Discovery of Novel Epoxyketone Peptides as Lipase Inhibitors

Abstract

Obesity is the most common nutritional disorder in the developed world and is associated with important comorbidities. Pancreatic lipase (PL) inhibitors play a key role in the metabolism of human fat. A series of novel epoxyketones peptide derivatives were investigated for their pancreatic lipase inhibitory activity. The epoxyketone moiety is a well-known reactive electrophile group that has been used as part of proteasome inhibitors in cancer therapy, and it is widely believed that these are very selective for targeting the proteasome active site. Here we investigated various peptide derivatives with an epoxide warhead for their anti-lipase activity. The assessment of these novel epoxyketones was performed by an in-house method that we developed for rapid screening and identification of lipase inhibitors using GC-FID. Herein, we present a novel anti-lipase pharmacophore based on epoxyketone peptide derivatives that showed potent anti-lipase activity. Many of these derivatives had comparable or more potent activity than the clinically used lipase inhibitors such as orlistat. In addition, the lipase appears to be inhibited by a wide range of epoxyketone analogues regardless of the configuration of the epoxide in the epoxyketone moiety. The presented data in this study shows the first example of the use of epoxyketone peptides as novel lipase inhibitors.

Covalent macrocyclic proteasome inhibitors mitigate resistance inPlasmodium falciparum

“…The instability of 8304-epoxy is likely due to the susceptibility of the epoxy ring opening as well as the epoxyketone being a substrate for other enzymes such as serine hydrolases, while the vinyl sulfone is much more stable due to its lower general reactivity. 30,31 These results reinforce our previous work in suggesting that the vinyl sulfone is the optimal electrophilic warhead for the development of an irreversible covalent proteasome drug inhibitor.…”

Covalent Macrocyclic Proteasome Inhibitors Mitigate Resistance in Plasmodium falciparum

“…However, it was much less stable than 8304-vs in both human and mouse microsomes (Figure S9). The instability of 8304-epoxy is likely due to the susceptibility of the epoxy ring opening as well as the epoxyketone being a substrate for other enzymes such as serine hydrolases, while the vinyl sulfone is much more stable due to its lower general reactivity. , These results reinforce our previous work in suggesting that the vinyl sulfone is the optimal electrophilic warhead for the development of an irreversible covalent proteasome drug.…”

A rationally engineered specific near-infrared fluorogenic substrate of human pancreatic lipase for functional imaging and inhibitor screening

“…Over the past few decades, versatile compounds exhibiting strong PL inhibitory activities have been identified, among which, orlistat, the only FDA-approved PL inhibitor for weight loss, has a significant inhibitory effect. [13][14][15][16] Nevertheless, the side effects of orlistat such as the possibility of headaches and hepatitis should be noted. 17,18 Recently, there has been growing evidence that some herbs showcase the potential to suppress obesity and can be used as natural alternative therapies against obesity with fewer side effects.…”