Ketomethylene isosteric amide bond replacements via the zinc -mediated chain extension of N -protected amino acids

A methodology for the chain extension of N-protected amino acid beta-keto esters to gamma-keto esters utilizing a zinc carbenoid was developed. The reaction was used on amino acids containing various protective groups and a variety of side chain functionality. This method was used in the incorporation of ketomethylene isosteric amino acid replacements within amino acid sequences. The usefulness of the method on molecules supported by a solid phase was explored

Gut Microbiome: Profound Implications For Diet And Disease

The gut microbiome plays an important role in human health and influences the development of chronic diseases ranging from metabolic disease to gastrointestinal disorders and colorectal cancer. Of increasing prevalence in Western societies, these conditions carry a high burden of care. Dietary patterns and environmental factors have a profound effect on shaping gut microbiota in real time. Diverse populations of intestinal bacteria mediate their beneficial effects through the fermentation of dietary fiber to produce short-chain fatty acids, endogenous signals with important roles in lipid homeostasis and reducing inflammation. Recent progress shows that an individual’s starting microbial profile is a key determinant in predicting their response to intervention with live probiotics. The gut microbiota is complex and challenging to characterize. Enterotypes have been proposed using metrics such as alpha species diversity, the ratio of Firmicutes to Bacteroidetes phyla, and the relative abundance of beneficial genera (e.g., Bifidobacterium, Akkermansia) versus facultative anaerobes (E. coli), pro-inflammatory Ruminococcus, or nonbacterial microbes. Microbiota composition and relative populations of bacterial species are linked to physiologic health along different axes. We review the role of diet quality, carbohydrate intake, fermentable FODMAPs, and prebiotic fiber in maintaining healthy gut flora. The implications are discussed for various conditions including obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, depression, and cardiovascular disease

Prospective identification of parasitic sequences in phage display screens

Phage display empowered the development of proteins with new function and ligands for clinically relevant targets. In this report, we use next-generation sequencing to analyze phage-displayed libraries and uncover a strong bias induced by amplification preferences of phage in bacteria. This bias favors fast-growing sequences that collectively constitute <0.01% of the available diversity. Specifically, a library of 10[superscript 9] random 7-mer peptides (Ph.D.-7) includes a few thousand sequences that grow quickly (the ‘parasites’), which are the sequences that are typically identified in phage display screens published to date. A similar collapse was observed in other libraries. Using Illumina and Ion Torrent sequencing and multiple biological replicates of amplification of Ph.D.-7 library, we identified a focused population of 770 ‘parasites’. In all, 197 sequences from this population have been identified in literature reports that used Ph.D.-7 library. Many of these enriched sequences have confirmed function (e.g. target binding capacity). The bias in the literature, thus, can be viewed as a selection with two different selection pressures: (i) target-binding selection, and (ii) amplification-induced selection. Enrichment of parasitic sequences could be minimized if amplification bias is removed. Here, we demonstrate that emulsion amplification in libraries of ~10[superscript 6] diverse clones prevents the biased selection of parasitic clones

A Lifetime Of Chemical Exposure - Dangers To Human Health

Dr. Cory Theberge, from UNE\u27s College of Pharmacy, gives an overview of contaminants of emerging concern in the environment, how they end up there, and the scope of the problem in the United States. Dr. Richard Peterson, from UNE\u27s Department of Environmental Studies, introduces the presentation.https://dune.une.edu/pharmsci_facpres/1000/thumbnail.jp

Chain Extension of Amino Acid Skeletons: Preparation of Ketomethylene Isosteres

Ketomethylene isosteric replacements for peptide bonds were generated through a zinc carbenoid-mediated chain extension reaction in which a variety of amino acid-derived β-keto esters are converted to γ-keto esters in a single step. The reaction tolerates a variety of protecting groups and amino acid side chains with no epimerization of the amino acid stereocenter

A Divergent Diastereoselective Approach to Bicyclopropanes

The diastereoselective cyclopropanation of three stereoisomerically unique vinylcyclopropanes was studied. The selective preparation of six stereoisomeric bicyclopropanes was accomplished by an iterative reagent-controlled process. With the exception of the cis-syntrans-bicyclopropane, all isomers can be prepared in a diastereomeric excess of greater than 5:1

Diastereoselective Synthesis of Bicyclopropanes

Diastereoselective cyclopropanation of a trans-substituted vinyl cyclopropane was studied. The stereochemistry of the major and minor isomers was assigned by diastereoselective synthesis of the two isomers

Studies on the Diastereoselective Preparation of Bicyclopropanes

The identification of two natural products, FR-900848 and U-106305, has stimulated interest concerning the relationship between configurational isomerism, conformational isomerism, and biological activity of polycyclopropanes. Efforts to investigate the relationship between configurational and conformational isomerism through molecular modeling suggest that significantly different three-dimensional structures will result from unique primary structures. Any effort to address these issues demands that stereoselective methods for the preparation of polycyclopropanes be developed. We have investigated the application of zinc−carbenoid cyclopropanation in the presence of chiral dioxaboralanes to the preparation of eight stereochemically unique bicyclopropanes. The trans-vinylcyclopropane starting materials demonstrated very little substrate-induced stereoselectivity, while the cis-vinylcyclopropane demonstrates modest to excellent stereocontrol. A model for the substrate-based stereocontrol is proposed. We also used the spectroscopic data gathered in this investigation to probe the substrate-mediated stereocontrol in the rhodium(II)-catalyzed cyclopropanation of vinylcyclopropanes with ethyl diazoacetate

Gut Microbiome: Profound Implications for Diet and Disease

The gut microbiome plays an important role in human health and influences the development of chronic diseases ranging from metabolic disease to gastrointestinal disorders and colorectal cancer. Of increasing prevalence in Western societies, these conditions carry a high burden of care. Dietary patterns and environmental factors have a profound effect on shaping gut microbiota in real time. Diverse populations of intestinal bacteria mediate their beneficial effects through the fermentation of dietary fiber to produce short-chain fatty acids, endogenous signals with important roles in lipid homeostasis and reducing inflammation. Recent progress shows that an individual’s starting microbial profile is a key determinant in predicting their response to intervention with live probiotics. The gut microbiota is complex and challenging to characterize. Enterotypes have been proposed using metrics such as alpha species diversity, the ratio of Firmicutes to Bacteroidetes phyla, and the relative abundance of beneficial genera (e.g., Bifidobacterium, Akkermansia) versus facultative anaerobes (E. coli), pro-inflammatory Ruminococcus, or nonbacterial microbes. Microbiota composition and relative populations of bacterial species are linked to physiologic health along different axes. We review the role of diet quality, carbohydrate intake, fermentable FODMAPs, and prebiotic fiber in maintaining healthy gut flora. The implications are discussed for various conditions including obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, depression, and cardiovascular disease