Peptide Based Interleukin-1.BETA. Converting Enzyme(ICE) Inhibitors: Synthesis, Structure Activity Relationships and Crystallographic Study of the ICE-inhibitor Complex.

Abstract

Based on the X-ray structure of the complex of Ac-Tyr-Val-Ala-Asp-H (L-709049) and interleukin-1 beta converting enzyme (ICE), we synthesized compounds which were derived from 2-NapCO-Val-Pro-Asp-CH2OPh (1) to obtain a potent inhibitor in the cell assay. Among these compounds, (3S)-N-methanesulfonyl-3-[[1-[N-(2-naphthoyl)-L-valyl]-L-prolyl]amino]- 4-oxobutanamide (27c) showed high potency not only in the enzyme assay but also cell assay with IC50 values of 38 nM and 0.23 microM, respectively. Compound 27c, with a c log P value of 1.76, had a more hydrophilic character compared with 1. Compound 27c also dose dependently inhibited LPS-primed ATP-induced IL-1 beta release in mice. The crystal structure of the complex of compound 27c and ICE revealed that compound 27c had further interactions with ICE in the naphthoyl group at the P4 position and in the methyl group of the methanesulfonamidecarbonyl group at the P1 position, compared with L-709049. To our knowledge, compound 27c is the first example that shows a strong inhibitory activity without the carboxyl group at the P1 position.

Design and Development of Halogenated Chalcone Derivatives as Potential Anticancer Agents

“…In the present investigation, in silico docking studies were performed using the crystal structure of interleukin-1beta convertase (caspase-1) (PDB ID: 1BMQ) [13,21] to recognize the hypothetical binding mode of the ligands with the receptor in order to design a series of novel halogenated chalcone derivatives (7a-h) as possible anticancer agents. To investigate the ability of molecular docking to The docking pose closely resembled the cocrystallized conformation.…”

New Approaches and Therapeutics Targeting Apoptosis in Disease

“…Only a few classes of inhibitors without aspartate at P1 have been reported so far. One example was developed by Okamoto et al (1999) who replaced the P1 aspartate carboxyl group with an acyl-sulfonamide. The most potent compound of this series exhibited effective caspase inhibition not only in vitro (IC 50 38 nM), but also comparably in vivo (IC 50 230 nM).…”

Discovery of an allosteric site in the caspases

“…As critical mediators of apoptosis and the inflammatory response they represent an important class of drug targets for stroke, ischemia, cancer, and inflammatory diseases (2). The active sites of all caspases stringently prefer an electrophilic carbonyl and an aspartyl functionality that have frustrated drug discovery efforts (3)(4)(5)(6)(7), so despite their biological significance in cell death and survival, to date no caspase-directed therapies are available. Given the weighty consequences in cell survival for inappropriate activation, caspases are known to be regulated by both binding to inhibitor of apoptosis proteins (IAPs), and by proteolytic cleavage during zymogen activation (8).…”