Cyclic pentapeptides of chiral sequence DLDDL as scaffold for antagonism of G‐protein coupled receptors: Synthesis,activity and conformational analysis by NMR and molecular dynamics of ITF 1565 a substance P inhibitor

Under the hypotheses of a structurally related binding site for antagonists of G‐protein coupled receptors and the ability of cyclic pentapeptides of chiral sequence D ¹L ²D ³D ⁴L ⁵ to form rigid structures with which probe the pharmacophoric specificity of these receptors, inhibitors of substance P were designed based on available structure–activity relationships. ITF 1565, cyclo[D ‐Trp¹‐Pro²‐D ‐Lys³‐D ‐Trp⁴‐Phe⁵], antagonized substance P activity mediated by type 1 neurokinin receptor (NK1) whereas it acted weakly against NK2 and did not inhibit endothelin at all. The preferential conformation of the peptide was obtained from nmr spectroscopy and computer calculations, and shown to contain the same βII‐turn and γ′‐turn found in other cyclic pentapeptides with the same chiral sequence. The structure of the peptide was compared with that of the β‐D ‐glucose molecule that has been proposed as a semirigid scaffold for antagonists of G‐protein coupled receptors. The γ′‐turn of the cyclic peptide superimposed well with β‐D ‐glucose in the chair conformation. Furthermore, when the side chains were considered, the aromatic groups of the two molecules were found to generally overlap. These results support the view of G‐protein coupled receptors as possessing structurally similar binding sites for antagonists and suggest that cyclic pentapeptides of chiral sequence D ¹L ²D ³D ⁴L ⁵ may be useful as semirigid scaffolds for the design of antagonists of this family of receptors. © 1999 John Wiley & Sons, Inc. Biopoly 50: 211–219, 1999     

Macrocyclic inhibitors of Factor XIa: Discovery of alkyl-substituted macrocyclic amide linkers with improved potency

Optimization of macrocyclic inhibitors of FXIa is described which focused on modifications to both the macrocyclic linker and the P1 group. Increases in potency were discovered through interactions with a key hydrophobic region near the S1 prime pocket by substitution of the macrocyclic linker with small alkyl groups. Both the position of substitution and the absolute stereochemistry of the alkyl groups on the macrocyclic linker which led to improved potency varied depending on the ring size of the macrocycle. Replacement of the chlorophenyltetrazole cinnamide P1 in these optimized macrocycles reduced the polar surface area and improved the oral bioavailability for the series, albeit at the cost of a decrease in potency.     

Anaerobic ammonium oxidation in sediments of surface flow constructed wetlands treating swine wastewater

Applied Microbiology and Biotechnology - Anaerobic ammonium oxidation (anammox) was suggested to be involved in the nitrogen (N) removal process in constructed wetlands (CWs). Nevertheless, its...     

Identification of alternatively spliced <Emphasis Type="Italic">MsRan</Emphasis> transcripts involved in low temperature response in <Emphasis Type="Italic">Musa</Emphasis> spp.

Ran is involved in response to external stimuli. In this study, six MsRan gene cDNA sequences were isolated from wild banana (Musa spp. AB group) from Sanming City, China. Sequence analysis reveals that MsRan3A, MsRan3A-1a, and MsRan3C contained Ran protein domains including a GTP hydrolysis domain, a RanGAP-binding domain, and an acidic tail, whereas two G boxes (G4 and G5) were absent in MsRan3A-6a. The physicochemical property of MsRan3A, MsRan3A-1a, MsRan3A-6a, and MsRan3C appeared to differ significantly. Real time quantitative PCR (qPCR) analysis indicates that MsRan3A-1, MsRan3A-5, MsRan3A-6, MsRan3A-6a, and MsRan3C-1 were expressed in roots, leaves, peduncles, bracts, flowers, peels, and pulp of the wild banana. MsRan3A-1a was expressed at extremely low levels in these tissues and was undetectable by qPCR. The MsRan genes were found to be involved in responses to a low temperature stress but with different response patterns. Furthermore, salicylic acid significantly enhanced MsRan gene expressions suggesting the involvement of these genes in salicylic acid signal transduction.     

Autophagy-related protein ATG5 regulates histone H2B mono-ubiquitylation by translational control of RNF20

<正>Autophagy is an evolutionarily conserved lysosome-mediated catabolic process(Klionsky,2007).Autophagy is believed to be essential for cell survival,especially when cells were exposed to stresses,such as nutrient starvation.The activation of autophagy under starvation allows cells to survive by providing essential crudes for cell construction via degrading intracellular substrates     

TLR3 activation induces S100A7 to regulate keratinocyte differentiation after skin injury

Human S100A7 (psoriasin) is highly expressed in psoriasis and other inflammatory diseases; however, the function of S100A7 in wound repair remains largely unknown. Here we demonstrated that skin injury increased the expression of S100A7. Damaged cells from wounded skin induced the expression of S100A7 via the activation of Toll-like receptor 3 (TLR3) followed by the activation of p38 MAPK. S100A7, in turn, acted on keratinocytes to induce the expression of terminal differentiation marker gene loricrin through the activation of p38 MAPK and caspase-1. The differentiation of keratinocytes induced by S100A7 resulted in skin stratification, thus efficiently promoting wound closure. Taken together, our results demonstrate that the activation of TLR3 accelerates wound closure via the induction of S100A7 to induce keratinocyte differentiation. These findings also provide new insights into the development of different forms of treatment with skin wounds.