Abstract
Thirty optically active nonprotein α-amino acids and peptides based thereon have been screened for their ability to interact with bovine trypsin and proteinase K from Tritirachium album Limber, which belong to the group of serine proteases. Both structure-based drug design approach and determination of enzyme activity have been used to identify low molecular weight inhibitors of trypsin and proteinase K. Compounds have been selected that according to the docking analysis were able to interact with trypsin and proteinase K. Following the docking analysis measurement of enzymes activity (2R,3S)-β-hydroxyleucine and (2S,3R)-β-hydroxyleucine inhibited both enzymes activity, whereas (S)-α-methyl-β-phenylalanine, (R)-α-methyl-β-phenylalanine, (S)-allylglycine, (R)-allylglycine, (S)-α-allylalanine, (R)-α-allylalanine and allo-O-ethylthreonine inhibited only proteinase K; and N-formyl-(S)-methionyl-(2S,3R)-hydroxyleucine, N-formyl-(S)-methionyl-(2R,3S)-hydroxyleucine, N-formyl-(S)-methionyl-(S)-allylglycine and N-formyl-(S)-methionyl-(R)-allylglycine inhibited trypsin. It has been shown that inhibition of trypsin by (2R,3S)-β-hydroxyleucine and N-formyl-(S)-methionyl-(2R,3S)-hydroxyleucine is of a competitive mode.
Similar content being viewed by others
Change history
10 March 2023
A Correction to this paper has been published: https://doi.org/10.1007/s00726-023-03259-4
References
Barrett GC (ed) (1985) Chemistry and biochemistry of the amino acids. Chapman and Hall, London
Cornish-Bowden A (ed) (1979) Principles of enzyme kinetics. Butterworth & Co. 78-102
Coughlin P, Sun J, Cerruti L, Salem HH, Bird P (1993) Cloning and molecular characterization of a human intracellular serine proteinase inhibitor. Proc Natl Acad Sci USA 90:9417–9421
Gade W, Brown JL (1981) Purification, characterization and possible function of alpha-N-acylamino acid hydrolase from bovine liver. Biochim Biophys Acta 13:86–93
Goulet MT (1995) Synthesis and structure—activity relations of thieno[2, 3 α-]pyridine-2, 4-dione derivatives as potent GnRH receptor antagonosts. Annu Rep Med Chem 30:169–177
Hsu JTA, Wang H-Ch, Chen G-Wu, Shih Sh-Ru (2006) Antiviral drug discovery targeting to viral proteases. Curr Pharm Des 12:1301–1314
Miller A, Hinrichs W, Womn WM, Saengerj W (1994) Crystal structure of calcium-free proteinase K at 1.5-A resolution. J Biol Chem 269:23108–23111
Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a Lamarcian genetic algorithm and empirical binding free energy function. J Comput Chem 19:1639–1662
Mueller NH, Yon C, Ganesh VK, Padmanabhan R (2007) Characterization of the West Nile virus protease substrate specificity and inhibitors. Int J Biochem Cell Biol 39:606–614
Murthy KHM, Clum S, Padmanabhan R (1999) Dengue virus NS3 serine protease. J Biol Chem 274:5573–5580
Rinderknecht H (1993) Pancreatic secretory enzymes. In: Go VLW, D iMagno EP, Gardner JD, Lebenthal E, Reber HA, Scheele GA (eds) The pancreas: biology, pathobiology, and disease. Raven, New York, pp 219–251
Schramm HJ, Boetzel J, Butnnner J, Fritsche E, Gohring W, Jaeger E, Konig S, Thumfart O, Wenger T, Nagel NE, Schramm W (1995) The inhibition of human immunodeficiency virus proteases by ‘interface peptides’. Antiviral Res 30:155–170
Shapiro L, Pott GB, Ralston AH (2001) Alpha-1-antitrypsin inhibits human immunodeficiency virus type 1. FASEB J 15:115–122
Steinkulher C, Kock U, Narjes F, Matassa VG (2001) Hepatitis C virus serine protease inhibitors: current progress and future challenges. Curr Med Chem 8:919–932
Stroud RM, Kay LM, Dickerson RE (1974) The structure of bovine trypsin: electron density maps of the inhibited enzyme at 5 Angstrom and 2–7 Angstrom resolutions. J Mol Biol 83:185–208
Van Der Baan J, Barnik J, Bickelhaupt F (1983) Antibiotic A 19009. Structural investigation and synthesis. Antibiotics 36:784–790
Worthington (1997) Enzymes and related biochemicals. Millipore Corporation, Bredford, pp 197–198
Zablotna E, Kret A, Jaskiewicz A, Olma A, Leplawy MT, Rolka K (2006) Introduction of alpha- hydroxymethylamino acid residues in substrate specificity P1 position of trypsin inhibitor SFTI-1 from sunflower seeds retain its activity. Biochem Biophys Res Commun 340:823–828
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hovhannisyan, N., Harutyunyan, S., Hovhannisyan, A. et al. The novel inhibitors of serine proteases. Amino Acids 37, 531–536 (2009). https://doi.org/10.1007/s00726-009-0257-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-009-0257-4