A5079894417- Complement system in diseases
- Chemical Synthesis and Analysis
- Asymmetric Synthesis and Catalysis
- Monoclonal and Polyclonal Antibodies Research
- Synthesis and Catalytic Reactions
- Diabetes Treatment and Management
- Receptor Mechanisms and Signaling
- Regulation of Appetite and Obesity
- Synthetic Organic Chemistry Methods
- Biochemical Analysis and Sensing Techniques
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Chemical synthesis and alkaloids
- Blood Coagulation and Thrombosis Mechanisms
- Pharmacology and Obesity Treatment
- Platelet Disorders and Treatments
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Carbohydrate Chemistry and Synthesis
- Click Chemistry and Applications
- Adenosine and Purinergic Signaling
- Computational Drug Discovery Methods
- Nanoparticle-Based Drug Delivery
- Metabolism, Diabetes, and Cancer
- Synthesis and Reactivity of Sulfur-Containing Compounds
- Synthesis of heterocyclic compounds
Eli Lilly (United States)
2021-2023
Indianapolis Zoo
2021
University of Arizona
2006-2012
University of Pennsylvania
2008-2012
University of Tübingen
2012
National Institutes of Health
2012
National Cancer Institute
2012
Center for Cancer Research
2012
Nordland Hospital
2012
With an increasing prevalence of obesity, there is a need for new therapies to improve body weight management and metabolic health. Multireceptor agonists in development may provide approaches fulfill this unmet medical need. LY3437943 novel triple agonist peptide at the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide (GIPR), glucagon-like peptide-1 (GLP-1R). In vitro, shows balanced GCGR GLP-1R activity but more GIPR activity. obese mice, administration decreased...
Rationale: Multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE), are inflammatory disorders of the central nervous system (CNS). The function platelets in pathologies is thus far poorly defined. Objective: We addressed role mediating CNS inflammation EAE. Methods Results: found that were present human MS lesions as well mice subjected to EAE but not from control nondiseased mice. Platelet depletion at effector-inflammatory phase resulted significantly...
The C5a anaphylatoxin receptor (C5aR; CD88) is activated as part of the complement cascade and exerts important inflammatory, antimicrobial, regulatory functions, at least in part, via crosstalk with TLRs. However, periodontal pathogen Porphyromonas gingivalis can control C5aR activation by generating through its own C5 convertase-like enzymatic activity. In this paper, we show that P. uses mechanism to proactively selectively inhibit TLR2-induced IL-12p70, whereas same pathogen-instigated...
Therapeutic modulation of the complement system has become increasingly important in line with growing recognition role numerous diseases. Compstatin, a peptidic inhibitor that acts at central level cascade, is currently clinical evaluation but routes to improve its efficacy have not yet been fully explored. Here, we report improvements both inhibitory potency and pharmacokinetic parameters compstatin broaden applications. Selective modification N-terminus non-proteinogenic amino acids...
Abstract Exposure of nonself surfaces such as those biomaterials or transplanted cells and organs to host blood frequently triggers innate immune responses, thereby affecting both their functionality tolerability. Activation the alternative pathway complement plays a decisive role in this unfavorable reaction. Whereas previous studies demonstrated that immobilization physiological regulators activation (RCA) can attenuate foreign body-induced activation, simple efficient approaches for...
Human mast cells express the G protein coupled receptor (GPCR) for C5a (CD88). Previous studies indicated that could cause cell degranulation, at least in part, via a mechanism similar to proposed basic neuropeptides such as substance P, possibly involving Mas-related gene 2 (MrgX2). We therefore sought more clearly define specificity C5a-induced degranulation. found LAD2, human line, and CD34<sup>+</sup> cell-derived primary functional MrgX1 MrgX2 but immature line HMC-1 does not. A potent...
Disulfide bonds are essential for the structural stability and biological activity of many bioactive peptides. However, these labile to reducing agents, which can limit therapeutic utility such Substitution a disulfide bond with reduction-resistant cystathionine bridge is an attractive means improving while imposing minimal perturbation peptide. We have applied this approach complement inhibitor compstatin, disulfide-containing peptide currently in clinical trials age-related macular...
Delayed gastric emptying (GE) is a well-known effect of glucagon-like peptide-1 (GLP-1).1, 2 Similarly, glucagon (GCG) has been shown to slow GE in rodents and humans,3, 4 while glucose-dependent insulinotropic polypeptide (GIP) does not appear impact GE.1, Retatrutide (LY3437943) novel GIP/GLP-1/GCG receptor agonist (RA) under investigation for chronic weight management its complications. It more potent at the human GIP less GCG GLP-1 receptors versus native hormones, with half-life...
Combined glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 (GLP1R) agonism is superior to single GLP1R with respect glycemic control weight loss in obese patients or without type 2 diabetes. As insulin resistance obesity are strong risk factors for nonalcoholic fatty liver disease (NAFLD), the current study we investigated effects of combined GIPR/GLP1R on NAFLD development.Male APOE∗3-Leiden.CETP mice, a humanized model diabetic dyslipidemia when fed...
Compstatin is a 13-residue peptide that inhibits activation of the complement system by binding to central component C3 and its fragments C3b C3c. A combination theoretical experimental approaches has previously allowed us develop analogs original compstatin with up 264-fold higher activity; one these now in clinical trials for treatment age-related macular degeneration (AMD). Here we used functional assays, surface plasmon resonance (SPR), isothermal titration calorimetry (ITC) assess...
Abstract Confirming clinical evidence, we recently demonstrated that a blunt chest trauma considerably impaired fracture healing in rats, possibly via the interaction of posttraumatic systemic inflammation with local processes, underlying mechanisms being unknown. An important trigger is complement system, potent anaphylatoxin C5a. Therefore, investigated whether impairment by severe resulted from systemically activated complement. Rats received and femur osteotomy stabilized an external...
Combined agonism of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 (GLP1R) is superior to single GLP1R in terms glycemic control lowering body weight individuals with obesity or without type 2 diabetes mellitus. As both GIPR signaling have also been implicated improving inflammatory responses lipid handling, two crucial players atherosclerosis development, here we aimed investigate effects combined GIPR/GLP1R APOE*3-Leiden.CETP mice, a...
Multifunctionalized amino acids, especially acids with unsaturation, are important, demanding building blocks in peptide chemistry. Here we present a summary of our most recent study using the thio-Claisen rearrangement for synthesis anti-β-functionalized γ,δ-unsaturated acids. Investigations on scope, limitations, chemoselectivities and stereoselectivities regarding an FeBr(3)-catalyzed allylation strategy thio-enolate dianion formation asymmetric documented. An explanation chirality...
A novel synthesis of optically active anti-β-substituted γ,δ-unsaturated amino acids via a thio-Claisen rearrangement has been achieved. 2,5-diphenylpyrrolidine was used as C2-symmetric chiral auxiliary to control the stereochemistry, giving good yields and excellent diastereoselectivities enantioselectivities.
Anti-beta-substituted gamma,delta-unsaturated amino acids have been synthesized via a novel design of the Eschenmoser-Claisen rearrangement. The rearrangement gives good isolated yields and excellent diastereoselectivity due to (Z)-N,O-ketene acetal formation pseudochairlike conformations reaction intermediates. Upon reductive hydrolysis, important alcohols were for first time this methodology.
Optically active anti-β-substituted γ,δ-unsaturated amino acids are important synthetic building blocks in organic synthesis and for peptidomimetics. A novel asymmetric Eschenmoser−Claisen rearrangement with use of a C2-symmetric chiral auxiliary was developed to generate this type acid. Excellent diastereoselectivities high enantioselectivities (87−93% ee) were obtained after the removed via iodolactonization/zinc reduction.