The NF-κB signaling pathway is an attractive therapeutic target for cancer and chronic inflammatory diseases. In this study, we report the first strategy to achieve NF-κB inhibition with a peptide inhibitor loaded into perfluorocarbon nanoparticles with the use of a simple post-formulation mixing approach that utilizes an amphipathic cationic fusion peptide linker strategy for cargo insertion. A stable peptide-nanoparticle complex is formed (dissociation constant ~0.14 μM) and metered inhibition of both NF-κB signaling and downstream gene expression (ICAM-1) is demonstrated in leukemia/lymphoma cells. This post-formulation cargo loading strategy enables the use of a generic synthetic or biologic lipidic nanostructure for drug conjugation that permits flexible specification of types and doses of peptides and/or other materials as diagnostic or therapeutic agents for metered incorporation and cellular delivery.
A series of potent electrophilic affinity labels (IC 50 = 0.1-5 nM) containing either a bromoacetamide or isothiocyanate based on the mu opioid receptor (MOR) selective peptide dermorphin were prepared. All four analogs exhibited wash resistant inhibition of [ 3 H]DAMGO binding at subnanomolar to nanomolar concentrations, suggesting that these analogs bind covalently to MOR. To our knowledge these peptides are the highest affinity peptide-based affinity labels for MOR reported to date.Narcotic analgesics produce pain relief generally through activation of mu opioid receptors (MOR), # but the use of these analgesics is limited by their side effects, namely respiratory depression, tolerance, constipation and physical dependence. 1 Therefore there is an ongoing need to develop novel analgesics with fewer side effects. Understanding receptor-ligand interactions at the molecular level can facilitate the design of novel opioid ligands. Since the cloning of the three major opioid receptors, MOR, delta opioid receptors (DOR) and kappa opioid receptors (KOR), in the 1990s and determination of their sequences, 2, 3 there have been considerable advancements in understanding opioid receptor-ligand interactions. These studies have utilized chimeric receptors (such as MOR/KOR chimeras, etc.) and site-directed mutagenesis. 4 Although these approaches have provided considerable information regarding receptor-ligand interactions, interpreting the results can be complicated by changes in the secondary or tertiary structures of the proteins. 4 Also while these approaches provide information about which residues in the receptor may interact with the ligand, they often do not provide information about what portions of the ligand are involved in these interactions. Affinity labels, which are ligands that interact with their target in a non-equilibrium manner, 5 can provide detailed information about specific receptor-ligand interactions, 6, 7 and the information obtained from affinity labels can compliment results obtained from molecular biology and computational methods. The interaction of affinity labels with the receptor occurs in a two-step manner. 5 In the first step, the ligand binds reversibly to its receptor. In the second step, which can further increase the selectivity of the ligand for its receptor, the ligand binds irreversibly, provided an appropriate nucleophile in the receptor is in close proximity to the reactive group in the ligand. Affinity labels can be either photoaffinity or electrophilic affinity labels. The electrophilic affinity label naltrexamine derivative β-funaltrexamine (β-FNA), a well studied affinity label for MOR, was the first affinity label (and one of only two affinity labels 8 ) for opioid receptors whose covalent attachment point (Lys 233 in MOR) has been successfully determined. 7Although a number of non-peptide affinity labels for opioid receptors have been reported in the literature, 1, 5 until recently peptide-based affinity labels have been mostly limited to photoaffinity labels. 5 A ...
Number of promising drug molecules against microbial translocation are currently under various stages of trials and the results of these trials will hopefully contribute significantly toward effective therapeutic intervention. However, studies also need to explore the effect of combination drugs to abrogate microbial translocation.
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