Naturally occurring muraymycin nucleoside antibiotics represent a promising class of novel antibacterial agents. The structural complexity suggests the investigation of simplified analogues as potential lead structures, which can then be further optimized towards highly potent antimicrobials. Herein we report studies on muraymycin-derived potential lead structures lacking an aminoribose motif found in most naturally occurring muraymycins. We have identified a 5'-defunctionalized motif to be ideal in terms of stability and chemical accessibility and have synthesized a full-length muraymycin analogue based on this structure using a novel fully stereocontrolled route. The obtained 5'-deoxy analogue of the natural product muraymycin C4 showed good inhibitory properties towards the bacterial target protein MraY, sufficient pharmacokinetic stability and no cytotoxicity against human cells, thus making it a promising lead for antibacterial drug development.

Nonalcoholic fatty liver disease (NAFLD) is considered to be the most common liver disorder in Western countries with a prevalence of 20-30% of the adult population ( 1, 2 ). There is a strong correlation between the characteristics of the metabolic syndrome, such as obesity and diabetes mellitus, and NAFLD/nonalcoholic steatohepatitis (NASH) ( 3 ).The "two-hit" hypothesis represents a common model to describe the development and progression of fatty liver diseases. A simple steatosis can stand for the fi rst step in early liver pathogenesis ( 4, 5 ). The progression from simple steatosis to NASH requires a "second hit" mediated by reactive oxygen species and release of infl ammatory cytokines ( 6 ). This infl ammatory environment can result in hepatic cirrhosis and fi nally in hepatocellular carcinoma (HCC) ( 7 ).The development of hepatosteatosis can be induced by different mechanisms. The synthesis of lipids is regulated in a complex interplay induced by a set of lipogenic transcription factors, among which liver X receptor ␣ (LXR-␣ / NR1H3), sterol regulatory element binding transcription factor 1 (SREBF1/SREBP1), and carbohydrate responsive element binding protein (ChREBP/MLXIPL) represent the most important ones ( 8 ). In this context, the fact that MLXIPL controls 50% of hepatic lipogenesis by regulating glycolytic and lipogenic gene expression ( 9 ) illustrates the Abstract Liver-specifi c overexpression of the insulin-like growth factor 2 ( IGF2 ) mRNA binding protein p62/ IGF2BP2-2 induces a fatty liver, which highly expresses IGF2 . Because IGF2 expression is elevated in patients with steatohepatitis, the aim of our study was to elucidate the role and interconnection of p62 and IGF2 in lipid metabolism. Expression of p62 and IGF2 highly correlated in human liver disease. p62 induced an elevated ratio of C18:C16 and increased fatty acid elongase 6 (ELOVL6) protein, the enzyme catalyzing the elongation of C16 to C18 fatty acids and promoting nonalcoholic steatohepatitis in mice and humans. The p62 overexpression induced the activation of the ELOVL6 transcriptional activator sterol regulatory element binding transcription factor 1 (SREBF1). Recombinant IGF2 induced the nuclear translocation of SREBF1 and a neutralizing IGF2 antibody reduced ELOVL6 and mature SREBF1 protein levels. Concordantly, p62 and IGF2 correlated with ELOVL6 in human livers. Decreased palmitoyl-CoA levels, as found in p62 transgenic livers, can explain the lipogenic action of ELOVL6. Accordingly, p62 represents an inducer of hepatic C18 fatty acid production via a SREBF1-dependent induction of ELOVL6. These fi ndings underline the detrimental role of p62 in liver disease. -Laggai, S., S. M. Kessler, S.

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The protein kinase C-related kinase 2 (PRK2)-interacting fragment (PIF) pocket of phosphoinositide-dependent kinase-1 (PDK1) was proposed as a novel target site for allosteric modulators. In the present work, we describe the design, synthesis, and structure-activity relationship of a series of 2-(3-oxo-1,3-diphenylpropyl)malonic acids as potent allosteric activators binding to the PIF pocket. Some congeners displayed AC(50) values for PDK1 activation in the submicromolar range. The potency of the best compounds to stabilize PDK1 in a thermal stability shift assay was in the same order of magnitude as that of the PIF pocket binding peptide PIFtide, suggesting comparable binding affinities to the PIF pocket. The crystal structure of PDK1 in complex with compound 4h revealed that additional ionic interactions are mainly responsible for the increased potency compared to the monocarboxylate analogues. Notably, several compounds displayed high selectivity for PDK1. Employing a prodrug strategy, we were able to corroborate the novel mechanism of action in cells.