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Chemical Compound Review

pepstatin     (3S,4S)-3-hydroxy-4-[[(2S)-2- [[(3S,4S)-3...

Synonyms: Pepstatine, Pepstatin A, Ia Quinidine, UPCMLD-DP141, IAP Antagonist, ...
 
 
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Disease relevance of pepstatin

  • In this report we show that retrovirus proteases belong to the aspartyl proteinase group and demonstrate an inhibition by the aspartyl proteinase-specific inhibitor, pepstatin A, on the activity of bovine leukaemia, Moloney murine leukaemia and human T-cell leukaemia virus proteases [1].
  • Pepstatin, an ascites retardant of L1210 tumor-bearing mice [2].
  • The treatment of cells with pepstatin at various times possibly retards the early stage of infection with murine sarcoma virus [3].
  • This cleavage was inhibited by pepstatin A, a known inhibitor of HIV protease [4].
  • The crystal structure of a pepstatin-insensitive carboxyl proteinase from Pseudomonas sp. 101 (PSCP) has been solved by single-wavelength anomalous diffraction using the absorption peak of bromide anions [5].
 

Psychiatry related information on pepstatin

 

High impact information on pepstatin

  • Monensin treatment resulted in morphologically abnormal endosomes, while pepstatin only inhibited VTG cleavage and the subsequent fusion of endosomes with yolk platelets [7].
  • Although progress has been made in the design of inhibitors for clinical use by modification of angiotensinogen sequences, and as pepstatin analogues or with reduced peptide bonds, we have now provided the basis for a more rational approach by the use of interactive computer graphics techniques to build a three-dimensional model of renin [8].
  • The effect of pepstatin on the kinetics of ascitic fluid accumulation in L1210 tumor-bearing mice (DBA/2) was observed [2].
  • The term "ascites retardant" is suggested for the pharmacologic actions of pepstatin, since it prevents fluid accumulation without diminishing the cell count [2].
  • Induction of CDR1 generates a small mobile signal, and CDR1 action is blocked by the protease inhibitor pepstatin and by mutations in the protease active sites [9].
 

Chemical compound and disease context of pepstatin

 

Biological context of pepstatin

 

Anatomical context of pepstatin

 

Associations of pepstatin with other chemical compounds

 

Gene context of pepstatin

  • The defective gene in this hereditary disorder, CLN2, encodes a recently identified lysosomal pepstatin-insensitive acid protease [30].
  • Results further demonstrate that the pathway can be blocked by treatment with pharmacologic doses of a specific protease inhibitor, pepstatin-A, even in the presence of a mutated NF-kappa B inhibitor, I-kappa B alpha [31].
  • Proteolysis was totally blocked by the protease inhibitor pepstatin A, and specificity of Cath-D cleavage was demonstrated using a large chemokine panel [32].
  • VEGF/FGF-2-stimulated tube formation was dependent on metalloproteinase function [it is inhibited by the addition of tissue inhibitor of metalloproteinases-2 (TIMP-2)], whereas aprotinin, E64 [trans-epoxysuccinyl-L-leucylamido (4-guanidino)-butane] and pepstatin had no effect [33].
  • Inhibition of cathepsin D by pepstatin A suppressed the activity of transglutaminase 1 [34].
 

Analytical, diagnostic and therapeutic context of pepstatin

References

  1. Inhibition of retroviral protease activity by an aspartyl proteinase inhibitor. Katoh, I., Yasunaga, T., Ikawa, Y., Yoshinaka, Y. Nature (1987) [Pubmed]
  2. Pepstatin, an ascites retardant of L1210 tumor-bearing mice. Greenbaum, L.M., Semente, G. J. Natl. Cancer Inst. (1977) [Pubmed]
  3. Effect of protease inhibitors on focus formation by murine sarcoma virus. Yuasa, Y., Shimojo, H., Aoyagi, T., Umezawa, H. J. Natl. Cancer Inst. (1975) [Pubmed]
  4. beta-Galactosidase containing a human immunodeficiency virus protease cleavage site is cleaved and inactivated by human immunodeficiency virus protease. Baum, E.Z., Bebernitz, G.A., Gluzman, Y. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  5. Carboxyl proteinase from Pseudomonas defines a novel family of subtilisin-like enzymes. Wlodawer, A., Li, M., Dauter, Z., Gustchina, A., Uchida, K., Oyama, H., Dunn, B.M., Oda, K. Nat. Struct. Biol. (2001) [Pubmed]
  6. Aspartyl protease inhibitor pepstatin binds to the presenilins of Alzheimer's disease. Evin, G., Sharples, R.A., Weidemann, A., Reinhard, F.B., Carbone, V., Culvenor, J.G., Holsinger, R.M., Sernee, M.F., Beyreuther, K., Masters, C.L. Biochemistry (2001) [Pubmed]
  7. Specific proteolysis regulates fusion between endocytic compartments in Xenopus oocytes. Opresko, L.K., Karpf, R.A. Cell (1987) [Pubmed]
  8. Three-dimensional structure, specificity and catalytic mechanism of renin. Blundell, T., Sibanda, B.L., Pearl, L. Nature (1983) [Pubmed]
  9. An extracellular aspartic protease functions in Arabidopsis disease resistance signaling. Xia, Y., Suzuki, H., Borevitz, J., Blount, J., Guo, Z., Patel, K., Dixon, R.A., Lamb, C. EMBO J. (2004) [Pubmed]
  10. Comparison of antigen presentation of influenza A nucleoprotein expressed in attenuated AroA- Salmonella typhimurium with that of live virus. Brett, S.J., Rhodes, J., Liew, F.Y., Tite, J.P. J. Immunol. (1993) [Pubmed]
  11. Ab initio molecular dynamics-based assignment of the protonation state of pepstatin A/HIV-1 protease cleavage site. Piana, S., Sebastiani, D., Carloni, P., Parrinello, M. J. Am. Chem. Soc. (2001) [Pubmed]
  12. Protease activity associated with loss of adhesiveness in mouse teratocarcinoma. Meyer, J.T., Thompson, P.M., Behringer, R., Steiner, R.C., Saxton, W.M., Oppenheimer, S.B. Exp. Cell Res. (1983) [Pubmed]
  13. Purification and characterization of a metallo-endoproteinase from mouse kidney. Beynon, R.J., Shannon, J.D., Bond, J.S. Biochem. J. (1981) [Pubmed]
  14. Synergistic Interactions of the Antiretroviral Protease Inhibitors Saquinavir and Ritonavir with Chloroquine and Mefloquine against Plasmodium falciparum In Vitro. Skinner-Adams, T.S., Andrews, K.T., Melville, L., McCarthy, J., Gardiner, D.L. Antimicrob. Agents Chemother. (2007) [Pubmed]
  15. Cathepsin D protease mediates programmed cell death induced by interferon-gamma, Fas/APO-1 and TNF-alpha. Deiss, L.P., Galinka, H., Berissi, H., Cohen, O., Kimchi, A. EMBO J. (1996) [Pubmed]
  16. Activity of purified biosynthetic proteinase of human immunodeficiency virus on natural substrates and synthetic peptides. Kräusslich, H.G., Ingraham, R.H., Skoog, M.T., Wimmer, E., Pallai, P.V., Carter, C.A. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  17. Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis. Erdal, H., Berndtsson, M., Castro, J., Brunk, U., Shoshan, M.C., Linder, S. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  18. The molecular structure and catalytic mechanism of a novel carboxyl peptidase from Scytalidium lignicolum. Fujinaga, M., Cherney, M.M., Oyama, H., Oda, K., James, M.N. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  19. Role of macrophage lysosomal enzymes in the degradation of nucleosomes of apoptotic cells. Odaka, C., Mizuochi, T. J. Immunol. (1999) [Pubmed]
  20. Fibronectin receptors of human keratinocytes and their expression during cell culture. Toda, K., Tuan, T.L., Brown, P.J., Grinnell, F. J. Cell Biol. (1987) [Pubmed]
  21. Identification of beta-secretase-like activity using a mass spectrometry-based assay system. Grüninger-Leitch, F., Berndt, P., Langen, H., Nelboeck, P., Döbeli, H. Nat. Biotechnol. (2000) [Pubmed]
  22. Inflamed fibronectin: an altered fibronectin enhances neutrophil adhesion. Vercellotti, G.M., McCarthy, J., Furcht, L.T., Jacob, H.S., Moldow, C.F. Blood (1983) [Pubmed]
  23. Stress-induced apoptosis is impaired in cells with a lysosomal targeting defect but is not affected in cells synthesizing a catalytically inactive cathepsin D. Tardy, C., Tyynelä, J., Hasilik, A., Levade, T., Andrieu-Abadie, N. Cell Death Differ. (2003) [Pubmed]
  24. Prolongation of serum half-life of interleukin 2 and augmentation of lymphokine-activated killer cell activity by pepstatin in mice. Ohnishi, H., Lin, K.M., Chu, T.M. Cancer Res. (1990) [Pubmed]
  25. Proteases in cyst fluid from human gross cyst breast disease. Kesner, L., Yu, W.S., Bradlow, H.L., Breed, C.W., Fleisher, M. Cancer Res. (1988) [Pubmed]
  26. Cleavage of the calpain inhibitor, calpastatin, during apoptosis. Pörn-Ares, M.I., Samali, A., Orrenius, S. Cell Death Differ. (1998) [Pubmed]
  27. Human BACE forms dimers and colocalizes with APP. Schmechel, A., Strauss, M., Schlicksupp, A., Pipkorn, R., Haass, C., Bayer, T.A., Multhaup, G. J. Biol. Chem. (2004) [Pubmed]
  28. The mechanism of basophil histamine release induced by pepstatin A. Marone, G., Columbo, M., Soppelsa, L., Condorelli, M. J. Immunol. (1984) [Pubmed]
  29. Mode of inhibition of acid proteases by pepstatin. Marciniszyn, J., Hartsuck, J.A., Tang, J. J. Biol. Chem. (1976) [Pubmed]
  30. Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder. Sleat, D.E., Gin, R.M., Sohar, I., Wisniewski, K., Sklower-Brooks, S., Pullarkat, R.K., Palmer, D.N., Lerner, T.J., Boustany, R.M., Uldall, P., Siakotos, A.N., Donnelly, R.J., Lobel, P. Am. J. Hum. Genet. (1999) [Pubmed]
  31. Hodgkin disease: pharmacologic intervention of the CD40-NF kappa B pathway by a protease inhibitor. Annunziata, C.M., Safiran, Y.J., Irving, S.G., Kasid, U.N., Cossman, J. Blood (2000) [Pubmed]
  32. Cathepsin D specifically cleaves the chemokines macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta, and SLC that are expressed in human breast cancer. Wolf, M., Clark-Lewis, I., Buri, C., Langen, H., Lis, M., Mazzucchelli, L. Am. J. Pathol. (2003) [Pubmed]
  33. Endothelial tubulogenesis within fibrin gels specifically requires the activity of membrane-type-matrix metalloproteinases (MT-MMPs). Lafleur, M.A., Handsley, M.M., Knäuper, V., Murphy, G., Edwards, D.R. J. Cell. Sci. (2002) [Pubmed]
  34. Cathepsin D is involved in the regulation of transglutaminase 1 and epidermal differentiation. Egberts, F., Heinrich, M., Jensen, J.M., Winoto-Morbach, S., Pfeiffer, S., Wickel, M., Schunck, M., Steude, J., Saftig, P., Proksch, E., Schütze, S. J. Cell. Sci. (2004) [Pubmed]
  35. Cathepsin D-mediated processing of procollagen: lysosomal enzyme involvement in secretory processing of procollagen. Helseth, D.L., Veis, A. Proc. Natl. Acad. Sci. U.S.A. (1984) [Pubmed]
  36. Human immunodeficiency virus has an aspartic-type protease that can be inhibited by pepstatin A. Seelmeier, S., Schmidt, H., Turk, V., von der Helm, K. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  37. The biosynthetic pathway of renin in mouse submandibular gland. Catanzaro, D.F., Mullins, J.J., Morris, B.J. J. Biol. Chem. (1983) [Pubmed]
  38. Accelerated amyloid deposition in mice treated with the aspartic protease inhibitor, pepstatin. Yamada, T., Liepnieks, J., Benson, M.D., Kluve-Beckerman, B. J. Immunol. (1996) [Pubmed]
 
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