thrombosis. Nature 451, 914-918 (2008).
43. Macfarlane, R. G. An enzyme cascade in the blood clotting mechanism, and its function as a biochemical amplifier. Nature 202, 498-499 (1964).
44. Gustafsson, D. et al. A new oral anticoagulant: the 50-year challenge. Nature Rev. Drug Discov. 3, 649-659 (2004). (Pubitemid 39173506)
45. Markwardt, F. The development of hirudin as an antithrombotic drug. Thromb. Res. 74, 1-23 (1994). (Pubitemid 24257425)
46. White, H. D. & Chew, D. P. Bivalirudin: an anticoagulant for acute coronary syndromes and coronary interventions. Expert Opin. Pharmacother. 3, 777-788 (2002). (Pubitemid 34649707)
47. Okamoto, S. A synthetic thrombin inhibitor taking extremely active stereostructure. Thromb. Haemost. 42, A205 (1979).
48. Walenga, J. M. An overview of the direct thrombin inhibitor argatroban. Pathophysiol. Haemost. Thromb. 32 (Suppl. 3), 9-14 (2002). (Pubitemid 37449298)
49. Boudes, P. F. The challenges of new drugs benefits and risks analysis: lessons from the ximelagatran FDA Cardiovascular Advisory Committee. Contemp. Clin. Trials 27, 432-440 (2006). (Pubitemid 44189275)
50. Brandstetter, H. et al. Refined 2.3 Ε X-ray crystal structure of bovine thrombin complexes formed with the benzamidine and arginine-based thrombin inhibitors NAPAP, 4-TAPAP and MQPA. A starting point for improving antithrombotics. J. Mol. Biol. 226, 1085-1099 (1992).
51. Hauel, N. H. et al. Structure-based design of novel potent nonpeptide thrombin inhibitors. J. Med. Chem. 45, 1757-1766 (2002). (Pubitemid 34415371)
52. Eisert, W. G. et al. Dabigatran: an oral novel potent reversible nonpeptide inhibitor of thrombin. Arterioscler. Thromb. Vasc. Biol. 30, 1885-1889 (2010).
53. Schulman, S. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N. Engl. J. Med. 361, 2342-2352 (2009).
54. Fujikawa, K., Legaz, M. E., Kato, H. & Davie, E. W. The mechanism of activation of bovine factor IX (Christmas factor) by bovine factor XIa (activated plasma thromboplastin antecedent). Biochemistry 13, 4508-4516 (1974).
55. Nutt, E. et al. The amino acid sequence of antistasin. A potent inhibitor of factor Xa reveals a repeated internal structure. J. Biol. Chem. 263, 10162-10167 (1988).
56. Tuszynski, G. P., Gasic, T. B. & Gasic, G. J. Isolation and characterization of antistasin. An inhibitor of metastasis and coagulation. J. Biol. Chem. 262, 9718-9723 (1987). (Pubitemid 17102618)
57. Waxman, L., Smith, D. E., Arcuri, K. E. & Vlasuk, G. P. Tick anticoagulant peptide (TAP) is a novel inhibitor of blood coagulation factor Xa. Science 248, 593-596 (1990).
58. Bauer, K. A. et al. Fondaparinux, a synthetic pentasaccharide: the first in a new class of antithrombotic agents-the selective factor Xa inhibitors. Cardiovasc. Drug Rev. 20, 37-52 (2002). (Pubitemid 34657226)
59. Perzborn, E., Roehrig, S., Straub, A., Kubitza, D. & Misselwitz, F. The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor. Nature Rev. Drug Discov. 10, 61-75 (2011).
60. Becker, R. C., Alexander, J., Dyke, C. K. & Harrington, R. A. Development of DX-9065a, a novel direct factor Xa antagonist, in cardiovascular disease. Thromb. Haemost. 92, 1182-1193 (2004). (Pubitemid 39642524)
61. Sato, K. et al. YM-60828, a novel factor Xa inhibitor: separation of its antithrombotic effects from its prolongation of bleeding time. Eur. J. Pharmacol. 339, 141-146 (1997). (Pubitemid 28021858)
62. Lam, P. Y. et al. Structure-based design of novel guanidine/benzamidine mimics: potent and orally bioavailable factor Xa inhibitors as novel anticoagulants. J. Med. Chem. 46, 4405-4418 (2003). (Pubitemid 37238744)
63. Pinto, D. J. et al. Discovery of 1-[3-(aminomethyl)phenyl]-N-3-fluoro- 2′-(methylsulfonyl)-[1,1'-biphenyl]4-yl]3-(trifluoromethyl) 1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa. J. Med. Chem. 44, 566-578 (2001). (Pubitemid 32156098)
64. Roehrig, S. et al. Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]1,3-oxazolidin-5-yl} methyl)thiophene-2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor. J. Med. Chem. 48, 5900-5908 (2005). (Pubitemid 41324601)
65. Eriksson, B. I., Quinlan, D. J. & Eikelboom, J. W. Novel oral factor Xa and thrombin inhibitors in the management of thromboembolism. Annu. Rev. Med. 62, 41-57 (2011).
66. Giacobini, E. Cholinesterases: new roles in brain function and in Alzheimer's disease. Neurochem. Res. 28, 515-522 (2003). (Pubitemid 36314842)
67. Bowen, D. M., Smith, C. B., White, P. & Davison, A. N. Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain 99, 459-496 (1976).
68. Davies, P. & Maloney, A. J. Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet 2, 1403 (1976). (Pubitemid 8004505)
69. Perry, E. K., Gibson, P. H., Blessed, G., Perry, R. H. & Tomlinson, B. E. Neurotransmitter enzyme abnormalities in senile dementia. Choline acetyltransferase and glutamic acid decarboxylase activities in necropsy brain tissue. J. Neurol. Sci. 34, 247-265 (1977). (Pubitemid 8188071)
70. Bartus, R. T., Dean, R. L., Beer, B. & Lippa, A. S. The cholinergic hypothesis of geriatric memory dysfunction. Science 217, 408-414 (1982).
71. Hansen, R. A., Gartlehner, G., Kaufer, D. J., Lohr, K. N. & Carey, T. Drug class review on Alzheimer's drugs: final report. Drug Class Reviews (2006).
72. Ellis, J. M. Cholinesterase inhibitors in the treatment of dementia. J. Am. Osteopath. Assoc. 105, 145-158 (2005). (Pubitemid 40604672)
73. Casida, J. E. & Quistad, G. B. Serine hydrolase targets of organophosphorus toxicants. Chem. Biol. Interact. 157-158, 277-283 (2005). (Pubitemid 41757663)
74. Kawakami, Y. et al. The rationale for E2020 as a potent acetylcholinesterase inhibitor. Bioorg. Med. Chem. 4, 1429-1446 (1996). (Pubitemid 26319994)
75. Nochi, S., Asakawa, N. & Sato, T. Kinetic-study on the inhibition of acetylcholinesterase by 1-benzyl-4-[(5,6-dimethoxy-l-indanon)2-Yl] methylpiperidine hydrochloride (E2020). Biol. Pharm. Bull. 18, 1145-1147 (1995).
76. Sugimoto, H., Iimura, Y., Yamanishi, Y. & Yamatsu, K. Synthesis and structure-activity relationships of acetylcholinesterase inhibitors: 1-benzyl-4-[(5, 6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine hydrochloride and related compounds. J. Med. Chem. 38, 4821-4829 (1995).
77. Harvey, A. L. The pharmacology of galanthamine and its analogues. Pharmacol. Ther. 68, 113-128 (1995).
78. Thomsen, T. & Kewitz, H. Selective inhibition of human acetylcholinesterase by galanthamine in vitro and in vivo. Life Sci. 46, 1553-1558 (1990). (Pubitemid 20177958)
79. Thomsen, T., Bickel, U., Fischer, J. P. & Kewitz, H. Stereoselectivity of cholinesterase inhibition by galanthamine and tolerance in humans. Eur. J. Clin. Pharmacol. 39, 603-605 (1990).
80. Hemsworth, B. A. & West, G. B. The anticholinesterase activity of physostigmine. J. Pharm. Pharmacol. 20, 406-407 (1968).
81. Kennedy, J. S. et al. Preferential cerebrospinal fluid acetylcholinesterase inhibition by rivastigmine in humans. J. Clin. Psychopharmacol. 19, 513-521 (1999).
82. Kathuria, S. et al. Modulation of anxiety through blockade of anandamide hydrolysis. Nature Med. 9, 76-81 (2003). (Pubitemid 36098263)
83. Long, J. Z. et al. Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nature Chem. Biol. 5, 37-44 (2009).
84. Bongers, J., Lambros, T., Ahmad, M. & Heimer, E. P. Kinetics of dipeptidyl peptidase IV proteolysis of growth hormone-releasing factor and analogs. Biochim. Biophys. Acta 1122, 147-153 (1992).
85. Rosenblum, J. S. & Kozarich, J. W. Prolyl peptidases: a serine protease subfamily with high potential for drug discovery. Curr. Opin. Chem. Biol. 7, 496-504 (2003). (Pubitemid 36980841)
86. Murphy, K. G., Dhillo, W. S. & Bloom, S. R. Gut peptides in the regulation of food intake and energy homeostasis. Endocr. Rev. 27, 719-727 (2006). (Pubitemid 44936055)
87. Thorens, B. Glucagon-like peptide-1 and control of insulin secretion. Diabetes Metab. 21, 311-318 (1995). (Pubitemid 26022284)
88. Meier, J. J., Nauck, M. A., Schmidt, W. E. & Gallwitz, B. Gastric inhibitory polypeptide: the neglected incretin revisited. Regul. Pept. 107, 1-13 (2002). (Pubitemid 34876440)
89. Drucker, D. J. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology 122, 531-544 (2002). (Pubitemid 34117003)
90. Holst, J. J. & Deacon, C. F. Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. Diabetes 47, 1663-1670 (1998). (Pubitemid 28476238)
91. Feng, J. et al. Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV. J. Med. Chem. 50, 2297-2300 (2007). (Pubitemid 46799241)
92. Lambeir, A. M. et al. Dipeptide-derived diphenyl phosphonate esters: mechanism-based inhibitors of dipeptidyl peptidase IV. Biochim. Biophys. Acta 1290, 76-82 (1996).
93. Hughes, T. E., Mone, M. D., Russell, M. E., Weldon, S. C. & Villhauer, E. B. NVP-DPP728 (1-[[[2-[(5-cyano-pyridin-2-yl)amino]ethyl]amino] acetyl]-2-cyano-(S)-pyrrolidine), a slow-binding inhibitor of dipeptidyl peptidase IV. Biochemistry 38, 11597-11603 (1999).
94. Oefner, C. et al. High-resolution structure of human apo dipeptidyl peptidase IV/CD26 and its complex with 1-[([2-[(5-iodopyridin-2-yl)amino]-ethyl] amino)-acetyl]-2-cyano-(S)-pyrrol idine. Acta Crystallogr. D Biol. Crystallogr. 59, 1206-1212 (2003). (Pubitemid 36872357)
95. Villhauer, E. B. et al. 1-[2-[(5-cyanopyridin-2-yl)amino]ethylamino] acetyl-2-(S)-pyrrolidinecarbon itrile: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J. Med. Chem. 45, 2362-2365 (2002). (Pubitemid 34595207)
96. Magnin, D. R. et al. Synthesis of novel potent dipeptidyl peptidase IV inhibitors with enhanced chemical stability: interplay between the N-terminal amino acid alkyl side chain and the cyclopropyl group of α-aminoacyl-l- cis-4,5-methanoprolinenitrile-based inhibitors. J. Med. Chem. 47, 2587-2598 (2004). (Pubitemid 38580095)
97. Augeri, D. J. et al. Discovery and preclinical profile of saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 48, 5025-5037 (2005). (Pubitemid 41033142)
98. Kim, D. et al. (2R)-4-oxo-4-[3-(trifluoromethyl)5,6-dihydro[1,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 48, 141-151 (2005). (Pubitemid 40105255)
99. Eckhardt, M. et al. 8-(3-(R)-aminopiperidin-1-yl)7-but-2-ynyl-3-methyl-1- (4-methyl-quinazolin 2-ylmethyl)3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 50, 6450-6453 (2007). (Pubitemid 350309082)
100. Xu, J. et al. Discovery of potent and selective β-homophenylalanine based dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 14, 4759-4762 (2004). (Pubitemid 39490304)
101. Cravatt, B. F. et al. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384, 83-87 (1996). (Pubitemid 26374593)
102. Naidu, P. S. et al. Evaluation of fatty acid amide hydrolase inhibition in murine models of emotionality. Psychopharmacology 192, 61-70 (2007). (Pubitemid 46673891)
103. Cravatt, B. F. et al. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc. Natl Acad. Sci. USA 98, 9371-9376 (2001). (Pubitemid 32743923)
104. Lichtman, A. H. et al. Reversible inhibitors of fatty acid amide hydrolase that promote analgesia: evidence for an unprecedented combination of potency and selectivity. J. Pharmacol. Exp. Ther. 311, 441-448 (2004). (Pubitemid 39391527)
105. Russo, R. et al. The fatty acid amide hydrolase inhibitor URB597 (cyclohexylcarbamic acid 3′-carbamoylbiphenyl-3-yl ester) reduces neuropathic pain after oral administration in mice. J. Pharmacol. Exp. Ther. 322, 236-242 (2007). (Pubitemid 46956375)
106. Justinova, Z. et al. Fatty acid amide hydrolase inhibition heightens anandamide signaling without producing reinforcing effects in primates. Biol. Psychiatry 64, 930-937 (2008).
107. Ahn, K. et al. Novel mechanistic class of fatty acid amide hydrolase inhibitors with remarkable selectivity. Biochemistry 46, 13019-13030 (2007). (Pubitemid 350086220)
108. Ahn, K. et al. Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain. Chem. Biol. 16, 411-420 (2009).
109. Khanna, I. K. & Alexander, C. W. Fatty acid amide hydrolase inhibitors-progress and potential. CNS Neurol. Disord. Drug Targets 10, 545-558 (2011).
110. Zalewski, A., Macphee, C. & Nelson, J. J. Lipoprotein-associated phospholipase A2: a potential therapeutic target for atherosclerosis. Curr. Drug Targets Cardiovasc. Haematol. Disord. 5, 527-532 (2005). (Pubitemid 43008525)
111. Packard, C. J. et al. Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group. N. Engl. J. Med. 343, 1148-1155 (2000).
112. MacPhee, C. H. et al. Lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase, generates two bioactive products during the oxidation of low-density lipoprotein: use of a novel inhibitor. Biochem. J. 338, 479-487 (1999).
113. Davis, B. et al. Electrospray ionization mass spectrometry identifies substrates and products of lipoprotein-associated phospholipase A2 in oxidized human low density lipoprotein. J. Biol. Chem. 283, 6428-6437 (2008).
114. Blackie, J. A. et al. The identification of clinical candidate SB-480848: a potent inhibitor of lipoprotein-associated phospholipase A2. Bioorg. Med. Chem. Lett. 13, 1067-1070 (2003). (Pubitemid 36331801)
115. Boyd, H. F. et al. 2-(alkylthio)pyrimidin-4-ones as novel, reversible inhibitors of lipoprotein-associated phospholipase A2. Bioorg. Med. Chem. Lett. 10, 395-398 (2000). (Pubitemid 30125198)
116. Wilensky, R. L. et al. Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nature Med. 14, 1059-1066 (2008).
117. Mallela, J., Yang, J. & Shariat-Madar, Z. Prolylcarboxypeptidase: a cardioprotective enzyme. Int. J. Biochem. Cell Biol. 41, 477-481 (2009).
118. Wallingford, N. et al. Prolylcarboxypeptidase regulates food intake by inactivating α-MSH in rodents. J. Clin. Invest. 119, 2291-2303 (2009).
119. Zhou, C. et al. Design and synthesis of prolylcarboxypeptidase (PrCP) inhibitors to validate PrCP as a potential target for obesity. J. Med. Chem. 53, 7251-7263 (2010).
120. Shen, H. C. et al. Discovery of benzimidazole pyrrolidinyl amides as prolylcarboxypeptidase inhibitors. Bioorg. Med. Chem. Lett. 21, 1299-1305 (2011).
121. Lehner, R. & Verger, R. Purification and characterization of a porcine liver microsomal triacylglycerol hydrolase. Biochemistry 36, 1861-1868 (1997). (Pubitemid 27086283)
122. Lehner, R. & Vance, D. E. Cloning and expression of a cDNA encoding a hepatic microsomal lipase that mobilizes stored triacylglycerol. Biochem. J. 343, 1-10 (1999). (Pubitemid 29473871)
123. Dolinsky, V. W., Gilham, D., Alam, M., Vance, D. E. & Lehner, R. Triacylglycerol hydrolase: role in intracellular lipid metabolism. Cell. Mol. Life Sci. 61, 1633-1651 (2004). (Pubitemid 38962045)
124. Wei, E. et al. Loss of TGH/Ces3 in mice decreases blood lipids, improves glucose tolerance, and increases energy expenditure. Cell Metab. 11, 183-193 (2010).
125. Gilham, D. et al. Inhibitors of hepatic microsomal triacylglycerol hydrolase decrease very low density lipoprotein secretion. FASEB J. 17, 1685-1687 (2003).
126. Zechner, R., Kienesberger, P. C., Haemmerle, G., Zimmermann, R. & Lass, A. Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores. J. Lipid Res. 50, 3-21 (2009).
127. Das, S. K. et al. Adipose triglyceride lipase contributes to cancer-associated cachexia. Science 333, 233-238 (2011).
128. McCoy, M. G. et al. Characterization of the lipolytic activity of endothelial lipase. J. Lipid Res. 43, 921-929 (2002). (Pubitemid 34602614)
129. Ma, K. et al. Endothelial lipase is a major genetic determinant for high-density lipoprotein concentration, structure, and metabolism. Proc. Natl Acad. Sci. USA 100, 2748-2753 (2003). (Pubitemid 36297570)
130. Ishida, T. et al. Endothelial lipase is a major determinant of HDL level. J. Clin. Invest. 111, 347-355 (2003). (Pubitemid 36182211)
131. Goodman, K. B. et al. Discovery of potent, selective sulfonylfuran urea endothelial lipase inhibitors. Bioorg. Med. Chem. Lett. 19, 27-30 (2009).
132. Kato, T., Okada, M. & Nagatsu, T. Distribution of post-proline cleaving enzyme in human brain and the peripheral tissues. Mol. Cell. Biochem. 32, 117-121 (1980). (Pubitemid 11101252)
133. Wilk, S. Prolyl endopeptidase. Life Sci. 33, 2149-2157 (1983). (Pubitemid 14234451)
134. Lopez, A., Tarrago, T. & Giralt, E. Low molecular weight inhibitors of prolyl oligopeptidase: a review of compounds patented from 2003 to 2010. Expert Opin. Ther. Pat. 21, 1023-1044 (2011).
135. Bakker, A. V., Jung, S., Spencer, R. W., Vinick, F. J. & Faraci, W. S. Slow tight-binding inhibition of prolyl endopeptidase by benzyloxycarbonyl- prolyl-prolinal. Biochem. J. 271, 559-562 (1990). (Pubitemid 20344777)
136. Toide, K., Iwamoto, Y., Fujiwara, T. & Abe, H. JTP-4819: a novel prolyl endopeptidase inhibitor with potential as a cognitive enhancer. J. Pharmacol. Exp. Ther. 274, 1370-1378 (1995).
137. Barelli, H. et al. S 17092-1, a highly potent, specific and cell permeant inhibitor of human proline endopeptidase. Biochem. Biophys. Res. Commun. 257, 657-661 (1999). (Pubitemid 29301498)
138. Bellemere, G., Morain, P., Vaudry, H. & Jegou, S. Effect of S 17092, a novel prolyl endopeptidase inhibitor, on substance P and α-melanocyte- stimulating hormone breakdown in the rat brain. J. Neurochem. 84, 919-929 (2003). (Pubitemid 36330646)
139. Nolte, W. M., Tagore, D. M., Lane, W. S. & Saghatelian, A. Peptidomics of prolyl endopeptidase in the central nervous system. Biochemistry 48, 11971-11981 (2009).
140. Toide, K. et al. Effect of a novel prolyl endopeptidase inhibitor, JTP-4819, on neuropeptide metabolism in the rat brain. Naunyn Schmiedebergs Arch. Pharmacol. 353, 355-362 (1996). (Pubitemid 26092052)
141. Shinoda, M., Okamiya, K. & Toide, K. Effect of a novel prolyl endopeptidase inhibitor, JTP-4819, on thyrotropin-releasing hormone-like immunoreactivity in the cerebral cortex and hippocampus of aged rats. Jpn J. Pharmacol. 69, 273-276 (1995).
142. Schneider, J. S., Giardiniere, M. & Morain, P. Effects of the prolyl endopeptidase inhibitor S 17092 on cognitive deficits in chronic low dose MPTP-treated monkeys. Neuropsychopharmacology 26, 176-182 (2002). (Pubitemid 34093080)
143. Morain, P. et al. S 17092: a prolyl endopeptidase inhibitor as a potential therapeutic drug for memory impairment. Preclinical and clinical studies. CNS Drug Rev. 8, 31-52 (2002). (Pubitemid 34651314)
144. Morain, P., Boeijinga, P. H., Demazieres, A., De Nanteuil, G. & Luthringer, R. Psychotropic profile of S 17092, a prolyl endopeptidase inhibitor, using quantitative EEG in young healthy volunteers. Neuropsychobiology 55, 176-183 (2007). (Pubitemid 47525238)
145. Lambeir, A. M. Translational research on prolyl oligopeptidase inhibitors: the long road ahead. Expert Opin. Ther. Pat. 21, 977-981 (2011).
146. Puustinen, P. et al. PME-1 protects extracellular signal-regulated kinase pathway activity from protein phosphatase 2A-mediated inactivation in human malignant glioma. Cancer Res. 69, 2870-2877 (2009).
147. Andreasen, P. A., Egelund, R. & Petersen, H. H. The plasminogen activation system in tumor growth, invasion, and metastasis. Cell. Mol. Life Sci. 57, 25-40 (2000). (Pubitemid 30105328)
148. Nomura, D. K., Dix, M. M. & Cravatt, B. F. Activity-based protein profiling for biochemical pathway discovery in cancer. Nature Rev. Cancer 10, 630-638 (2010).
149. Scanlan, M. J. et al. Molecular cloning of fibroblast activation protein α, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. Proc. Natl Acad. Sci. USA 91, 5657-5661 (1994). (Pubitemid 24174387)
150. Rettig, W. J. et al. Regulation and heteromeric structure of the fibroblast activation protein in normal and transformed cells of mesenchymal and neuroectodermal origin. Cancer Res. 53, 3327-3335 (1993). (Pubitemid 23223305)
151. Garin-Chesa, P., Old, L. J. & Rettig, W. J. Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc. Natl Acad. Sci. USA 87, 7235-7239 (1990).
152. Cheng, J. D. et al. Promotion of tumor growth by murine fibroblast activation protein, a serine protease, in an animal model. Cancer Res. 62, 4767-4772 (2002).
153. Cheng, J. D. et al. Abrogation of fibroblast activation protein enzymatic activity attenuates tumor growth. Mol. Cancer Ther. 4, 351-360 (2005). (Pubitemid 40443920)
154. Adams, S. et al. PT-100, a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism. Cancer Res. 64, 5471-5480 (2004). (Pubitemid 39006571)
155. Kraman, M. et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-α. Science 330, 827-830 (2010).
156. Edosada, C. Y. et al. Selective inhibition of fibroblast activation protein protease based on dipeptide substrate specificity. J. Biol. Chem. 281, 7437-7444 (2006). (Pubitemid 43847515)
157. Wolf, B. B., Quan, C., Tran, T., Wiesmann, C. & Sutherlin, D. On the edge of validation-cancer protease fibroblast activation protein. Mini Rev. Med. Chem. 8, 719-727 (2008).
158. Patterson, S. D. & Aebersold, R. H. Proteomics: the first decade and beyond. Nature Genet. 33, S311-S323 (2003).
159. Yates, J. R. Mass spectral analysis in proteomics. Annu. Rev. Biophys. Biomol. Struct. 33, 297-316 (2004).
160. Domon, B. & Aebersold, R. Mass spectrometry and protein analysis. Science 312, 212-217 (2006).
161. Cravatt, B. F., Simon, G. M. & Yates, J. R. The biological impact of mass-spectrometry-based proteomics. Nature 450, 991-1000 (2007). (Pubitemid 350273629)
162. Golub, T. R. et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286, 531-537 (1999).
163. Brown, P. O. & Botstein, D. Exploring the new world of the genome with DNA microarrays. Nature Genet. 21, 33-37 (1999). (Pubitemid 29031489)
164. Evans, M. J. & Cravatt, B. F. Mechanism-based profiling of enzyme families. Chem. Rev. 106, 3279-3301 (2006). (Pubitemid 44376936)
165. Cravatt, B. F., Wright, A. T. & Kozarich, J. W. Activity-based protein profiling: from enzyme chemistry to proteomic chemistry. Annu. Rev. Biochem. 77, 383-414 (2008).
166. Liu, Y., Patricelli, M. P. & Cravatt, B. F. Activity-based protein profiling: the serine hydrolases. Proc. Natl Acad. Sci. USA 96, 14694-14699 (1999). (Pubitemid 30019702)
167. Weerapana, E., Simon, G. M. & Cravatt, B. F. Disparate proteome reactivity profiles of carbon electrophiles. Nature Chem. Biol. 4, 405-407 (2008). (Pubitemid 351860548)
168. Kato, D. et al. Activity-based probes that target diverse cysteine protease families. Nature Chem. Biol. 1, 33-38 (2005).
169. Weerapana, E. et al. Quantitative reactivity profiling predicts functional cysteines in proteomes. Nature 468, 790-795 (2010).
170. Patricelli, M. P. et al. Functional interrogation of the kinome using nucleotide acyl phosphates. Biochemistry 46, 350-358 (2007). (Pubitemid 46105428)
171. Salisbury, C. M. & Cravatt, B. F. Activity-based probes for proteomic profiling of histone deacetylase complexes. Proc. Natl Acad. Sci. USA 104, 1171-1176 (2007). (Pubitemid 46183977)
172. Salisbury, C. M. & Cravatt, B. F. Optimization of activity-based probes for proteomic profiling of histone deacetylase complexes. J. Am. Chem. Soc. 130, 2184-2194 (2008). (Pubitemid 351287995)
173. Madsen, M. A., Deryugina, E. I., Niessen, S., Cravatt, B. F. & Quigley, J. P. Activity-based protein profiling implicates urokinase activation as a key step in human fibrosarcoma intravasation. J. Biol. Chem. 281, 15997-16005 (2006). (Pubitemid 43848493)
174. Pan, Z. et al. Development of activity-based probes for trypsin-family serine proteases. Bioorg. Med. Chem. Lett. 16, 2882-2885 (2006).
175. Jessani, N. et al. Carcinoma and stromal enzyme activity profiles associated with breast tumor growth in vivo. Proc. Natl Acad. Sci. USA 101, 13756-13761 (2004). (Pubitemid 39298480)
176. Jessani, N. et al. A streamlined platform for high-content functional proteomics of primary human specimens. Nature Methods 2, 691-697 (2005). (Pubitemid 41223096)
177. Blankman, J. L., Simon, G. M. & Cravatt, B. F. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoyl- glycerol. Chem. Biol. 14, 1347-1356 (2007). (Pubitemid 350257008)
178. Mahrus, S. & Craik, C. S. Selective chemical functional probes of granzymes A and B reveal granzyme B is a major effector of natural killer cell-mediated lysis of target cells. Chem. Biol. 12, 567-577 (2005). (Pubitemid 40727931)
179. Barglow, K. T. & Cravatt, B. F. Discovering disease-associated enzymes by proteome reactivity profiling. Chem. Biol. 11, 1523-1531 (2004). (Pubitemid 39527279)
180. Morak, M. et al. Differential activity-based gel electrophoresis for comparative analysis of lipolytic and esterolytic activities. J. Lipid Res. 50, 1281-1292 (2009).
181. Kaschani, F. et al. Diversity of serine hydrolase activities of unchallenged and botrytis-infected Arabidopsis thaliana. Mol. Cell. Proteomics 8, 1082-1093 (2009).
182. Jessani, N., Liu, Y., Humphrey, M. & Cravatt, B. F. Enzyme activity profiles of the secreted and membrane proteome that depict cancer cell invasiveness. Proc. Natl Acad. Sci. USA 99, 10335-10340 (2002).
183. Chiang, K. P., Niessen, S., Saghatelian, A. & Cravatt, B. F. An enzyme that regulates ether lipid signaling pathways in cancer annotated by multidimensional profiling. Chem. Biol. 13, 1041-1050 (2006). (Pubitemid 44557068)
184. Chang, J. W., Nomura, D. K. & Cravatt, B. F. A potent and selective inhibitor of KIAA1363/AADACL1 that impairs prostate cancer pathogenesis. Chem. Biol. 18, 476-484 (2011).
185. Nomura, D. K. et al. Monoacylglycerol lipase exerts dual control over endocannabinoid and fatty acid pathways to support prostate cancer. Chem. Biol. 18, 846-856 (2011).
186. Long, J. Z., Nomura, D. K. & Cravatt, B. F. Characterization of monoacylglycerol lipase inhibition reveals differences in central and peripheral endocannabinoid metabolism. Chem. Biol. 16, 744-753 (2009).
187. Kinsey, S. G. et al. Blockade of endocannabinoid-degrading enzymes attenuates neuropathic pain. J. Pharmacol. Exp. Ther. 330, 902-910 (2009).
188. Nomura, D. K. et al. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science 334, 809-813 (2011).
189. Woitach, J. T., Zhang, M., Niu, C. H. & Thorgeirsson, S. S. A retinoblastoma-binding protein that affects cell-cycle control and confers transforming ability. Nature Genet. 19, 371-374 (1998). (Pubitemid 28357910)
190. Shields, D. J. et al. RBBP9: a tumor-associated serine hydrolase activity required for pancreatic neoplasia. Proc. Natl Acad. Sci. USA 107, 2189-2194 (2010).
191. Bachovchin, D. A., Brown, S. J., Rosen, H. & Cravatt, B. F. Identification of selective inhibitors of uncharacterized enzymes by high-throughput screening with fluorescent activity-based probes. Nature Biotech. 27, 387-394 (2009).
192. Bachovchin, D. A. et al. Oxime esters as selective, covalent inhibitors of the serine hydrolase retinoblastoma-binding protein 9 (RBBP9). Bioorg. Med. Chem. Lett. 20, 2254-2258 (2010).
193. Kidd, D., Liu, Y. & Cravatt, B. F. Profiling serine hydrolase activities in complex proteomes. Biochemistry 40, 4005-4015 (2001). (Pubitemid 32280438)
194. Greenbaum, D. et al. Chemical approaches for functionally probing the proteome. Mol. Cell. Proteomics 1, 60-68 (2002).
195. Johnson, D. S., Weerapana, E. & Cravatt, B. F. Strategies for discovering and derisking covalent, irreversible enzyme inhibitors. Future Med. Chem. 2, 949-964 (2010).
196. Potashman, M. H. & Duggan, M. E. Covalent modifiers: an orthogonal approach to drug design. J. Med. Chem. 52, 1231-1246 (2009).
197. Knuckley, B. et al. A fluopol-ABPP HTS assay to identify PAD inhibitors. Chem. Commun. (Camb.) 46, 7175-7177 (2010).
198. Bachovchin, D. A. et al. Organic synthesis toward small-molecule probes and drugs special feature: academic cross-fertilization by public screening yields a remarkable class of protein phosphatase methylesterase-1 inhibitors. Proc. Natl Acad. Sci. USA 108, 6811-6816 (2011).
199. Lee, J., Chen, Y., Tolstykh, T. & Stock, J. A specific protein carboxyl methylesterase that demethylates phosphoprotein phosphatase 2A in bovine brain. Proc. Natl Acad. Sci. USA 93, 6043-6047 (1996). (Pubitemid 26190799)
200. Sontag, J. M., Nunbhakdi-Craig, V., Mitterhuber, M., Ogris, E. & Sontag, E. Regulation of protein phosphatase 2A methylation by LCMT1 and PME-1 plays a critical role in differentiation of neuroblastoma cells. J. Neurochem. 115, 1455-1465 (2010).
201. Bachovchin, D. A. et al. Discovery and optimization of sulfonyl acrylonitriles as selective, covalent inhibitors of protein phosphatase methylesterase-1. J. Med. Chem. 54, 5229-5236 (2011).
202. Berlin, J. M. & Fu, G. C. Enantioselective nucleophilic catalysis: the synthesis of aza-β-lactams through [2 + 2] cycloadditions of ketenes with azo compounds. Angew. Chem. Int. Ed. Engl. 47, 7048-7050 (2008).
203. Wood, W. J., Patterson, A. W., Tsuruoka, H., Jain, R. K. & Ellman, J. A. Substrate activity screening: a fragment-based method for the rapid identification of nonpeptidic protease inhibitors. J. Am. Chem. Soc. 127, 15521-15527 (2005). (Pubitemid 41572526)
204. Patterson, A. W. et al. Identification of selective, nonpeptidic nitrile inhibitors of cathepsin S using the substrate activity screening method. J. Med. Chem. 49, 6298-6307 (2006). (Pubitemid 44595207)
205. Salisbury, C. M. & Ellman, J. A. Rapid identification of potent nonpeptidic serine protease inhibitors. Chembiochem. 7, 1034-1037 (2006). (Pubitemid 44049437)
206. Edwards, P. D., Zottola, M. A., Davis, M., Williams, J. & Tuthill, P. A. Peptidyl α-ketoheterocyclic inhibitors of human neutrophil elastase. 3. In vitro and in vivo potency of a series of peptidyl α- ketobenzoxazoles. J. Med. Chem. 38, 3972-3982 (1995).
207. Erlanson, D. A. et al. Site-directed ligand discovery. Proc. Natl Acad. Sci. USA 97, 9367-9372 (2000). (Pubitemid 30650781)
208. Erlanson, D. A., Wells, J. A. & Braisted, A. C. Tethering: fragment-based drug discovery. Annu. Rev. Biophys. Biomol. Struct. 33, 199-223 (2004). (Pubitemid 38829958)
209. Hagel, M. et al. Selective irreversible inhibition of a protease by targeting a noncatalytic cysteine. Nature Chem. Biol. 7, 22-24 (2011).
210. Levy, J. H. & O'Donnell, P. S. The therapeutic potential of a kallikrein inhibitor for treating hereditary angioedema. Expert Opin. Investig. Drugs 15, 1077-1090 (2006). (Pubitemid 44314659)
211. Stoop, A. A. & Craik, C. S. Engineering of a macromolecular scaffold to develop specific protease inhibitors. Nature Biotech. 21, 1063-1068 (2003). (Pubitemid 37064736)
212. Dennis, M. S. & Lazarus, R. A. Kunitz domain inhibitors of tissue factor-factor VIIa. II. Potent and specific inhibitors by competitive phage selection. J. Biol. Chem. 269, 22137-22144 (1994).
213. Xuan, J. A. et al. Antibodies neutralizing hepsin protease activity do not impact cell growth but inhibit invasion of prostate and ovarian tumor cells in culture. Cancer Res. 66, 3611-3619 (2006).
214. Sun, J., Pons, J. & Craik, C. S. Potent and selective inhibition of membrane-type serine protease 1 by human single-chain antibodies. Biochemistry 42, 892-900 (2003). (Pubitemid 36159520)
215. Lazarus, R. A., Olivero, A. G., Eigenbrot, C. & Kirchhofer, D. Inhibitors of tissue factor. Factor VIIa for anticoagulant therapy. Curr. Med. Chem. 11, 2275-2290 (2004). (Pubitemid 39172349)
216. Edwards, A. M. et al. Too many roads not taken. Nature 470, 163-165 (2011).
217. Subramanian, A. R., Kaufmann, M. & Morgenstern, B. DIALIGN-TX: greedy and progressive approaches for segment-based multiple sequence alignment. Algorithms Mol. Biol. 3, 6 (2008).