Improving the Selectivity of Engineered Protease Inhibitors: Optimizing the P2 Prime Residue Using a Versatile Cyclic Peptide Library

Journal of Medicinal Chemistry

Volumn 58, Issue 20, 2015, Pages 8257-8268

  De Veer, Simon J ^a   Wang, Conan K ^b   Harris, Jonathan M ^a   Craik, David J ^b   Swedberg, Joakim E ^b  

^a QUEENSLAND UNIVERSITY OF TECHNOLOGY   (Australia)

^b UNIVERSITY OF QUEENSLAND   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

BLOOD CLOTTING FACTOR; BOWMAN BIRK INHIBITOR; CHYMOTRYPSIN TRYPSIN; CYCLOPEPTIDE; KALLIKREIN INHIBITOR; MATRIPTASE; MATRIPTASE INHIBITOR; PLASMIN; PLASMIN INHIBITOR; SERINE PROTEINASE INHIBITOR; THROMBIN; THROMBIN INHIBITOR; UNCLASSIFIED DRUG; KALLIKREIN; SFTI-1 PEPTIDE, SUNFLOWER;

AMINO ACID SEQUENCE; ARTICLE; BLOOD CLOTTING; DRUG DESIGN; DRUG SCREENING; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITOR INTERACTION; ENZYME STRUCTURE; FIBRINOLYSIS; INHIBITION CONSTANT; MOLECULAR DYNAMICS; MOLECULAR MODEL; PEPTIDE LIBRARY; PROTEIN ENGINEERING; PROTON NUCLEAR MAGNETIC RESONANCE; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; DRUG EFFECTS; SYNTHESIS;

AMINO ACID SEQUENCE; BLOOD COAGULATION; DRUG DESIGN; DRUG EVALUATION, PRECLINICAL; FIBRINOLYSIS; KALLIKREINS; MODELS, MOLECULAR; PEPTIDES, CYCLIC; PROTEIN ENGINEERING; SERINE PROTEINASE INHIBITORS;

EID: 84945377050     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b01148     Document Type: Article

References (62)

1. Bachovchin, D. A.; Cravatt, B. F. The pharmacological landscape and therapeutic potential of serine hydrolases Nat. Rev. Drug Discovery 2012, 11, 52-68 10.1038/nrd3620
2. Drag, M.; Salvesen, G. S. Emerging principles in protease-based drug discovery Nat. Rev. Drug Discovery 2010, 9, 690-701 10.1038/nrd3053
3. Mullard, A. 2013 FDA drug approvals Nat. Rev. Drug Discovery 2014, 13, 85-89 10.1038/nrd4239
4. Coussens, L. M.; Fingleton, B.; Matrisian, L. M. Matrix metalloproteinase inhibitors and cancer: trials and tribulations Science 2002, 295, 2387-2392 10.1126/science.1067100
5. Rosenbloom, D. I.; Hill, A. L.; Rabi, S. A.; Siliciano, R. F.; Nowak, M. A. Antiretroviral dynamics determines HIV evolution and predicts therapy outcome Nat. Med. 2012, 18, 1378-1385 10.1038/nm.2892
6. Rong, L.; Dahari, H.; Ribeiro, R. M.; Perelson, A. S. Rapid emergence of protease inhibitor resistance in hepatitis C virus Sci. Transl. Med. 2010, 2, 30ra32 10.1126/scitranslmed.3000544
7. Scott, C. J.; Taggart, C. C. Biologic protease inhibitors as novel therapeutic agents Biochimie 2010, 92, 1681-1688 10.1016/j.biochi.2010.03.010
8. Laskowski, M., Jr.; Kato, I. Protein inhibitors of proteinases Annu. Rev. Biochem. 1980, 49, 593-626 10.1146/annurev.bi.49.070180.003113
9. Laskowski, M., Jr.; Qasim, M. A. What can the structures of enzyme-inhibitor complexes tell us about the structures of enzyme substrate complexes? Biochim. Biophys. Acta, Protein Struct. Mol. Enzymol. 2000, 1477, 324-337 10.1016/S0167-4838(99)00284-8
10. Rawlings, N. D.; Waller, M.; Barrett, A. J.; Bateman, A. MEROPS: the database of proteolytic enzymes, their substrates and inhibitors Nucleic Acids Res. 2014, 42, D503-509 10.1093/nar/gkt953
11. Finkenstadt, W. R.; Laskowski, M., Jr. Peptide bond cleavage on trypsin-trypsin inhibitor complex formation J. Biol. Chem. 1965, 240, 962-963
12. Finkenstadt, W. R.; Laskowski, M., Jr. Resynthesis by trypsin of the cleaved peptide bond in modified soybean trypsin inhibitor J. Biol. Chem. 1967, 242, 771-773
13. Bode, W.; Huber, R. Natural protein proteinase inhibitors and their interaction with proteinases Eur. J. Biochem. 1992, 204, 433-451 10.1111/j.1432-1033.1992.tb16654.x
14. Schechter, I.; Berger, A. On the size of the active site in proteases. I. Papain Biochem. Biophys. Res. Commun. 1967, 27, 157-162 10.1016/S0006-291X(67)80055-X
15. Roberts, B. L.; Markland, W.; Ley, A. C.; Kent, R. B.; White, D. W.; Guterman, S. K.; Ladner, R. C. Directed evolution of a protein: selection of potent neutrophil elastase inhibitors displayed on M13 fusion phage Proc. Natl. Acad. Sci. U. S. A. 1992, 89, 2429-2433 10.1073/pnas.89.6.2429
16. Markland, W.; Ley, A. C.; Ladner, R. C. Iterative optimization of high-affinity protease inhibitors using phage display. 2. Plasma kallikrein and thrombin Biochemistry 1996, 35, 8058-8067 10.1021/bi952629y
17. Cicardi, M.; Levy, R. J.; McNeil, D. L.; Li, H. H.; Sheffer, A. L.; Campion, M.; Horn, P. T.; Pullman, W. E. Ecallantide for the treatment of acute attacks in hereditary angioedema N. Engl. J. Med. 2010, 363, 523-531 10.1056/NEJMoa0905079
18. Lu, W.; Zhang, W.; Molloy, S. S.; Thomas, G.; Ryan, K.; Chiang, Y.; Anderson, S.; Laskowski, M., Jr. Arg15-Lys17-Arg18 turkey ovomucoid third domain inhibits human furin J. Biol. Chem. 1993, 268, 14583-14585
19. Martin, F.; Dimasi, N.; Volpari, C.; Perrera, C.; Di Marco, S.; Brunetti, M.; Steinkuhler, C.; De Francesco, R.; Sollazzo, M. Design of selective eglin inhibitors of HCV NS3 proteinase Biochemistry 1998, 37, 11459-11468 10.1021/bi980283w
20. Grzesiak, A.; Krokoszynska, I.; Krowarsch, D.; Buczek, O.; Dadlez, M.; Otlewski, J. Inhibition of six serine proteinases of the human coagulation system by mutants of bovine pancreatic trypsin inhibitor J. Biol. Chem. 2000, 275, 33346-33352 10.1074/jbc.M006085200
21. Harris, J. L.; Backes, B. J.; Leonetti, F.; Mahrus, S.; Ellman, J. A.; Craik, C. S. Rapid and general profiling of protease specificity by using combinatorial fluorogenic substrate libraries Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 7754-7759 10.1073/pnas.140132697
22. Swedberg, J. E.; Nigon, L. V.; Reid, J. C.; de Veer, S. J.; Walpole, C. M.; Stephens, C. R.; Walsh, T. P.; Takayama, T. K.; Hooper, J. D.; Clements, J. A.; Buckle, A. M.; Harris, J. M. Substrate-guided design of a potent and selective kallikrein-related peptidase inhibitor for kallikrein 4 Chem. Biol. 2009, 16, 633-643 10.1016/j.chembiol.2009.05.008
23. Swedberg, J. E.; de Veer, S. J.; Sit, K. C.; Reboul, C. F.; Buckle, A. M.; Harris, J. M. Mastering the canonical loop of serine protease inhibitors: enhancing potency by optimizing the internal hydrogen bond network PLoS One 2011, 6, e19302 10.1371/journal.pone.0019302
24. de Veer, S. J.; Swedberg, J. E.; Parker, E. A.; Harris, J. M. Non-combinatorial library screening reveals subsite cooperativity and identifies new high efficiency substrates for kallikrein-related peptidase 14 Biol. Chem. 2012, 393, 331-341 10.1515/bc-2011-250
25. de Veer, S. J.; Swedberg, J. E.; Akcan, M.; Rosengren, K. J.; Brattsand, M.; Craik, D. J.; Harris, J. M. Engineered protease inhibitors based on sunflower trypsin inhibitor-1 (SFTI-1) provide insights into the role of sequence and conformation in Laskowski mechanism inhibition Biochem. J. 2015, 469, 243-253 10.1042/BJ20150412
26. Madala, P. K.; Tyndall, J. D.; Nall, T.; Fairlie, D. P. Update 1 of: Proteases universally recognize beta strands in their active sites Chem. Rev. 2010, 110, PR1-31 10.1021/cr900368a
27. Luckett, S.; Garcia, R. S.; Barker, J. J.; Konarev, A. V.; Shewry, P. R.; Clarke, A. R.; Brady, R. L. High-resolution structure of a potent, cyclic proteinase inhibitor from sunflower seeds J. Mol. Biol. 1999, 290, 525-533 10.1006/jmbi.1999.2891
28. Li, P.; Jiang, S.; Lee, S. L.; Lin, C. Y.; Johnson, M. D.; Dickson, R. B.; Michejda, C. J.; Roller, P. P. Design and synthesis of novel and potent inhibitors of the type II transmembrane serine protease, matriptase, based upon the sunflower trypsin inhibitor-1 J. Med. Chem. 2007, 50, 5976-5983 10.1021/jm0704898
29. Fittler, H.; Avrutina, O.; Glotzbach, B.; Empting, M.; Kolmar, H. Combinatorial tuning of peptidic drug candidates: high-affinity matriptase inhibitors through incremental structure-guided optimization Org. Biomol. Chem. 2013, 11, 1848-1857 10.1039/c3ob27469a
30. Korsinczky, M. L.; Schirra, H. J.; Rosengren, K. J.; West, J.; Condie, B. A.; Otvos, L.; Anderson, M. A.; Craik, D. J. Solution structures by 1H NMR of the novel cyclic trypsin inhibitor SFTI-1 from sunflower seeds and an acyclic permutant J. Mol. Biol. 2001, 311, 579-591 10.1006/jmbi.2001.4887
31. Gariani, T.; McBride, J. D.; Leatherbarrow, R. J. The role of the P2′ position of Bowman-Birk proteinase inhibitor in the inhibition of trypsin. Studies on P2′ variation in cyclic peptides encompassing the reactive site loop Biochim. Biophys. Acta, Protein Struct. Mol. Enzymol. 1999, 1431, 232-237 10.1016/S0167-4838(99)00035-7
32. Antalis, T. M.; Bugge, T. H.; Wu, Q. Membrane-anchored serine proteases in health and disease Prog. Mol. Biol. Transl. Sci. 2011, 99, 1-50 10.1016/B978-0-12-385504-6.00001-4
33. Quimbar, P.; Malik, U.; Sommerhoff, C. P.; Kaas, Q.; Chan, L. Y.; Huang, Y. H.; Grundhuber, M.; Dunse, K.; Craik, D. J.; Anderson, M. A.; Daly, N. L. High-affinity cyclic peptide matriptase inhibitors J. Biol. Chem. 2013, 288, 13885-13896 10.1074/jbc.M113.460030
34. Magdolen, V.; Sommerhoff, C. P.; Fritz, H.; Schmitt, M. Kallikrein-Related Peptidases: Characterization, Regulation, and Interactions within the Protease Web; Walter de Gruyter GmbH: Berlin, 2012; pp 1-410.
35. Lawrence, M. G.; Lai, J.; Clements, J. A. Kallikreins on steroids: structure, function, and hormonal regulation of prostate-specific antigen and the extended kallikrein locus Endocr. Rev. 2010, 31, 407-446 10.1210/er.2009-0034
36. de Veer, S. J.; Furio, L.; Harris, J. M.; Hovnanian, A. Proteases: common culprits in human skin disorders Trends Mol. Med. 2014, 20, 166-178 10.1016/j.molmed.2013.11.005
37. Prassas, I.; Eissa, A.; Poda, G.; Diamandis, E. P. Unleashing the therapeutic potential of human kallikrein-related serine proteases Nat. Rev. Drug Discovery 2015, 14, 183-202 10.1038/nrd4534
38. Debela, M.; Magdolen, V.; Schechter, N.; Valachova, M.; Lottspeich, F.; Craik, C. S.; Choe, Y.; Bode, W.; Goettig, P. Specificity profiling of seven human tissue kallikreins reveals individual subsite preferences J. Biol. Chem. 2006, 281, 25678-25688 10.1074/jbc.M602372200
39. Mackman, N. Triggers, targets and treatments for thrombosis Nature 2008, 451, 914-918 10.1038/nature06797
40. Edmunds, L. H., Jr. Managing fibrinolysis without aprotinin Ann. Thorac. Surg. 2010, 89, 324-331 10.1016/j.athoracsur.2009.10.043
41. Deanda, A., Jr.; Spiess, B. D. Aprotinin revisited J. Thorac. Cardiovasc. Surg. 2012, 144, 998-1002 10.1016/j.jtcvs.2012.06.035
42. Di Nisio, M.; Middeldorp, S.; Buller, H. R. Direct thrombin inhibitors N. Engl. J. Med. 2005, 353, 1028-1040 10.1056/NEJMra044440
43. Swedberg, J. E.; Harris, J. M. Plasmin substrate binding site cooperativity guides the design of potent peptide aldehyde inhibitors Biochemistry 2011, 50, 8454-8462 10.1021/bi201203y
44. Bajaj, M. S.; Ogueli, G. I.; Kumar, Y.; Vadivel, K.; Lawson, G.; Shanker, S.; Schmidt, A. E.; Bajaj, S. P. Engineering kunitz domain 1 (KD1) of human tissue factor pathway inhibitor-2 to selectively inhibit fibrinolysis: properties of KD1-L17R variant J. Biol. Chem. 2011, 286, 4329-4340 10.1074/jbc.M110.191163
45. Kocsis, A.; Kekesi, K. A.; Szasz, R.; Vegh, B. M.; Balczer, J.; Dobo, J.; Zavodszky, P.; Gal, P.; Pal, G. Selective inhibition of the lectin pathway of complement with phage display selected peptides against mannose-binding lectin-associated serine protease (MASP)-1 and -2: significant contribution of MASP-1 to lectin pathway activation J. Immunol. 2010, 185, 4169-4178 10.4049/jimmunol.1001819
46. Gitlin, A.; Debowski, D.; Karna, N.; Łęgowska, A.; Stirnberg, M.; Gutschow, M.; Rolka, K. Inhibitors of Matriptase-2 Based on the Trypsin Inhibitor SFTI-1 ChemBioChem 2015, 16, 1601-1607 10.1002/cbic.201500200
47. de Veer, S. J.; Ukolova, S. S.; Munro, C. A.; Swedberg, J. E.; Buckle, A. M.; Harris, J. M. Mechanism-based selection of a potent kallikrein-related peptidase 7 inhibitor from a versatile library based on the sunflower trypsin inhibitor SFTI-1 Biopolymers 2013, 100, 510-518 10.1002/bip.22231
48. Tan, X.; Soualmia, F.; Furio, L.; Renard, J. F.; Kempen, I.; Qin, L.; Pagano, M.; Pirotte, B.; El Amri, C.; Hovnanian, A.; Reboud-Ravaux, M. Toward the first class of suicide inhibitors of kallikreins involved in skin diseases J. Med. Chem. 2015, 58, 598-612 10.1021/jm500988d
49. Sales, K. U.; Masedunskas, A.; Bey, A. L.; Rasmussen, A. L.; Weigert, R.; List, K.; Szabo, R.; Overbeek, P. A.; Bugge, T. H. Matriptase initiates activation of epidermal pro-kallikrein and disease onset in a mouse model of Netherton syndrome Nat. Genet. 2010, 42, 676-683 10.1038/ng.629
50. Miller, G. S.; List, K. The matriptase-prostasin proteolytic cascade in epithelial development and pathology Cell Tissue Res. 2013, 351, 245-253 10.1007/s00441-012-1348-1
51. Basel-Vanagaite, L.; Attia, R.; Ishida-Yamamoto, A.; Rainshtein, L.; Ben Amitai, D.; Lurie, R.; Pasmanik-Chor, M.; Indelman, M.; Zvulunov, A.; Saban, S.; Magal, N.; Sprecher, E.; Shohat, M. Autosomal recessive ichthyosis with hypotrichosis caused by a mutation in ST14, encoding type II transmembrane serine protease matriptase Am. J. Hum. Genet. 2007, 80, 467-477 10.1086/512487
52. Salameh, M. A.; Soares, A. S.; Hockla, A.; Radisky, D. C.; Radisky, E. S. The P(2)′ residue is a key determinant of mesotrypsin specificity: engineering a high-affinity inhibitor with anticancer activity Biochem. J. 2011, 440, 95-105 10.1042/BJ20110788
53. Szmola, R.; Kukor, Z.; Sahin-Toth, M. Human mesotrypsin is a unique digestive protease specialized for the degradation of trypsin inhibitors J. Biol. Chem. 2003, 278, 48580-48589 10.1074/jbc.M310301200
54. Hedstrom, L. Serine protease mechanism and specificity Chem. Rev. 2002, 102, 4501-4524 10.1021/cr000033x
55. Radisky, E. S.; Koshland, D. E., Jr. A clogged gutter mechanism for protease inhibitors Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 10316-10321 10.1073/pnas.112332899
56. Zakharova, E.; Horvath, M. P.; Goldenberg, D. P. Structure of a serine protease poised to resynthesize a peptide bond Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 11034-11039 10.1073/pnas.0902463106
57. Bianchini, E. P.; Louvain, V. B.; Marque, P. E.; Juliano, M. A.; Juliano, L.; Le Bonniec, B. F. Mapping of the catalytic groove preferences of factor Xa reveals an inadequate selectivity for its macromolecule substrates J. Biol. Chem. 2002, 277, 20527-20534 10.1074/jbc.M201139200
58. Abbenante, G.; Leung, D.; Bond, T.; Fairlie, D. P. An efficient Fmoc strategy for the rapid synthesis of peptide para-nitroanilidies Lett. Pept. Sci. 2000, 7, 347-351 10.1007/BF02443598
59. Guex, N.; Peitsch, M. C. SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling Electrophoresis 1997, 18, 2714-2723 10.1002/elps.1150181505
60. Humphrey, W.; Dalke, A.; Schulten, K. VMD: visual molecular dynamics J. Mol. Graphics 1996, 14, 33-38 27-38. 10.1016/0263-7855(96)00018-5
61. Phillips, J. C.; Braun, R.; Wang, W.; Gumbart, J.; Tajkhorshid, E.; Villa, E.; Chipot, C.; Skeel, R. D.; Kale, L.; Schulten, K. Scalable molecular dynamics with NAMD J. Comput. Chem. 2005, 26, 1781-1802 10.1002/jcc.20289
62. Sievers, F.; Wilm, A.; Dineen, D.; Gibson, T. J.; Karplus, K.; Li, W.; Lopez, R.; McWilliam, H.; Remmert, M.; Soding, J.; Thompson, J. D.; Higgins, D. G. Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega Mol. Syst. Biol. 2011, 7, 539 10.1038/msb.2011.75