E-64 Explained

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

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]

See also

• Aloxistatin

Notes and References

1. Hanada K, Tamai M, Yamagishi M, Ohmura S, Sawada J, Tanaka I . Isolation and Characterization of E–64, a New Thiol Protease Inhibitor. Agric. Biol. Chem. . 42 . 3. 523–528. 1978 . 10.1080/00021369.1978.10863014. free.
2. Varughese K, Ahmed F, Carey P, Hasnain S, Huber C, Storer A . Crystal structure of a papain-E-64 complex . Biochemistry . 28 . 3 . 1332–2. 1989 . 2713367 . 10.1021/bi00429a058.
3. Barrett A, Kembhavi A, Brown M, Kirschke H, Knight C, Tamai M, Hanada K . 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. 1982 . 7044372 . 10.1042/bj2010189. 1163625.