2 research outputs found
DataSheet1_9-PAHSA displays a weak anti-inflammatory potential mediated by specific antagonism of chemokine G protein-coupled receptors.docx
Introduction: 9-PAHSA belongs to a class of endogenous mammalian bioactive lipids, fatty acid esters of hydroxy fatty acids (FAHFA), that are present in circulation at nanomolar concentrations in mice and humans. Published preclinical data suggest beneficial effects of 9-PAHSA treatment on glucose metabolism as well as modulation of immune function. However, receptor molecules with high affinity towards these lipids have not been identified so far.Methods: In a broad screen of a panel of G protein-coupled receptors (GPCRs) we discovered that 9-PAHSA displays antagonist activity with an IC50 in the micromolar range on selected chemokine receptors, namely, CCR6, CCR7, CXCR4, and CXCR5. The potential immunomodulatory activities in a human cellular model of innate immunity were then investigated.Results and discussion: In our in vitro experiments, a weak anti-inflammatory potential for high concentrations of 9-PAHSA (10–100 µM) could be detected, as treatment reduced the LPS-induced secretion of certain chemokines, such as CXCL10, MIP-1 beta and MCP. Regarding metabolic effects, we re-investigated 9-PAHSA on glucose metabolism and insulin sensitivity in vitro and in mice confirming conclusions from our earlier study that FAHFAs lack glucoregulatory activity following an acute treatment. In conclusion, the specific interactions with a subset of chemokine receptors may contribute to weak anti-inflammatory properties of 9-PAHSA, but further studies are needed to confirm its in anti-inflammatory potential in vivo.</p
Dual Glucagon-like Peptide 1 (GLP-1)/Glucagon Receptor Agonists Specifically Optimized for Multidose Formulations
Novel peptidic dual
agonists of the glucagon-like peptide 1 (GLP-1)
and glucagon receptor are reported to have enhanced efficacy over
pure GLP-1 receptor agonists with regard to treatment of obesity and
diabetes. We describe novel exendin-4 based dual agonists designed
with an activity ratio favoring the GLP-1 versus the glucagon receptor.
As result of an iterative optimization procedure that included molecular
modeling, structural biological studies (X-ray, NMR), peptide design
and synthesis, experimental activity, and solubility profiling, a
candidate molecule was identified. Novel SAR points are reported that
allowed us to fine-tune the desired receptor activity ratio and increased
solubility in the presence of antimicrobial preservatives, findings
that can be of general applicability for any peptide discovery project.
The peptide was evaluated in chronic <i>in vivo</i> studies
in obese diabetic monkeys as translational model for the human situation
and demonstrated favorable blood glucose and body weight lowering
effects