A5017935803- Peptidase Inhibition and Analysis
- Diabetes Treatment and Management
- Neuropeptides and Animal Physiology
- Cell death mechanisms and regulation
- Pancreatic function and diabetes
- Chemical Synthesis and Analysis
- Ubiquitin and proteasome pathways
- Phagocytosis and Immune Regulation
- Autophagy in Disease and Therapy
- Trace Elements in Health
- Mitochondrial Function and Pathology
- Metabolism, Diabetes, and Cancer
- RNA and protein synthesis mechanisms
- Inflammatory mediators and NSAID effects
- Receptor Mechanisms and Signaling
- Biochemical and Molecular Research
- Synthesis and Biological Evaluation
- Cytokine Signaling Pathways and Interactions
- Monoclonal and Polyclonal Antibodies Research
- PARP inhibition in cancer therapy
- interferon and immune responses
- Enzyme Structure and Function
- Bioactive Compounds and Antitumor Agents
- Blood Coagulation and Thrombosis Mechanisms
- DNA Repair Mechanisms
Kallyope (United States)
2017-2021
Merck & Co., Inc., Rahway, NJ, USA (United States)
2007-2017
Duke Medical Center
1994-2012
Duke University Hospital
1994-2012
Duke University
2012
Harvard University
2003
Merck Canada Inc. (Canada)
1997-2003
Merck Institute for Science Education
2003
Cold Spring Harbor Laboratory
1998
Johns Hopkins University
1996-1998
There is compelling evidence that members of the caspase (interleukin-1β converting enzyme/CED-3) family cysteine proteases and cytotoxic lymphocyte-derived serine protease granzyme B play essential roles in mammalian apoptosis. Here we use a novel method employing positional scanning substrate combinatorial library to rigorously define their individual specificities. The results divide these into three distinct groups suggest several have redundant functions. specificity caspases 2, 3, 7...
Studies with peptide-based and macromolecular inhibitors of the caspase family cysteine proteases have helped to define a central role for these enzymes in inflammation mammalian apoptosis. A clear interpretation studies has been compromised by an incomplete understanding selectivity molecules. Here we describe several coxpox serpin CrmA against 10 human caspases. The peptide aldehydes that were examined (Ac-WEHD-CHO, Ac-DEVD-CHO, Ac-YVAD-CHO,<i>t</i>-butoxycarbonyl-IETD-CHO,...
A novel series of β-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors dipeptidyl peptidase IV (DPP-IV) for the treatment type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (1) is a potent, orally active DPP-IV inhibitor (IC50 = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in...
Ezetimibe is a potent inhibitor of cholesterol absorption that has been approved for the treatment hypercholesterolemia, but its molecular target elusive. Using genetic approach, we recently identified Niemann-Pick C1-Like 1 (NPC1L1) as critical mediator and an essential component ezetimibe-sensitive pathway. To determine whether NPC1L1 direct ezetimibe, have developed binding assay shown labeled ezetimibe glucuronide binds specifically to single site in brush border membranes human...
Proteolysis mediated by the interleukin 1 beta-converting enzyme (ICE) homologues is an important mechanism of apoptotic process. The ICE homologue apopain/CPP-32/Yama (subsequently referred to as apopain) cleaves poly(ADP-ribose)polymerase (PARP) early during apoptosis. Additional apoptosis-specific protein cleavages have been observed in which direct involvement ICE-like proteases has postulated. These substrates include 70-kD component U1-ribonucleoprotein (U1-70kD), and catalytic subunit...
The neurodegenerative diseases Huntington disease, dentatorubropallidoluysian atrophy, spinocerebellar atrophy type 3, and spinal bulbar muscular are caused by expansion of a polyglutamine tract within their respective gene products. There is increasing evidence that generation truncated proteins containing an expanded may be key step in the pathogenesis these disorders. We now report that, similar to huntingtin, atrophin-1, ataxin-3, androgen receptor cleaved apoptotic extracts....
Dipeptidyl peptidase (DPP)-IV inhibitors are a new approach to the treatment of type 2 diabetes. DPP-IV is member family serine peptidases that includes quiescent cell proline dipeptidase (QPP), DPP8, and DPP9; key regulator incretin hormones, but functions other members unknown. To determine importance selective inhibition for diabetes, we tested DPP-IV, DPP8/DPP9, or QPP in 2-week rat toxicity studies acute dog tolerability studies. In rats, DPP8/9 inhibitor produced alopecia,...
Cysteine proteases of the interleukin 1β Converting Enzyme (ICE)/CED-3 family have been implicated in effector process apoptosis several systems, including Fas-mediated apoptosis. We recently isolated and partially characterized a protease present extracts from anti-Fas antibody treated Jurkat T cells that promotes apoptotic changes nuclei (Schlegel, J., Peters, I., Orrenius, S.(1995) FEBS Lett. 364, 139-142). now show this cleaves poly(ADP-ribose) polymerase (PARP) with high efficiency...
Inhibitors of dipeptidyl peptidase-4 (DPP-4), a key regulator the actions incretin hormones, exert antihyperglycemic effects in type 2 diabetic patients. A major unanswered question concerns potential ability DPP-4 inhibition to have beneficial disease-modifying effects, specifically attenuate loss pancreatic beta-cell mass and function. Here, we investigated potent selective inhibitor, an analog sitagliptin (des-fluoro-sitagliptin), on glycemic control function mouse model with defects...
Caspase-3–mediated proteolysis is a critical element of the apoptotic process. Recent studies have demonstrated central role for mitochondrial proteins (e.g., Bcl-2 and cytochrome c) in activation caspase-3, by process that involves interaction several protein molecules. Using antibodies specifically recognize precursor form we demonstrate caspase-3 proenzyme has cytosolic distribution nonapoptotic cells. The contained intermembrane space. Delivery variety stimuli accompanied loss staining...
Oxyntomodulin (OXM) is a glucagon-like peptide 1 (GLP-1) receptor (GLP1R)/glucagon (GCGR) dual agonist that reduces body weight in obese subjects through increased energy expenditure and decreased intake. The metabolic effects of OXM have been attributed primarily to GLP1R agonism. We examined whether long acting GLP1R/GCGR exerts diet-induced mice are distinct from those obtained with GLP1R-selective agonist.We developed protease-resistant agonist, DualAG, corresponding GLPAG, matched for...
5'-Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades investigation, the biological roles AMPK and its potential as drug target remain incompletely understood, largely because lack optimized pharmacological tools. We developed MK-8722, potent, direct, allosteric activator all 12 mammalian complexes. In rodents rhesus monkeys, MK-8722-mediated activation skeletal muscle induced robust, durable,...
Caspases are an extended family of cysteine proteases that play critical roles in apoptosis. Animals deficient caspases-2 or -3, which share very similar tetrapeptide cleavage specificities, exhibit different phenotypes, suggesting the unique features individual caspases may account for distinct regulation and specialized functions. Recent studies demonstrate apoptotic stimuli transduced by proteolytic pathways, with multiple components machinery clustering at subcellular sites. We here...
Huntington's disease is a neurodegenerative disorder caused by CAG expansion that results in of polyglutamine tract at the extreme N terminus huntingtin (htt). htt with proapoptotic different cell types. Here, we show caspase inhibitors diminish toxicity htt. Additionally, define itself as an important substrate generating site-directed mutant resistant to caspase-3 cleavage positions 513 and 530 caspase-6 position 586. In contrast cleavable htt, caspase-resistant expanded has reduced...
W e reported previously that human interleukin-lp converting enzyme (ICE) is regulated by the CrmA serpin encoded cowpox virus.We now report mechanism and kinetics of this unusual inhibition a cysteine proteinase member superfamily thought to inhibit serine proteinases only.CrmA possesses several characteristics typical number inhibitory serpins.It conformationally unstable, unfolding around 3 M urea, stable denaturation in 8 urea upon complex formation with ICE.CrmA rapidly inhibits ICE an...
Dipeptidyl peptidase IV (DP-IV), a member of the prolyl oligopeptidase family peptidases, is involved in metabolic inactivation glucose-dependent insulinotropic hormone, glucagon-like peptide 1 (GLP-1), and other incretin hormones. Here, we investigated impact DP-IV deficiency on body weight control insulin sensitivity mice. Whereas WT mice displayed accelerated gain hyperinsulinemia when fed high-fat diet (HFD), lacking gene encoding (DP-IV -/- ) are refractory to development obesity...