A5025242485- Phosphodiesterase function and regulation
- Protein Kinase Regulation and GTPase Signaling
- Metabolism, Diabetes, and Cancer
- Pancreatic function and diabetes
- SARS-CoV-2 and COVID-19 Research
- Blood Coagulation and Thrombosis Mechanisms
- Immunotherapy and Immune Responses
- Protease and Inhibitor Mechanisms
- vaccines and immunoinformatics approaches
- Blood properties and coagulation
- Nitric Oxide and Endothelin Effects
- Phagocytosis and Immune Regulation
- Diabetes Treatment and Management
- Platelet Disorders and Treatments
- Mast cells and histamine
- Cell death mechanisms and regulation
- Monoclonal and Polyclonal Antibodies Research
- Enzyme Catalysis and Immobilization
- Mycotoxins in Agriculture and Food
- Heart Rate Variability and Autonomic Control
- Plant biochemistry and biosynthesis
- Sexual function and dysfunction studies
- Synthesis and biological activity
- Blood disorders and treatments
- Mitochondrial Function and Pathology
Oncomedics (France)
2023
GlaxoSmithKline (France)
2003-2019
Inserm
1990-1993
Hôpital Purpan
1990-1991
Hôpital Lariboisière
1991
Université Toulouse III - Paul Sabatier
1989-1990
AMPK (AMP-activated protein kinase) is activated allosterically by AMP and phosphorylation of Thr172 within the catalytic α subunit. Here we show that mutations in regulatory γ subunit reduce allosteric activation kinase AMP. In addition to its effect, significantly reduces dephosphorylation PP (protein phosphatase)2Cα. Moreover, a mutation almost completely abolishes inhibitory effect on dephosphorylation. We were unable detect any either LKB1 or CaMKKβ (Ca2+/calmodulin-dependent β) using...
AMP-activated protein kinase (AMPK) is a major therapeutic target for the treatment of diabetes. We investigated effect short-term overexpression AMPK specifically in liver by adenovirus-mediated transfer gene encoding constitutively active form AMPKα2 (AMPKα2-CA). Hepatic AMPKα2-CA expression significantly decreased blood glucose levels and gluconeogenic expression. streptozotocin-induced ob/ob diabetic mice abolished hyperglycemia In normal mouse liver, considerably refeeding-induced...
The alkaloid drug berberine (BBR) was recently described to decrease plasma cholesterol and triglycerides (TGs) in hypercholesterolemic patients by increasing expression of the hepatic low density lipoprotein receptor (LDLR). Using HepG2 human hepatoma cells, we found that BBR inhibits TG synthesis a similar manner AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide 1-β-ribofuranoside (AICAR). Significant increases AMPK phosphorylation activity were observed when...
Abstract In light of the recent accumulated knowledge on SARS-CoV-2 and its mode human cells invasion, binding viral spike glycoprotein to Angiotensin Converting Enzyme 2 (hACE2) receptor plays a central role in cell entry. We designed series peptides mimicking N -terminal helix hACE2 protein which contains most contacting residues at site, exhibiting high helical folding propensity aqueous solution. Our best peptide-mimics are able block pulmonary infection with an inhibitory concentration...
Modification of the hydantoin ring in previously described lead compound 2a has led to discovery 12a, tadalafil, a highly potent and selective PDE5 inhibitor. The replacement by piperazinedione cis-11a which showed similar inhibitory potency. Introduction 3,4-methylenedioxy substitution on phenyl position 6 inhibitor cis-11c with increased cellular Optimization chain identification racemic cis-N-methyl derivative 11i. High diastereospecificity for inhibition was observed series cis-(6R,12aR)...
Phosphatidylinositol (PtdIns)-4- and -3-kinases, PtdIns(4)P-5-kinase, diacylglycerol (DAG) kinase, PtdIns-phospholipase C were all detected in cytoskeletons of resting human platelets. The total cytoskeletal enzyme activities greatly increased upon thrombin stimulation the intact cells. Those reached a maximum after 60-s for PtdIns(4)P-5-kinase phospholipase C, while other kinases appeared to be slightly delayed. Specific stimulated from about 4-fold (PtdIns-3-kinase) 6-fold...
Starting from ethyl beta-carboline-3-carboxylate (beta-CCE), 1, a modest inhibitor of type 5 phosphodiesterase (PDE5), series functionalized tetrahydro-beta-carboline derivatives has been identified as novel chemical class potent and selective PDE5 inhibitors. Optimization the side chain on hydantoin ring initial lead compound 2 aromatic position led to identification 6e, highly inhibitor, with greater selectivity for vs PDE1-4 than sildenafil. Compound 6e demonstrated long-lasting...
RIP1 kinase regulates necroptosis and inflammation may play an important role in contributing to a variety of human pathologies, including inflammatory neurological diseases. Currently, inhibitors have advanced into early clinical trials for evaluation diseases such as psoriasis, rheumatoid arthritis, ulcerative colitis amyotrophic lateral sclerosis Alzheimer's disease. In this paper, we report on the design potent highly selective dihydropyrazole (DHP) starting from high-throughput screen...
Abstract 32P-Labeled human platelets were incubated with thrombin (1 unit/ml) for 5 min at 37 degrees C under conditions allowing maximal synthesis of [32P]phosphatidylinositol 3',4'-bisphosphate (PtdIns(3,4)P2). Incorporation 32P into the latter phosphoinositide was dose-dependently reduced (to a level averaging 60%) by tetrapeptide RGDS, an inhibitor fibrinogen binding to activated glycoprotein IIb-IIIa (alpha IIb-beta 3 integrin). Identical results obtained gamma-chain dodecapeptide...
Soluble guanylate cyclase (sGC), the primary mediator of nitric oxide (NO) bioactivity, exists as reduced (NO-sensitive) and oxidized (NO-insensitive) forms. We tested hypothesis that cardiovascular protective effects NO-insensitive sGC activation would be potentiated under conditions oxidative stress compared to those NO-sensitive stimulation. The activator GSK2181236A [a low, non-depressor dose, a high dose which lowered mean arterial pressure (MAP) by 5-10 mmHg] equi-efficacious doses...
Radioactive PtdIns(3)P was detected in human platelets incubated with [32P]Pi, but remained unaffected by thrombin treatment. In contrast, [32P]PtdIns(3,4)P2 absent from resting platelets, produced thrombin-activated a dose- and time-dependent manner. [32P]PtdInsP3 never found under these conditions. These changes are similar to those elicited other cells platelet-derived growth factor or the oncogene product pp60c-src.
Thrombospondin-1 (TSP-1) is a glycoprotein considered as key actor within the tumor microenvironment. Its binding to CD47, cell surface receptor, triggers programmed death. Previous studies allowed identification of 4N1K decapeptide derived from TSP-1/CD47 epitope. Here, we demonstrate that this peptide able induce selective apoptosis various cancer lines while sparing normal cells. A structure–activity relationship study led design first serum stable TSP-1 mimetic agonist trigger death...
Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple hits were observed different regions the active site, including some that bound a pocket created by movement protein side chain (approximately 13 Å from catalytic residue Ser273). Using structure guided design, we optimized this generate low nanomolar chemotype, which...
Lp-PLA2 has been explored as a target for number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery new fragment derived chemotype that interacts with active site Lp-PLA2. The starting hit was discovered through an X-ray screen showed no activity in bioassay (IC50 > 1 mM). optimized using variety structure-based drug design techniques, virtual screening, merging, improvement shape complementarity. A novel series inhibitors...
AMP-activated protein kinase (AMPK) is an evolutionarily conserved fuel-sensing enzyme that activated in shortage of energy and suppressed its surfeit. AMPK activation stimulates fatty acid oxidation, enhances insulin sensitivity, alleviates hyperglycemia hyperlipidemia, inhibits proinflammatory changes. Thus, a well-received therapeutic target for type 2 diabetes other metabolic disorders. Here, we will report the discovery pyrrolopyridone derivatives as direct activators. We illustrate...
Carnitine palmitoyl transferase 2 (CPT2) deficiency is one of the most common inherited fatty acid oxidation (FAO) defects and represents a prototypical mitochondrial metabolic myopathy. Recent studies have suggested pivotal role adenosine monophosphate-activated protein kinase (AMPK) in skeletal muscle plasticity homeostasis. Thus, we tested potential GSK773, novel direct AMPK activator, to improve or correct FAO capacities cells from patients harboring various mutations. We used controls'...
Abstract In the light of recent accumulated knowledge on SARS-CoV-2 and its mode human cells invasion, binding viral spike glycoprotein to Angiotensin Converting Enzyme 2 (hACE2) receptor plays a central role in cell entry. We designed series peptides mimicking N -terminal helix hACE2 protein which contains most contacting residues at site have high helical folding propensity aqueous solution. Our best peptide mimics bind virus with affinity are able block pulmonary infection an inhibitory...
In order to optimize the potency of first serum-stable peptide agonist CD47 (PKHB1) in triggering regulated cell death cancer cells, we designed a maturation process aimed mimic trimeric structure thrombospondin-1/CD47 binding epitope. For that purpose, an N-methylation scan PKHB1 sequence was realized prevent aggregation. Structural and pharmacological analyses were conducted assess conformational impact these chemical modifications on backbone biological activity. This structure–activity...
Rhenium(I) tricarbonyl complexes inhibited the 3chymotrypsin-like protease (3CLpro), a cathepsin cysteine protease, which is one of main proteases severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2 virus), but antiviral effect was not studied.On other hand, rhenium(I)-diselenoether complex (Re-diSe), Re(I)tricarbonyl compound with diselenide ligand, decreased production B and S in cancer normal cells at doses that did affect viability cells.Objective.To study Re-diSe on viral load...
Abstract Introduction: The Antibody-Drug Conjugates (ADCs)-based therapy has revealed a field of perspectives by increasing the specificity and efficacy anti-tumoral drug treatment. McSAF is company focused in bio-organic bioconjugates chemistry developed new linker technology solution, allowing to improve ADCs homogeneity stability resulting higher effect on HER2-positive breast tumor model (BT-474 cell line) CD30-positive non-Hodgkin's lymphoma (Karpas-299 line). Methods: activity...