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Increasing antibacterial resistance presents a major challenge in antibiotic discovery. One attractive target in Gram-negative bacteria is the unique asymmetric outer membrane (OM), which acts as a permeability barrier that protects the cell from external stresses, such as the presence of antibiotics. We describe a novel ␤-hairpin macrocyclic peptide JB-95 with potent antimicrobial activity against Escherichia coli. This peptide exhibits no cellular lytic activity, but electron microscopy and fluorescence studies reveal an ability to selectively disrupt the OM but not the inner membrane of E. coli. The discovery of novel antibiotics with new mechanisms of action is an important goal in antibiotic research to combat infections caused by multidrug-resistant bacteria, in particular Gram-negative microorganisms with their unique asymmetric outer membrane (OM) 3 (1). Naturally occurring cationic host defense peptides that form part of the innate immunity in many organisms have recently attracted great interest in the search for new clinically useful antibiotics (2). We explore here an approach to antibiotic discovery based upon host defense peptide-inspired macrocyclic peptidomimetics as a potential source of antibiotics displaying target selectivity and potency not seen with naturally occurring host defense peptides. In previous work (3), we described a family of macrocyclic ␤-hairpin peptidomimetics with potent and selective antimicrobial activity against Pseudomonas spp., which were shown to have a novel mechanism of action targeting the ␤-barrel outer membrane protein LptD in Pseudomonas aeruginosa and inhibiting its key lipopolysaccharide (LPS) transport function in OM biogenesis (4). We report here the discovery of a new conformationally constrained ␤-hairpin peptidomimetic (called JB-95) having potent antimicrobial activity against a panel of Grampositive and Gram-negative bacteria and, in particular, against Escherichia coli. JB-95 shows minimal inhibitory concentrations (MICs) of ϳ0.25 g/ml against E. coli, including many multidrug-resistant clinical strains. We report the solution structure of JB-95 and investigations into its mechanism of action against E. coli. Experimental ProceduresPeptide Synthesis-The methods for synthesis and characterization of all peptides have been described previously (5). JB-95 was of Ͼ95% purity by analytical reverse phase HPLC ( Antibacterial Assays-MICs were determined in microtiter plates in Mueller-Hinton-I (MH-I) medium using the broth

The world health organization (WHO) estimated that 18 million people are struck by Alzheimer's disease (AD). The USA, France, Germany, and other countries launched major programmes targeting the identification of risk factors, the improvement of caretaking, and fundamental research aiming to postpone the onset of AD. The glycogen synthase kinase 3 (GSK-3) is implicated in multiple cellular processes and has been linked to the pathogenesis of several diseases including diabetes mellitus, cancer, and AD. Inhibition of GSK-3 leads to neuroprotective effects, decreased β-amyloid production, and a reduction in tau hyperphosphorylation, which are all associated with AD. Various classes of small molecule GSK-3 inhibitors have been published in patents and original publications. Herein, we present a comprehensive summary of small molecules reported to interact with GSK-3. We illustrate the interactions of the inhibitors with the active site. Furthermore, we refer to the biological characterisation in terms of activity and selectivity for GSK-3, elucidate in vivo studies and pre-/clinical trials.

The glycogen synthase kinase-3 (GSK-3) has been linked to the pathogenesis of colorectal cancer, diabetes, cardiovascular disease, acute myeloid leukemia (AML), and Alzheimer's disease (AD). The debate on the respective contributions of GSK-3α and GSK-3β to AD pathology and AML is ongoing. Thus, the identification of potent GSK-3α-selective inhibitors, endowed with favorable pharmacokinetic properties, may elucidate the effect of GSK-3α inhibition in AD and AML models. The analysis of all available crystallized GSK-3 structures provided a simplified scheme of the relevant hot spots responsible for ligand binding and potency. This resulted in the identification of novel scorpion shaped GSK-3 inhibitors. It is noteworthy, compounds 14d and 15b showed the highest GSK-3α selectivity reported so far. In addition, compound 14d did not display significant inhibition of 48 out of 50 kinases in the test panel. The GSK-3 inhibitors were further profiled for efficacy and toxicity in the wild-type (wt) zebrafish embryo assay.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. Several single gene mutations have been linked to this disease. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) indicate LRRK2 as promising therapeutic target for the treatment of PD. LRRK2 mutations were observed in sporadic as well as familial PD patients and have been investigated intensively. LRRK2 is a large and complex protein, with multiple enzymatic and protein-interaction domains, each of which is effected by mutations. The most common mutation in PD patients is G2019S. Several LRRK2 inhibitors have been reported already, although the crystal structure of LRRK2 has not yet been determined. This review provides a summary of known LRRK2 inhibitors and will discuss recent in vitro and in vivo results of these inhibitors.

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