Design, Synthesis, and Structure–Activity Relationship Study of Epoxysuccinyl–Peptide Derivatives as Cathepsin B Inhibitors

Abstract

Cathepsin B is a lysosomal cysteine protease involved in many diseases. The present research demonstrates that derivatives of epoxysuccinyl-peptide are effective and selective cathepsin B inhibitors. We synthesized a series of epoxysuccinyl-peptide derivatives based on the well-known cathepsin B inhibitor E64d. Specifically, we substituted the 2-methylpropane group at the R 1 position of E64d with a sulfane, such as ethyl(methyl) sulfane or benzyl(methyl) sulfane. We also designed and synthesized a library of molecules with various substituents at the R 2 position of E64d to replace 2-methylbutane. By studying the structure-activity relationships of these newly synthesized molecules as cathepsin B inhibitors, we demonstrated that substituting ethyl(methyl) sulfane for 2-methylbutane (R 2 ) of E64d improves the inhibitory activity and selectivity for cathepsin B inhibition. Our new cathepsin B inhibitors were highly effective and selective.

Trichomonas gallinae Kills Host Cells Using Trogocytosis

“…E-64D, a widespread cysteine protease inhibitor derived from a natural fungal product, has been investigated for myotonic dystrophy treatment. However, it has not demonstrated success in human clinical trials, despite ongoing research for its potential application in spinal cord injury, stroke, and Alzheimer’s disease [ 40 ]. Given its history of use in treating several diseases, we speculated on its potential as a drug for avian trichomoniasis.…”

Synthesis of Thiol‐Containing Oligopeptides via Tandem Activation of γ‐Thiolactones by Silver‐DABCO Pair

“…Boc‐Met‐NHHex (2 h) . White solid (2.12 g, 95%); R f =0.5 (EtOAc : Hexane=1 : 9); 1 H NMR (300 MHz, CDCl 3 ): δ 0.87 (t, J =6.9, 3H, n Hex‐CH 3 ), 1.22–1.35 (m, 6H, n Hex‐CH 2 ×3), 1.43 (s, 9H, C(CH 3 ) 3 ), 1.46–1.51 (m, 2H, NHCH 2 CH 2 ), 1.85–2.16 (m, 2H, Hβ), 2.10 (s, 3H, SCH 3 ), 2.45–2.62 (m, 2H, Hγ), 3.24 (td, J =6.6, 6.3, 2H, NHCH 2 ), 4.21 (td, J =7.5, 7.4, 2H, Hα), 5.18–5.20 (br.…”

Synthetic Approaches of Epoxysuccinate Chemical Probes

“…[31] One of the most encountered reactive groups of mechanism based ABP targeting papain family of the cysteine proteases is the epoxide which has been shown to label this type of enzyme efficiently and selectively. [32][33][34][35][36][37][38][39][40][41][42] The epoxide forms a thioether bond, irreversibly modifying the active site (Figure 1). [26,38,39,43,44] The origin of the epoxide "warhead" in the form of epoxysuccinates stems from the natural product E-64 (l-trans-epoxysuccinyl-leucylamido(4-guanidino)butane), which was initially isolated in 1978, from Aspergillus japonicus TPR-46 by Hanada and coworkers.…”

“…One of the most encountered reactive groups of mechanism based ABP targeting papain family of the cysteine proteases is the epoxide which has been shown to label this type of enzyme efficiently and selectively [32–42] . The epoxide forms a thioether bond, irreversibly modifying the active site (Figure 1).…”