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E-64

E-64

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. It has since been shown to inhibit many cysteine peptidases such as papain, cathepsin B, cathepsin L, calpain and staphopain.

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, however published crystal structures of E-64 complexed with papain indicated that E-64 binds via the S subsites.

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

Biosynthesis of E-64

The biosynthetic pathway of E-64 was elucidated by the Tang group at UCLA, who identified the enzymes responsible for constructing the epoxysuccinyl warhead and assembling the peptide scaffold. This work enabled enzymatic synthesis of diverse E-64–related cysteine protease inhibitors.

See also

  • Aloxistatin

References

References

  1. (1978). "Isolation and Characterization of E–64, a New Thiol Protease Inhibitor". Agric. Biol. Chem..
  2. (1989). "Crystal structure of a papain-E-64 complex". Biochemistry.
  3. (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..
  4. (November 2025). "Enzymatic combinatorial synthesis of E-64 and related cysteine protease inhibitors". Nature Chemical Biology.
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epoxides guanidines protease-inhibitors carboxylic-acids carboxamides dipeptides
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