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Chemical Compound Review

statine     (3S,4S)-4-amino-3-hydroxy-6- methyl...

Synonyms: AHMHA, AG-F-66134, AC1L3XJJ, KB-60617, CTK8G3203, ...
 
 
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Disease relevance of statine

  • Relative to P1-P1' statine or Phe psi [CH2N]Pro-modified pseudopeptidyl inhibitors, compounds having Xaa psi[CH(OH)CH2]Yaa inserts were found to show significantly higher affinities to both enzymes, generally binding from 10 to 100 times stronger to HIV-1 protease than to the HIV-2 enzyme [1].
  • Based on the X-ray structure of the human immunodeficiency virus type-1 (HIV-1) protease in complex with the statine-derived inhibitor SDZ283-910, a 542 ps molecular dynamics trajectory was computed [2].
  • A series of inhibitors of human immunodeficiency virus type 1 (HIV-1) proteinase containing the 2-aralkyl-amino-substituted statine moiety as a novel transition-state analog was synthesized, with the aim to obtain compounds which combine anti-HIV potency with oral bioavailability [3].
  • Crystal structures of complexes of a D30N mutant of feline immunodeficiency virus protease (FIV PR) complexed with a statine-based inhibitor (LP-149), as well as with a substrate based on a modification of this inhibitor (LP-149S), have been solved and refined at resolutions of 2.0 and 1.85 A, respectively [4].
 

Psychiatry related information on statine

  • Unlike the statine series, we identified HE inhibitors without carboxylic acids on the C terminus, leading to enhanced cell penetration and making them attractive candidates for further drug development in Alzheimer's disease [5].
 

High impact information on statine

  • We report here new highly potent (IC50 = 10(-9)-10(-8) M) competitive inhibitors of renin in which statine, (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, is incorporated into analogues of the pig renin substrate (Fig. 1) [6].
  • Several x-ray structures of PMII have been described previously, but thus far, structure-guided drug design has been hampered by the fact that only inhibitors comprising a statine moiety or derivatives thereof have been published [7].
  • Simulation of the stopped-flow fluorescence transients provided estimates of the K(d) values of 1.4 +/- 0.2 microm and 39 +/- 2 nm for the piperidine and the fluorescently labeled statine, respectively [8].
  • To investigate the molecular basis for their high affinity for the GRPR, two classes of peptide antagonists, a statine analogue, JMV594 ([d-Phe(6),Stat(13)]Bn(6-14)), and a pseudopeptide analogue, JMV641 (d-Phe-Gln-Trp-Ala-Val-Gly-His-Leupsi(CHOH-CH(2))-(CH(2))(2)-CH(3)), were studied [9].
  • Inhibition of beta-site amyloid precursor protein-cleaving enzyme by a statine-based inhibitor has been studied using steady state and stopped-flow methods [10].
 

Chemical compound and disease context of statine

  • Various analogs of statine, a remarkable amino acid component of the protease inhibitor pepstatine, were synthesized and evaluated as tripeptide derivatives for their activity against cathepsin D and HIV-1 protease [11].
  • Two statine-based inhibitors of the enzyme, KH161 and KH164, were effective in blocking the replication of HIV-1 in acutely infected human T4 lymphoid cells, with potency approaching that of zidovudine (ZDV) when tested in parallel [12].
 

Biological context of statine

 

Anatomical context of statine

 

Associations of statine with other chemical compounds

 

Gene context of statine

  • A crystal structure of memapsin 2 complexed with a statine-based inhibitor spanning P(10)-P(4)' revealed the binding positions of P(5)-P(7) residues [23].
  • Novel renin inhibitors containing the amino acid statine [6].
  • Renin inhibitors. Syntheses of subnanomolar, competitive, transition-state analogue inhibitors containing a novel analogue of statine [24].
  • A set of 100 novel 2-heterosubstituted statine derivatives inhibiting human immunodeficiency virus type-1 proteinase has been investigated by comparative molecular field analysis [25].
  • RPR 103611 (14g), a statine derivative, was found to be inactive against HIV-1 protease, reverse transcriptase, and integrase as well as on gp120/CD4 binding. "Time of addition" experiments suggested interaction with an early step of HIV-1 replication [26].
 

Analytical, diagnostic and therapeutic context of statine

References

  1. Specificity and inhibition of proteases from human immunodeficiency viruses 1 and 2. Tomasselli, A.G., Hui, J.O., Sawyer, T.K., Staples, D.J., Bannow, C., Reardon, I.M., Howe, W.J., DeCamp, D.L., Craik, C.S., Heinrikson, R.L. J. Biol. Chem. (1990) [Pubmed]
  2. X-ray structure and conformational dynamics of the HIV-1 protease in complex with the inhibitor SDZ283-910: agreement of time-resolved spectroscopy and molecular dynamics simulations. Ringhofer, S., Kallen, J., Dutzler, R., Billich, A., Visser, A.J., Scholz, D., Steinhauser, O., Schreiber, H., Auer, M., Kungl, A.J. J. Mol. Biol. (1999) [Pubmed]
  3. SDZ PRI 053, an orally bioavailable human immunodeficiency virus type 1 proteinase inhibitor containing the 2-aminobenzylstatine moiety. Billich, A., Fricker, G., Müller, I., Donatsch, P., Ettmayer, P., Gstach, H., Lehr, P., Peichl, P., Scholz, D., Rosenwirth, B. Antimicrob. Agents Chemother. (1995) [Pubmed]
  4. Crystal structures of the inactive D30N mutant of feline immunodeficiency virus protease complexed with a substrate and an inhibitor. Laco, G.S., Schalk-Hihi, C., Lubkowski, J., Morris, G., Zdanov, A., Olson, A., Elder, J.H., Wlodawer, A., Gustchina, A. Biochemistry (1997) [Pubmed]
  5. Design and synthesis of hydroxyethylene-based peptidomimetic inhibitors of human beta-secretase. Hom, R.K., Gailunas, A.F., Mamo, S., Fang, L.Y., Tung, J.S., Walker, D.E., Davis, D., Thorsett, E.D., Jewett, N.E., Moon, J.B., John, V. J. Med. Chem. (2004) [Pubmed]
  6. Novel renin inhibitors containing the amino acid statine. Boger, J., Lohr, N.S., Ulm, E.H., Poe, M., Blaine, E.H., Fanelli, G.M., Lin, T.Y., Payne, L.S., Schorn, T.W., LaMont, B.I., Vassil, T.C., Stabilito, I.I., Veber, D.F., Rich, D.H., Bopari, A.S. Nature (1983) [Pubmed]
  7. X-ray structure of plasmepsin II complexed with a potent achiral inhibitor. Prade, L., Jones, A.F., Boss, C., Richard-Bildstein, S., Meyer, S., Binkert, C., Bur, D. J. Biol. Chem. (2005) [Pubmed]
  8. Novel inhibition of porcine pepsin by a substituted piperidine. Preference for one of the enzyme conformers. Marcinkeviciene, J., Kopcho, L.M., Yang, T., Copeland, R.A., Glass, B.M., Combs, A.P., Falahatpisheh, N., Thompson, L. J. Biol. Chem. (2002) [Pubmed]
  9. Molecular basis for selectivity of high affinity peptide antagonists for the gastrin-releasing peptide receptor. Tokita, K., Katsuno, T., Hocart, S.J., Coy, D.H., Llinares, M., Martinez, J., Jensen, R.T. J. Biol. Chem. (2001) [Pubmed]
  10. Mechanism of Inhibition of beta-site amyloid precursor protein-cleaving enzyme (BACE) by a statine-based peptide. Marcinkeviciene, J., Luo, Y., Graciani, N.R., Combs, A.P., Copeland, R.A. J. Biol. Chem. (2001) [Pubmed]
  11. Inhibition of cathepsin D by tripeptides containing statine analogs. Bessodes, M., Antonakis, K., Herscovici, J., Garcia, M., Rochefort, H., Capony, F., Lelièvre, Y., Scherman, D. Biochem. Pharmacol. (1999) [Pubmed]
  12. Impeded progression of Friend disease in mice by an inhibitor of retroviral proteases. Lai, M.H., Tang, J., Wroblewski, V., Dee, A.G., Margolin, N., Vlahos, C., Bowdon, B., Buckheit, R., Colacino, J., Hui, K.Y. J. Acquir. Immune Defic. Syndr. (1993) [Pubmed]
  13. Statine-containing renin inhibitor. Dissociation of blood pressure lowering and renin inhibition in sodium-deficient dogs. Blaine, E.H., Schorn, T.W., Boger, J. Hypertension (1984) [Pubmed]
  14. X-ray studies of aspartic proteinase-statine inhibitor complexes. Cooper, J.B., Foundling, S.I., Blundell, T.L., Boger, J., Jupp, R.A., Kay, J. Biochemistry (1989) [Pubmed]
  15. Pepstatin analogues as novel renin inhibitors. Guégan, R., Diaz, J., Cazaubon, C., Beaumont, M., Carlet, C., Clément, J., Demarne, H., Mellet, M., Richaud, J.P., Segondy, D. J. Med. Chem. (1986) [Pubmed]
  16. Molecular docking and 3D-QSAR studies on the binding mechanism of statine-based peptidomimetics with beta-secretase. Zuo, Z., Luo, X., Zhu, W., Shen, J., Shen, X., Jiang, H., Chen, K. Bioorg. Med. Chem. (2005) [Pubmed]
  17. Interaction of mouse submaxillary gland renin with a statine-containing, subnanomolar, competitive inhibitor. Poe, M., Perlow, D.S., Boger, J. J. Enzym. Inhib. (1985) [Pubmed]
  18. Biological activity of aspartic proteinase inhibitors related to pepstatin. Gunn, J.M., Owens, R.A., Liu, W.S., Glover, G.I. Acta Biol. Med. Ger. (1981) [Pubmed]
  19. Synthesis of all the stereoisomers of statine (4-amino-3-hydroxy-6-methylheptanoic acid). Inhibition of pepsin activity by N-carbobenzoxy-L-valyl-L-valyl-statine derived from the four stereoisomers. Liu, W.S., Smith, S.C., Glover, G.I. J. Med. Chem. (1979) [Pubmed]
  20. Synthesis of the novel pi-(benzyloxymethyl)-protected histidine analogue of statine. Inhibition of penicillopepsin by pepstatin-derived peptides containing different statine side-chain derivatives. Maibaum, J., Rich, D.H. J. Med. Chem. (1989) [Pubmed]
  21. 1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 1. Synthesis and biological properties of alkyl alcohol and statine derivatives. Roberts, D.A., Bradbury, R.H., Brown, D., Faull, A., Griffiths, D., Major, J.S., Oldham, A.A., Pearce, R.J., Ratcliffe, A.H., Revill, J. J. Med. Chem. (1990) [Pubmed]
  22. Anti-AIDS agents 49. Synthesis, anti-HIV, and anti-fusion activities of IC9564 analogues based on betulinic acid. Sun, I.C., Chen, C.H., Kashiwada, Y., Wu, J.H., Wang, H.K., Lee, K.H. J. Med. Chem. (2002) [Pubmed]
  23. Structural locations and functional roles of new subsites S5, S6, and S7 in memapsin 2 (beta-secretase). Turner, R.T., Hong, L., Koelsch, G., Ghosh, A.K., Tang, J. Biochemistry (2005) [Pubmed]
  24. Renin inhibitors. Syntheses of subnanomolar, competitive, transition-state analogue inhibitors containing a novel analogue of statine. Boger, J., Payne, L.S., Perlow, D.S., Lohr, N.S., Poe, M., Blaine, E.H., Ulm, E.H., Schorn, T.W., LaMont, B.I., Lin, T.Y. J. Med. Chem. (1985) [Pubmed]
  25. 3D-quantitative structure-activity relationships of human immunodeficiency virus type-1 proteinase inhibitors: comparative molecular field analysis of 2-heterosubstituted statine derivatives-implications for the design of novel inhibitors. Kroemer, R.T., Ettmayer, P., Hecht, P. J. Med. Chem. (1995) [Pubmed]
  26. Betulinic acid derivatives: a new class of specific inhibitors of human immunodeficiency virus type 1 entry. Soler, F., Poujade, C., Evers, M., Carry, J.C., Hénin, Y., Bousseau, A., Huet, T., Pauwels, R., De Clercq, E., Mayaux, J.F., Le Pecq, J.B., Dereu, N. J. Med. Chem. (1996) [Pubmed]
  27. Distribution of pepstatin and statine following oral and intravenous administration in rats. Tissue localisation by whole body autoradiography. Grant, D.A., Ford, T.F., McCulloch, R.J. Biochem. Pharmacol. (1982) [Pubmed]
 
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