Abstract
Proteases almost universally bind to their inhibitors and substrates in such a way that the component amino acid backbone is constrained into an extended β-strand conformation. One important general approach to inhibitor design, as discussed here, is to pre-organise the structure into this conformation. This can lead to improved potency, biostability, resistance to proteolytic degradation, and hence therapeutic potential. Here we present an overview of some different synthetic approaches that have been employed for introducing such a macrocycle, with reference to selected examples. We also briefly discuss some representative naturally occurring examples of such macrocyclic protease inhibitors.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Hilt W (2004) Ubiquitin-proteasome system - targets of programmed destruction: a primer to regulatory proteolysis in yeast. Cell Mol Life Sci 61:1615–1632
Hooper NM (2002) Proteases: a primer. Essays Biochem 38:1–8
Johnson LL, Dyer R, Hupe DJ (1998) Matrix metalloproteinases. Curr Opin Chem Biol 2:466–471
Beckett RP, Davidson AH, Drummond AH et al (1996) Recent advances in matrix metalloproteinase inhibitor research. Drug Discov Today 1:16–26
Biswas S, Harris F, Dennison S et al (2004) Calpains: targets of cataract prevention? Trends Mol Med 10:78–84
Nixon RA (2003) The calpains in aging and aging-related diseases. Ageing Res Rev 2:407–418
West ML, Fairlie DP (1995) Targeting Hiv-1 protease - a test of drug-design methodologies. Trends Pharmacol Sci 16:67–75
Tyndall JDA, Reid RC, Tyssen DP et al (2000) Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease. J Med Chem 43:3495–3504
Vassar R, Bennett BD, Babu-Khan S et al (1999) beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735–741
Schechte I, Berger A (1967) On size of active site in proteases. I. Papain. Biochem Biophys Res Commun 27:157
Cuerrier D, Moldoveanu T, Davies PL (2005) Determination of peptide substrate specificity for μ-calpain by a peptide library-based approach: the importance of primed side interactions. J Biol Chem 280:40632–40641
Loughlin WA, Tyndall JDA, Glenn MP et al (2010) Update 1 of: beta-strand mimetics. Chem Rev 110:Pr32–Pr69
Madala PK, Tyndall JDA, Nall T et al (2010) Update 1 of: proteases universally recognize beta strands in their active sites. Chem Rev 110:Pr1–Pr31
Adessi C, Soto C (2002) Converting a peptide into a drug: strategies to improve stability and bioavailability. Curr Med Chem 9:963–978
Gilon C, Halle D, Chorev M et al (1991) Backbone cyclization - a new method for conferring conformational constraint on peptides. Biopolymers 31:745–750
Borchardt R, Jeffrey A, Siahaan TJ et al (1997) Improvement of oral peptide bioavailability: peptidomimetics and prodrug strategies. Adv Drug Deliv Rev 27:235–256
Burton PS, Conradi RA, Ho NFH et al (1996) How structural features influence the biomembrane permeability of peptides. J Pharm Sci 85:1336–1340
McGeary RP, Fairlie DP (1998) Macrocyclic peptidomimetics: potential for drug development. Curr Opin Drug Discov Devel 1:208–217
Martin JL, Begun J, Schindeler A et al (1999) Molecular recognition of macrocyclic peptidomimetic inhibitors by HIV-1 protease. Biochemistry 38:7978–7988
Chen HY, Jiao WT, Jones MA et al (2012) New tripeptide-based macrocyclic calpain inhibitors formed by N-alkylation of histidine. Chem Biodivers 9:2473–2484
Reid RC, Kelso MJ, Scanlon MJ et al (2002) Conformationally constrained macrocycles that mimic tripeptide β-strands in water and aprotic solvents. J Am Chem Soc 124:5673–5683
Abell AD, Jones MA, Coxon JM et al (2009) Molecular modeling, synthesis, and biological evaluation of macrocyclic calpain inhibitors. Angew Chem Int Ed Engl 48:1455–1458
Jones MA, Coxon JM, McNabb SB et al (2009) Efficient large-scale synthesis of CAT811, a potent calpain inhibitor of interest in the treatment of cataracts. J Chem 62:671–675
Stuart BG, Coxon JM, Morton JD et al (2011) Molecular modeling: a search for a calpain inhibitor as a new treatment for cataractogenesis. J Med Chem 54:7503–7522
Tsantrizos YS, Bolger G, Bonneau P et al (2003) Macrocyclic inhibitors of the NS3 protease as potential therapeutic agents of hepatitis C virus infection. Angew Chem Int Ed Engl 42:1355–1360
Hanessian S, Yang GQ, Rondeau JM et al (2006) Structure-based design and synthesis of macroheterocyclic peptidomimetic inhibitors of the aspartic protease beta-site amyloid precursor protein cleaving enzyme (BACE). J Med Chem 49:4544–4567
Miller SJ, Blackwell HE, Grubbs RH (1996) Application of ring-closing metathesis to the synthesis of rigidified amino acids and peptides. J Am Chem Soc 118:9606–9614
Pehere AD, Abell AD (2012) New beta-strand templates constrained by Huisgen cycloaddition. Org Lett 14:1330–1333
Pehere AD, Sumby CJ, Abell AD (2013) New cylindrical peptide assemblies defined by extended parallel beta-sheets. Org Biomol Chem 11:425–429
Ebert M-O, Gardiner J, Ballet S et al (2009) Synthesis and high-resolution NMR structure of a β3-octapeptide with and without a tether introduced by olefin metathesis. Helv Chim Acta 92:2643–2658
Phillips AJ, Abell AD (1999) Ring-closing metathesis of nitrogen-containing compounds: applications to heterocycles, alkaloids and peptidomimetics. Aldrichim Acta 32:75–89
Machauer R, Laumen K, Veenstra S et al (2009) Macrocyclic peptidomimetic beta-secretase (BACE-1) inhibitors with activity in vivo. Bioorg Med Chem Lett 19:1366–1370
Ersmark K, Nervall M, Gutiérrez-de-Terán H et al (2006) Macrocyclic inhibitors of the malarial aspartic proteases plasmepsin I, II, and IV. Bioorg Med Chem 14(7):2197–2208
Stachel SJ, Coburn CA, Sankaranarayanan S et al (2006) Macrocyclic inhibitors of β-secretase: functional activity in an animal model. J Med Chem 49:6147–6150
Ghosh AK, Devasamudram T, Hong L et al (2005) Structure-based design of cycloamide–urethane-derived novel inhibitors of human brain memapsin 2 (β-secretase). Bioorg Med Chem Lett 15:15–20
Goudreau N, Brochu C, Cameron DR et al (2004) Potent inhibitors of the hepatitis C virus NS3 protease: design and synthesis of macrocyclic substrate-based β-strand mimics. J Org Chem 69:6185–6201
Machauer R, Veenstra S, Rondeau JM et al (2009) Structure-based design and synthesis of macrocyclic peptidomimetic beta-secretase (BACE-1) inhibitors. Bioorg Med Chem Lett 19:1361–1365
Pedersen DS, Abell A (2011) 1,2,3-Triazoles in peptidomimetic chemistry. Eur J Org Chem 2011:2399–2411
Pehere AD, Pietsch M, Gutschow M et al (2013) Synthesis and extended activity of triazole-containing macrocyclic protease inhibitors. Chem Eur J 19(24):7975–7981
Kase H, Kaneko M, Yamada K (1987) K-13, a novel inhibitor of angiotensin-I converting enzyme produced by micromonospora-halophytica subsp exilisia.1. Fermentation, isolation and biological properties. J Antibiot 40:450–454
Sano S, Ikai K, Katayama K et al (1986) Of4949, new inhibitors of aminopeptidase-B.2. Elucidation of structure. J Antibiot 39:1685–1696
Janetka JW, Satyshur KA, Rich DH (1996) A cyclic side-chain-linked biphenyl ether tripeptide: H3N + -cyclo-[Phe((4-0))-Phe-Phe((3-0))]-OMe.Cl-. Acta Crystallogr C 52:3112–3114
Janetka JW, Raman P, Satyshur K et al (1997) Novel cyclic biphenyl ether peptide beta-strand mimetics and HIV-protease inhibitors. J Am Chem Soc 119:441–442
Acknowledgement
Financial support from the Australian Research Council (ARC) is gratefully acknowledged.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media New York
About this chapter
Cite this chapter
Pehere, A.D., Abell, A.D. (2013). Macrocyclic Protease Inhibitors Constrained into a β-Strand Geometry. In: Chakraborti, S., Dhalla, N. (eds) Proteases in Health and Disease. Advances in Biochemistry in Health and Disease, vol 7. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9233-7_11
Download citation
DOI: https://doi.org/10.1007/978-1-4614-9233-7_11
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-9232-0
Online ISBN: 978-1-4614-9233-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)