Lantibiotics are antimicrobial peptides produced by bacteria. Some are employed for food preservation, whereas others have therapeutic potential due to their activity against organisms resistant to current antibiotics. They are ribosomally synthesized and posttranslationally modified by dehydration of serine and threonine residues followed by attack of thiols of cysteines to form monosulfide lanthionine and methyllanthionine rings, respectively. Chemical synthesis of peptide analogues is a powerful method to verify stereochemistry and access structure-activity relationships. However, solid supported synthesis of lantibiotics has been difficult due to problems in generating lanthionines and methyllanthionines with orthogonal protection and good stereochemical control. We report the solid-phase syntheses of both peptides of a two-component lantibiotic, lacticin 3147. Both successive and interlocking ring systems were synthesized on-resin, thereby providing a general methodology for this family of natural products.

Lactocin S is a lantibiotic peptide with potent antibacterial activity against a range of gram-positive bacteria. Because of challenges in obtaining sufficient quantities of this compound from natural sources, the stereochemistry of the lanthionine residues in lactocin S had not been confirmed. This report describes the chemical synthesis of lactocin S on chlorotrityl polystyrene resin in 10% overall yield using intramolecular cyclization to form the lanthionine rings and employing fragment coupling for the two N-terminal residues. This represents the first report of solid-supported synthesis of a naturally occurring lantibiotic. Comparison to lactocin S isolated from Lactobacillus sakei L45 using a combination of HPLC, MS/MS sequencing, bacterial testing, and chiral GC-MS analysis confirmed the initially proposed structure and the stereochemistry of the DL-lanthionine residues.

Background: Influenza virus NA is transported to the host cell surface. Results: Cdc42 promotes the transport of NA to the plasma membranes, whereas ARHGAP21 inhibits this process. Conclusion: Cdc42 positively and ARHGAP21 negatively regulate NA transport to the cell surface and virus replication. Significance: Identification of host factors involved in regulating NA transport is critical for understanding influenza virus replication.

Direct benzylation of carboxylic acids with toluene has been developed via palladium-catalyzed C-H acyloxylation under 1 atm of oxygen. This reaction demonstrates good functional group tolerance and high yields, providing a facile, atom-economic, and efficient method for the synthesis of benzyl esters.

Twisted molecules: A modular approach for the synthesis of tetrasubstituted helical alkenes by a palladium-catalyzed norbornene-mediated domino reaction is presented. This intermolecular domino process allows the formation of three C-C bonds in one operation through a C-H activation/carbopalladation/C-H activation sequence.

School composition effects have been consistently verified, but few studies ever attempted to study how school composition affects school achievement. Based on prior research findings, we employed multilevel mediation modeling to examine whether school processes mediate the effect of school composition upon school outcomes based on the data of 28 OECD countries in PISA 2003. These school process factors include school resources, opportunity to learn, school climate and school management. We find that school composition effects are partially mediated by school climate factors.

BackgroundAlthough DNA vaccine holds a great potential for cancer immunotherapy, effective long-lasting antitumoral immunity sufficient to induce durable responses in cancer patients remains to be achieved. Considering the pivotal role of dendritic cells (DC) in the antigen processing and presentation, we prepared DC-targeting DNA vaccines by fusing tumor-associated antigen HER2/neu ectodomain to single chain antibody fragment (scFv) from NLDC-145 antibody specific for DC-restricted surface molecule DEC-205 (scFvNLDC-145), and explored its antitumoral efficacy and underlying mechanisms in mouse breast cancer models.ResultsIn vivo targeting assay demonstrated that scFvNLDC-145 specifically delivered DNA vaccine-encoded antigen to DC. Compared with untargeted HER2/neu DNA vaccines, vaccination with scFvNLDC-145-HER2/neu markedly promoted the HER2/neu-specific cellular and humoral immune responses with long-lasting immune memory, resulting in effective protection against challenge of HER2/neu-positive D2F2/E2 breast tumor while ineffective in parental HER2/neu-negative D2F2 breast tumor. More importantly, in combination with temporary depletion of regulatory T cells (Treg) by low-dose cyclophosphamide, vaccination with scFvNLDC-145-HER2/neu induced the regression of established D2F2/E2 breast tumor and significantly retarded the development of spontaneous mammary carcinomas in transgenic BALB-neuT mice.ConclusionOur findings demonstrate that DC-targeted DNA vaccines for in vivo direct delivery of tumor antigens to DC could induce potent antigen-specific cellular and humoral immune responses and, if additional combination with systemic Treg depletion, was able to elicit an impressively therapeutic antitumoral activity, providing a rationale for further development of this approach for cancer treatment.

Neopetrosiamides A and B (2) from the marine sponge Neopetrosia sp. are two diastereomeric tricyclic peptides that inhibit tumor cell invasion associated with metastasis. The reported structures were chemically synthesized using solid-phase peptide synthesis and sequential stepwise disulfide bond formation in solution. The disulfide bond connectivity of the originally proposed structures was revised and confirmed by chemical synthesis together with a combination of HPLC analysis, disulfide mapping, and biological activity testing. This methodology was also utilized to generate analogues containing methionine or norleucine in place of the methionine sulfoxide at position 24. Compounds 4 and 6 demonstrated potent bioactivity comparable to that of the parent peptides.