A5046353676- Diabetes Treatment and Management
- Neuropeptides and Animal Physiology
- Receptor Mechanisms and Signaling
- Pancreatic function and diabetes
- Metabolism, Diabetes, and Cancer
- Monoclonal and Polyclonal Antibodies Research
- Computational Drug Discovery Methods
- Ion channel regulation and function
- Hippo pathway signaling and YAP/TAZ
- Peptidase Inhibition and Analysis
- SARS-CoV-2 and COVID-19 Research
- Diabetes Management and Research
- COVID-19 Clinical Research Studies
- Transgenic Plants and Applications
- Diabetes and associated disorders
- Peroxisome Proliferator-Activated Receptors
- Chemical Synthesis and Analysis
- Cardiac electrophysiology and arrhythmias
- Adipose Tissue and Metabolism
- PARP inhibition in cancer therapy
- Neuroendocrine regulation and behavior
- Immune Response and Inflammation
- Pharmacology and Obesity Treatment
- Plant Surface Properties and Treatments
- Endoplasmic Reticulum Stress and Disease
Scripps Research Institute
2019-2024
California Institute for Biomedical Research
2016-2024
Scripps (United States)
2019-2024
Scripps Institution of Oceanography
2019-2024
Genomics Institute of the Novartis Research Foundation
2009-2020
Bristol-Myers Squibb (United States)
2008
University of California, San Diego
2000-2001
La Jolla Institute For Molecular Medicine
2001
Abstract Insufficient pancreatic β-cell mass or function results in diabetes mellitus. While significant progress has been made regulating insulin secretion from β-cells diabetic patients, no pharmacological agents have described that increase replication humans. Here we report aminopyrazine compounds stimulate robust proliferation adult primary islets, most likely as a result of combined inhibition DYRK1A and GSK3B. Aminopyrazine-treated human islets retain functionality vitro after...
PPARdelta (peroxisome proliferator-activated receptor delta) is a regulator of lipid metabolism and has been shown to induce fatty acid oxidation (FAO). transgenic knock-out mice indicate an involvement in regulating mitochondrial biogenesis oxidative capacity; however, the precise mechanisms by which regulates these pathways skeletal muscle remain unclear. In this study, we determined effect selective agonism with synthetic ligand, GW501516, on FAO gene expression vitro vivo. Our results...
Autoimmune deficiency and destruction in either β-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia diabetes. Thus, promoting proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of potent selective DYRK1A inhibitor GNF2133, which was identified through optimization 6-azaindole screening hit. vitro, GNF2133 is able to proliferate both rodent human β-cells. vivo, demonstrated significant...
Abstract The loss of functional insulin-producing β-cells is a hallmark diabetes. Mammalian sterile 20-like kinase 1 (MST1) key regulator pancreatic β-cell death and dysfunction; its deficiency restores normoglycemia. identification MST1 inhibitors represents promising approach for β-cell-protective diabetes therapy. Here, we identify neratinib, an FDA-approved drug targeting HER2/EGFR dual kinases, as potent inhibitor, which improves survival under multiple diabetogenic conditions in human...
Chronic cutaneous wounds remain a persistent unmet medical need that decreases life expectancy and quality of life. Here, we report topical application PY-60, small-molecule activator the transcriptional coactivator Yes-associated protein (YAP), promotes regenerative repair in pig human models. Pharmacological YAP activation enacts reversible pro-proliferative program keratinocytes dermal cells results accelerated re-epithelization regranulation wound bed. These demonstrate transient...
There remains a need to develop novel SARS-CoV-2 therapeutic options that improve upon existing therapies by an increased robustness of response, fewer safety liabilities, and global-ready accessibility. Functionally critical viral main protease (Mpro, 3CLpro) is attractive target due its homology within the coronaviral family, lack thereof toward human proteases. In this disclosure, we outline advent 3CLpro inhibitor, CMX990, bearing unprecedented trifluoromethoxymethyl ketone warhead....
NOD2 (nucleotide-binding oligomerization domain-containing protein 2) is an internal pattern recognition receptor that recognizes bacterial peptidoglycan and stimulates host immune responses. Dysfunction of pathway has been associated with a number autoinflammatory disorders. To date, direct inhibitors have not described due to technical challenges targeting the oligomeric complex. Receptor interacting kinase 2 (RIPK2) intracellular serine/threonine/tyrosine kinase, key signaling partner,...
Existing long α-helix mimicking necessitates the retention of most natural amino acid residues to maintain their biological activity. Here, we report exploration helical sulfono-γ-AApeptides with entire unnatural backbones for ability structurally and functionally mimic glucagon-like peptide 1 (GLP-1). Our findings suggest that efficient construction novel GLP-1 receptor (GLP-1R) agonists could be achieved nanomolar potencies. In addition, resulting were also proved display remarkable...
The discovery, synthesis, and optimization of compound 1 from a high-throughput screening hit to highly potent selective peroxisome proliferator-activated receptor delta (PPARdelta) agonists are reported. synthesis structure-activity relationship in this series described detail. On the basis general schematic PPAR pharmacophore model, scaffold was divided into headgroup, linker, tailgroup successively optimized for activation using vitro transactivation assays. A (2-methylphenoxy)acetic acid...
Significance There is considerable interest in developing immunosuppressants that can specifically target effector memory T cells which are key to the pathogenesis of many inflammatory disorders. The potassium channel Kv1.3 has been found play an important role EM activation, but not naive and central cells. It proven challenging generate small molecules or antibodies potently selectively block function. We generated antibody fusions by grafting potent blocking peptides into...
Oxyntomodulin (OXM) is an intestinal peptide hormone that activates both glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptors. The natural reduces body weight in obese subjects exhibits direct acute glucoregulatory effects patients with type II diabetes. However, the clinical utility of OXM limited due to its lower vitro potency short vivo half-life. To overcome these issues, we developed stapled, long-acting, highly potent analogs balanced activities at GLP-1 GCG lead molecule O14...
3-Hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded generally safe, they to cause myopathy and, rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids mediated through inhibition of HMGR hepatocyte, whereas evidence suggests that myotoxicity is due within myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could...
Type 2 alveolar epithelial cells (AEC2s) are stem in the adult lung that contribute to lower airway repair. Agents promote selective expansion of these might stimulate regeneration compromised epithelium, an etiology-defining event several pulmonary diseases. From a high-content imaging screen drug repurposing library ReFRAME, we identified dipeptidyl peptidase 4 (DPP4) inhibitors, widely used type diabetes medications, selectively expand AEC2s and broadly efficacious mouse models damage....
Statins, because of their excellent efficacy and manageable safety profile, represent a key component in the current armamentarium for treatment hypercholesterolemia. Nonetheless, myopathy remains concern this important drug class. Cerivastatin was withdrawn from market myotoxicity concerns. BMS-423526 [{(3<i>R</i>,5<i>S</i>)-7-[4-(4-fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-5<i>H</i>-benzo[6,7]cyclohepta[1,2-<i>b</i>]pyridin-3-yl]-3,5-dihydroxy-heptenoic acid} sodium salt], similar to...
Abstract Glucagon‐like peptide‐1 (GLP‐1) receptor (GLP‐1R), glucagon (GCG) (GCGR), and glucose‐dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory polypeptide) (GIPR), are three metabolically related peptide hormone receptors. A novel approach to the generation of multifunctional antibody agonists that activate these receptors has been developed. Native or engineered for GLP‐1R, GCGR, GIPR were fused N‐terminus heavy chain light an antibody, either alone in pairwise...
Bariatric surgery results in increased intestinal secretion of hormones GLP-1 and anorexigenic PYY, which is believed to contribute the clinical efficacy associated with procedure. This observation raises question whether combination treatment gut hormone analogs might recapitulate mitigate significant risks surgery. Despite PYY demonstrating excellent safety profiles regard food intake reduction, weight loss, glucose control preclinical animal models, PYY-based therapeutic development...
Anorexigenic peptides offer promise as potential therapies targeting the escalating global obesity epidemic. Prolactin-releasing peptide (PrRP), a novel member of RFamide family secreted by hypothalamus, shows therapeutic decreasing food intake and body weight in rodent models via GPR10 activation. Here we describe design long-acting PrRP using our recently developed multiple ethylene glycol-fatty acid (MEG-FA) stapling platform. By incorporating serum albumin binding fatty acids onto...
Pancreatic β-cell apoptosis, a hallmark of the development type 1 diabetes (T1D), is associated with increased levels pro-inflammatory cytokines. Thus, an agent protecting β-cells from cytokine-induced stress should have impact on maintaining functional mass in T1D. Screening ∼2 million-compound library identified series 7-azaindole derivatives as capable rat insulinoma death induced by The screening hits were optimized to result GNF3809, compound which preserves insulin content and...
Unfolded protein response (UPR) is a stress that specific to the endoplasmic reticulum (ER). UPR activated upon accumulation of unfolded (or misfolded) proteins in ER's lumen restore folding capacity by increasing synthesis chaperones. In addition, also enhances degradation and reduces global alleviate additional ER. Herein, we describe cell-based ultra-high throughput screening (uHTS) campaign identifies small molecule can modulate ER cellular vivo disease models. Using asialoglycoprotein...
The effects of oxytocin on food intake and body weight reduction have been demonstrated in both animal models human clinical studies. Despite being efficacious, is enzymatically unstable thus considered to be unsuitable for long-term use patients with obesity. Herein, a series derivatives were engineered through conjugation fatty acid moieties that are known exhibit high binding affinities serum albumin. One analog (OT-12) particular was shown potent full agonist at the receptor (OTR) vitro...
Peptides are increasingly important resources for biological and therapeutic development, however, their intrinsic susceptibility to proteolytic degradation represents a big hurdle. As natural agonist GLP-1R, glucagon-like peptide 1 (GLP-1) is of significant clinical interest the treatment type-2 diabetes mellitus, but its in vivo instability short half-life have largely prevented application. Here, we describe rational design series α/sulfono-γ-AA hybrid analogues GLP-1 as GLP-1R agonists....
Owing to their pleiotropic metabolic benefits, glucagon-like peptide-1 receptor (GLP-1R) agonists have been successfully utilized for treating diseases, such as type 2 diabetes and obesity. As part of our efforts in developing long-acting peptide therapeutics, we previously reported a engineering strategy that combines side chain stapling with covalent integration serum protein-binding motif single step. Herein, used this develop second generation extendin-4 analog rigidified symmetrical...