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.[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.

## 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.[4]

See also

* Aloxistatin

## References

1. ↑ "Isolation and Characterization of E–64, a New Thiol Protease Inhibitor". Agric. Biol. Chem. 42 (3): 523–528. 1978. doi:10.1080/00021369.1978.10863014.
2. ↑ 2.0 2.1 "Crystal structure of a papain-E-64 complex". Biochemistry 28 (3): 1332–2. 1989. doi:10.1021/bi00429a058. PMID 2713367.
3. ↑ "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. doi:10.1042/bj2010189. PMID 7044372.
4. ↑ Liu, Mengting; Zang, Xin; Vlahakis, Niko W.; Rodriguez, Jose A.; Ohashi, Masao; Tang, Yi (November 2025). "Enzymatic combinatorial synthesis of E-64 and related cysteine protease inhibitors" (in en). Nature Chemical Biology 21 (11): 1783–1793. doi:10.1038/s41589-025-01907-2. ISSN 1552-4469. PMID 40346252.

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