E-64

E-64 is an epoxide which can irreversibly inhibit a wide range of cysteine peptidases.

E-64
Names
IUPAC name
(1S,2S)-2-(((S)-1-((4-Guanidinobutyl)amino)-4-methyl-1-oxopentan-2-yl)carbamoyl)cyclopropanecarboxylic acid
Other names
E 64; Proteinase Inhibitor E 64; N-[N-(L-3-trans-carboxyirane-2-carbonyl)-L-leucyl]-agmatine; [1-[N-[(L-3-trans-carboxyoxirane-2-carbonyl)-L-leucyl]amino]-4-guanidinobutane]
Identifiers
3D model (JSmol)
6666631
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.130.729
EC Number
  • 613-978-4
KEGG
UNII
  • InChI=1S/C15H27N5O5/c1-8(2)7-9(20-13(22)10-11(25-10)14(23)24)12(21)18-5-3-4-6-19-15(16)17/h8-11H,3-7H2,1-2H3,(H,18,21)(H,20,22)(H,23,24)(H4,16,17,19)/t9-,10-,11-/m0/s1
    Key: LTLYEAJONXGNFG-DCAQKATOSA-N
  • InChI=1/C15H27N5O5/c1-8(2)7-9(20-13(22)10-11(25-10)14(23)24)12(21)18-5-3-4-6-19-15(16)17/h8-11H,3-7H2,1-2H3,(H,18,21)(H,20,22)(H,23,24)(H4,16,17,19)/t9-,10-,11-/m0/s1
    Key: LTLYEAJONXGNFG-DCAQKATOBY
  • OC([C@@H]1[C@@H](C(N[C@@H](CC(C)C)C(NCCCCNC(N)=N)=O)=O)O1)=O
Properties
C15H27N5O5
Molar mass 357.411 g·mol−1
Hazards
GHS labelling:
GHS08: Health hazard
Warning
H371
P260, P264, P270, P309+P311, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

The compound was first isolated and identified from Aspergillus japonicus in 1978.[1] It has since been shown to inhibit many cysteine peptidases such as papain, cathepsin B, cathepsin L, calpain and staphopain.[2]

The low toxic effects of the inhibitor, in addition to its effective mechanism of action, makes E-64 a potential template for drugs to treat diseases where high levels of a cysteine proteases are the primary cause.

Structure and mechanism of inhibition

E-64 possesses a trans-epoxysuccinic acid group coupled to a modified dipeptide. The covalent attachment of E-64 to the active site cysteine occurs via nucleophillic attack from the thiol group of the cysteine on C2 of the epoxide. Early studies suggested that the amino-4-guanidinobutane bound in the S3' subsite and the leucyl group in the S2' subsite,[3] however published crystal structures of E-64 complexed with papain indicated that E-64 binds via the S subsites.[2]

Mechanism of irreversible inhibition of cysteine peptidases by E-64.

See also

References
  1. Hanada K, Tamai M, Yamagishi M, Ohmura S, Sawada J, Tanaka I (1978). "Isolation and Characterization of E–64, a New Thiol Protease Inhibitor". Agric. Biol. Chem. 42 (3): 523–528. doi:10.1080/00021369.1978.10863014.
  2. Varughese K, Ahmed F, Carey P, Hasnain S, Huber C, Storer A (1989). "Crystal structure of a papain-E-64 complex". Biochemistry. 28 (3): 1332–2. doi:10.1021/bi00429a058. PMID 2713367.
  3. Barrett A, Kembhavi A, Brown M, Kirschke H, Knight C, Tamai M, Hanada K (1982). "L-trans-Epoxysuccinyl-leucylamido(4-guanidino)butane (E-64) and its analogues as inhibitors of cysteine proteinases including cathepsins B, H and L." Biochem. J. 201 (1): 189–98. doi:10.1042/bj2010189. PMC 1163625. PMID 7044372.
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