“Don’t blame the shopkeeper!!” Food, drink and confectionery advertising and British Government market controls during the Second World War

A novel series of \u3b2-lactam derivatives that was designed and synthesized to target RGD-binding and leukocyte integrins is reported. The compound library was evaluated by investigating the effects on integrin-mediated cell adhesion and cell signaling in cell lines expressing \u3b1v\u3b23, \u3b1v\u3b25, \u3b1v\u3b26, \u3b15\u3b21, \u3b1IIb\u3b23, \u3b14\u3b21, and \u3b1L\u3b22 integrins. SAR analysis of the new series of azetidinones enabled the recognition of structural elements associated with integrin selectivity. We obtained selective and potent agonists that could induce cell adhesion and promote cell signaling mediated by \u3b1v\u3b23, \u3b1v\u3b25, \u3b15\u3b21, or \u3b14\u3b21 integrin, and antagonists for the integrins \u3b1v\u3b23 and \u3b15\u3b21, as well as \u3b14\u3b21 and \u3b1L\u3b22, preventing the effects elicited by the respective endogenous agonists

Selective glucocorticoid receptor properties of GSK866 analogs with cysteine reactive warheads

Synthetic glucocorticoids (GC) are the mainstay therapy for treatment of acute and chronic inflammatory disorders. Due to the high adverse effects associated with long-term use, GC pharmacology has focused since the nineties on more selective GC ligand-binding strategies, classified as selective glucocorticoid receptor (GR) agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). In the current study, GSK866 analogs with electrophilic covalent-binding warheads were developed with potential SEGRA properties to improve their clinical safety profile for long-lasting topical skin disease applications. Since the off-rate of a covalently binding drug is negligible compared to that of a non-covalent drug, its therapeutic effects can be prolonged and typically, smaller doses of the drug are necessary to reach the same level of therapeutic efficacy, thereby potentially reducing systemic side effects. Different analogs of SEGRA GSK866 coupled to cysteine reactive warheads were characterized for GR potency and selectivity in various biochemical and cellular assays. GR-and NF kappa B dependent reporter gene studies show favorable anti-inflammatory properties with reduced GR transactivation of two non-steroidal GSK866 analogs UAMC-1217 and UAMC-1218, whereas UAMC-1158 and UAMC-1159 compounds failed to modulate cellular GR activity. These results were further supported by GR immuno-localization and S211 phospho-GR western analysis, illustrating significant GR phosphoactivation and nuclear translocation upon treatment of GSK866, UAMC-1217, or UAMC-1218, but not in case of UAMC-1158 or UAMC-1159. Furthermore, mass spectrometry analysis of tryptic peptides of recombinant GR ligand-binding domain (LBD) bound to UAMC-1217 or UAMC-1218 confirmed covalent cysteine-dependent GR binding. Finally, molecular dynamics simulations, as well as glucocorticoid receptor ligand-binding domain (GR-LBD) coregulator interaction profiling of the GR-LBD bound to GSK866 or its covalently binding analogs UAMC-1217 or UAMC-1218 revealed subtle conformational differences that might underlie their SEGRA properties. Altogether, GSK866 analogs UAMC-1217 and UAMC-1218 hold promise as a novel class of covalent-binding SEGRA ligands for the treatment of topical inflammatory skin disorders

Quantitative Systems Pharmacology and Biased Agonism at Opioid Receptors: A Potential Avenue for Improved Analgesics

Chronic pain is debilitating and represents a significant burden in terms of personal and socio-economic costs. Although opioid analgesics are widely used in chronic pain treatment, many patients report inadequate pain relief or relevant adverse effects, highlighting the need to develop analgesics with improved efficacy/safety. Multiple evidence suggests that G protein-dependent signaling triggers opioid-induced antinociception, whereas arrestin-mediated pathways are credited with modulating different opioid adverse effects, thus spurring extensive research for G protein-biased opioid agonists as analgesic candidates with improved pharmacology. Despite the increasing expectations of functional selectivity, translating G protein-biased opioid agonists into improved therapeutics is far from being fully achieved, due to the complex, multidimensional pharmacology of opioid receptors. The multifaceted network of signaling events and molecular processes underlying therapeutic and adverse effects induced by opioids is more complex than the mere dichotomy between G protein and arrestin and requires more comprehensive, integrated, network-centric approaches to be fully dissected. Quantitative Systems Pharmacology (QSP) models employing multidimensional assays associated with computational tools able to analyze large datasets may provide an intriguing approach to go beyond the greater complexity of opioid receptor pharmacology and the current limitations entailing the development of biased opioid agonists as improved analgesics

. DS-70, a novel and potent \uf0614 integrin antagonist, is an effective treatment for experimental allergic conjunctivitis in guinea pigs

BACKGROUND AND PURPOSE Allergic conjunctivitis is an eye inflammation that involves the infiltration of immune cells into the conjunctiva via cell surfaceadhesion receptors, such as integrin \u3b14\u3b21. These receptors interact with adhesion molecules expressed on the conjunctival endothelium and may be a target to treat this disease. We synthesized DS-70, a novel \u3b1/\u3b2-peptidomimetic \u3b14 integrin antagonist, to prevent the conjunctival infiltration of immune cells and clinical symptoms in a model of allergic conjunctivitis. EXPERIMENTAL APPROACH In vitro, DS-70 was pharmacologically characterized using a scintillation proximity procedure to measure its affinity for \u3b14\u3b21 integrin, and its effect on cell adhesion mediated by different integrins was also evaluated. The effects of DS-70 on vascular cell adhesion molecule-1 (VCAM-1)-mediated degranulation of a human mast cell line and an eosinophilic cell line, which both express \u3b14\u3b21, and on VCAM-1-mediated phosphorylation of ERK 1/2 in Jurkat E6.1 cells were investigated. Effects of DS-70 administered in the conjunctival fornix of ovalbumin-sensitized guinea pigs were evaluated. KEY RESULTS DS-70 bound to integrin \u3b14\u3b21 with nanomolar affinity, prevented the adhesion of \u3b14 integrin-expressing cells, antagonized VCAM-1- mediated degranulation of mast cells and eosinophils and ERK 1/2 phosphorylation. Only 20% was degraded after an 8 h incubation with serum. DS-70 dose-dependently reduced the clinical symptoms of allergic conjunctivitis, conjunctival \u3b14 integrin expression and conjunctival levels of chemokines and cytokines in ovalbumin-sensitized guinea pigs. CONCLUSIONS AND IMPLICATIONS These findings highlight the role of \u3b14 integrin in allergic conjunctivitis and suggest that DS-70 is a potential treatment for this condition

Design and Pharmacological Characterization of α4β1 Integrin Cyclopeptide Agonists: Computational Investigation of Ligand Determinants for Agonism versus Antagonism

alpha 4 beta 1 integrin is a cell adhesion receptor deeply involved in the migration and accumulation of leukocytes. Therefore, integrin antagonists that inhibit leukocytes recruitment are currently regarded as a therapeutic opportunity for the treatment of inflammatory disorder, including leukocyte-related autoimmune diseases. Recently, it has been suggested that integrin agonists capable to prevent the release of adherent leukocytes might serve as therapeutic agents as well. However, very few alpha 4 beta 1 integrin agonists have been discovered so far, thus precluding the investigation of their potential therapeutic efficacy. In this perspective, we synthesized cyclopeptides containing the LDV recognition motif found in the native ligand fibronectin. This approach led to the discovery of potent agonists capable to increase the adhesion of alpha 4 integrin-expressing cells. Conformational and quantum mechanics computations predicted distinct ligand-receptor interactions for antagonists or agonists, plausibly referable to receptor inhibition or activation

Leukocyte Integrin Antagonists as a Novel Option to Treat Dry Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a complex multifactorial degenerative disease that leads to irreversible blindness. AMD affects the macula, the central part of the retina responsible for sharp central vision. Retinal pigment epithelium (RPE) is the main cellular type affected in dry AMD. RPE cells form a monolayer between the choroid and the neuroretina and are in close functional relationship with photoreceptors; moreover, RPE cells are part of the blood retina barrier that is disrupted in ocular diseases such as AMD. During ocular inflammation lymphocytes and macrophages are recruited, contact RPE and produce pro-inflammatory cytokines, which play an important role in AMD pathogenesis. The interaction between RPE and immune cells is mediated by leukocyte integrins, heterodimeric transmembrane receptors, and adhesion molecules, including VCAM-1 and ICAM-1. Within this frame, this study aimed to characterize RPE-leukocytes interaction and to investigate any potentially beneficial effects induced by integrin antagonists (DS-70, MN27 and SR714), developed in previous studies. ARPE-19 cells were co-cultured for different incubation times with Jurkat cells and apoptosis and necrosis levels were analyzed by flow cytometry. Moreover, we measured the mRNA levels of the pro-inflammatory cytokine IL-1\u3b2 and the expression of adhesion molecules VCAM-1 and ICAM-1. We found that RPE-lymphocyte interaction increased apoptosis and necrosis levels in RPE cells and the expression of IL-1\u3b2. This interaction was mediated by the binding of \u3b14\u3b21 and \u3b1L\u3b22 integrins to VCAM-1 and ICAM-1, respectively. The blockade of RPE-lymphocyte interaction with blocking antibodies highlighted the pivotal role played by integrins. Therefore, \u3b14\u3b21 and \u3b1L\u3b22 integrin antagonists were employed to disrupt RPE-lymphocyte crosstalk. Small molecule integrin antagonists proved to be effective in reducing RPE cell death and expression of IL-1\u3b2, demonstrating that integrin antagonists could protect RPE cells from detrimental effects induced by the interaction with immune cells recruited to the retina. Overall, the leukocyte integrin antagonists employed in the present study may represent a novel opportunity to develop new drugs to fight dry AMD

Identification of c[D-Trp-Phe-β-Ala-β-Ala], the First κ-Opioid Receptor-Specific Negative Allosteric Modulator

Recently, the fungus secondary metabolite cyclotetrapetide c[Trp-Phe-D-Pro-Phe] (CJ-15,208) and its derivatives deserved some attention for their unusual structure and distinctive in vitro and in vivo activity. These tryptophan-containing noncationic opioid peptides can be truly regarded as versatile picklocks capable of activating all opioid receptors. Intriguingly, minimal modification of the potent kappa-opioid receptor (KOR) agonist c[D-Trp-Phe-Gly-beta-Ala] (3) yielded c[D-Trp-Phe-beta-Ala-beta-Ala] (11), the first KOR-specific negative allosteric modulator (NAM) reported to-date. KOR exerts control over numerous functions in the central nervous system, including pain, depression, stress, mood, and reward. Hence, this KOR-selective NAM looks promising for modulating the KOR in addiction and neuropsychiatric disorders

Side chain effect in the modulation of αvβ3/α5β1 integrin activity via clickable isoxazoline-RGDmimetics: development of molecular delivery systems

View references (57) Construction of small molecule ligand (SML) based delivery systems has been performed starting from a polyfunctionalized isoxazoline scaffold, whose \u3b1v\u3b23 and \u3b15\u3b21 integrins\u2019 potency has been already established. The synthesis of this novel class of ligands was obtained by conjugation of linkers to the heterocyclic core via Huisgen-click reaction, with the aim to use them as \u201cshuttles\u201d for selective delivery of diagnostic agents to cancer cells, exploring the effects of the side chains in the interaction with the target. Compounds 17b and 24 showed excellent potency towards \u3b15\u3b21 integrin acting as selective antagonist and agonist respectively. Further investigations confirmed their effects on target receptor through the analysis of fibronectin-induced ERK1/2 phosphorylation. In addition, confocal microscopy analysis allowed us to follow the fate of EGFP conjugated \u3b15\u3b21 integrin and 17b FITC-conjugated (compound 31) inside the cells. Moreover, the stability in water solution at different values of pH and in bovine serum confirmed the possible exploitation of these peptidomimetic molecules for pharmaceutical application