“…Although the peptidyl boronate was the best of the series, it was still a relatively weak inhibitor comparable with the parent chloromethylketone, and it was not clear how to further improve its potency. The ketoamide was about 25-fold less potent, but since it could be extended to the prime side by a modification at the ketoamide nitrogen ( Chatterjee et al., 1999 , Liu et al., 2004 ), we next focused our attention on this class of compounds. Figure 2 A Screen of Electrophilic Warheads for the Inhibition of Rhomboid Proteases The optimized parent sequence Ac-RVRHA was linked to electrophilic warheads commonly used for targeting serine proteases (reviewed in Hedstrom, 2002 , Walker and Lynas, 2001 ).…”
SummaryRhomboid-family intramembrane proteases regulate important biological processes and have been associated with malaria, cancer, and Parkinson's disease. However, due to the lack of potent, selective, and pharmacologically compliant inhibitors, the wide therapeutic potential of rhomboids is currently untapped. Here, we bridge this gap by discovering that peptidyl α-ketoamides substituted at the ketoamide nitrogen by hydrophobic groups are potent rhomboid inhibitors active in the nanomolar range, surpassing the currently used rhomboid inhibitors by up to three orders of magnitude. Such peptidyl ketoamides show selectivity for rhomboids, leaving most human serine hydrolases unaffected. Crystal structures show that these compounds bind the active site of rhomboid covalently and in a substrate-like manner, and kinetic analysis reveals their reversible, slow-binding, non-competitive mechanism. Since ketoamides are clinically used pharmacophores, our findings uncover a straightforward modular way for the design of specific inhibitors of rhomboid proteases, which can be widely applicable in cell biology and drug discovery.
“…Although the peptidyl boronate was the best of the series, it was still a relatively weak inhibitor comparable with the parent chloromethylketone, and it was not clear how to further improve its potency. The ketoamide was about 25-fold less potent, but since it could be extended to the prime side by a modification at the ketoamide nitrogen ( Chatterjee et al., 1999 , Liu et al., 2004 ), we next focused our attention on this class of compounds. Figure 2 A Screen of Electrophilic Warheads for the Inhibition of Rhomboid Proteases The optimized parent sequence Ac-RVRHA was linked to electrophilic warheads commonly used for targeting serine proteases (reviewed in Hedstrom, 2002 , Walker and Lynas, 2001 ).…”
SummaryRhomboid-family intramembrane proteases regulate important biological processes and have been associated with malaria, cancer, and Parkinson's disease. However, due to the lack of potent, selective, and pharmacologically compliant inhibitors, the wide therapeutic potential of rhomboids is currently untapped. Here, we bridge this gap by discovering that peptidyl α-ketoamides substituted at the ketoamide nitrogen by hydrophobic groups are potent rhomboid inhibitors active in the nanomolar range, surpassing the currently used rhomboid inhibitors by up to three orders of magnitude. Such peptidyl ketoamides show selectivity for rhomboids, leaving most human serine hydrolases unaffected. Crystal structures show that these compounds bind the active site of rhomboid covalently and in a substrate-like manner, and kinetic analysis reveals their reversible, slow-binding, non-competitive mechanism. Since ketoamides are clinically used pharmacophores, our findings uncover a straightforward modular way for the design of specific inhibitors of rhomboid proteases, which can be widely applicable in cell biology and drug discovery.
“…The difference in calpain inhibitory potency was attributed to the inability of 34 to form a critical hydrogen bond at the active site of the enzyme. In a recent study, Chatterjee et al [110] reported a series of potent calpain I inhibitors such as 35 and 36 with substituents spanning the S' subsite of calpain.…”
Section: Sar Of the Address Region Of Calpain Inhibitorsmentioning
confidence: 99%
“…These examples clearly demonstrate that benzoheterocycles are good peptide mimetic replacements for Leu or Val at P 2 . Additionally, it has recently been demonstrated that replacement of the P 2 residue of α-ketoamides such as 60 (Ki = 10 nM) with a 2,6 difluorobenzoyl group as in 61 (Ki = 14 nM) affords equipotent calpain inhibitors [110]. This study revealed that the binding affinity offered by substituents spanning the P' address region of α-ketoamide inhibitors of calpain can adequately offset the loss in binding affinity due to the absence of a P 2 -amino acid residue.…”
Section: Sar Of the Address Region Of Calpain Inhibitorsmentioning
Calpain is unique among the cysteine protease family of enzymes in that it combines thiol protease activity with calmodulin-like activity. Despite its wide spread distribution the exact physiological function(s) of calpain is yet to be deciphered. The enzyme is however, implicated in a number of pathophysiological conditions. Due to the potential of calpain as a therapeutic target a number of inhibitors have been described for the enzyme. In this article we have grouped calpain inhibitors into those derived from natural sources, and those derived from chemical synthesis. Additionally, an overview of functional groups that have been used as warheads of calpain inhibitors is presented along with a discussion of the structure activity relationship studies of the address region of peptidyl calpain inhibitors. Recent work in this area has led to a better understanding of the structural requirements for tight binding of inhibitors to the active site of calpain. A discussion of peptidomimetic calpain inhibitors, nonpeptide calpain inhibitors, and selectivity of some calpain inhibitors are also presented. The recent disclosure of the crystal structure of a nonpeptide calpain inhibitor bound to a hydrophobic pocket on the calcium-binding domain of calpain has opened the door to future development of potent cell permeable nonpeptide calpain inhibitors.
“…[1, 2] In addition, they offer many applications in av ariety of chemical transformations. [3,4] The importance of such al inkagec an be inferred from the amount of work that has gone into the development of chemistry around a-ketoamides in past few years. [5, 6] Our continued interesti n the use of commercially available terminal alkynes as coupling partners under different conditions [7] prompted us to revisit certainv aluable reactions known to construct a-ketoamides.…”
As imple and practical method for synthesizing a-ketoamidesh as been developed involving Cu(OTf) 2 -promoted oxidative amidation-diketonization of terminal alkynes with primary/secondary amines. This method has aw ide substrate scope, and atmospheric oxygen acts as the oxidant.
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