Construction of diverse peptide structural architectures via chemoselective peptide ligation.

Herein, we report the development of a facile synthetic strategy for constructing diverse peptide structural architectures via chemoselective peptide ligation. The key advancement involved is to utilize the benzofuran moiety as the peptide salicylaldehyde ester surrogate, and Dap-Ser/Lys-Ser dipeptide as the hydroxyl amino functionality, which could be successfully introduced at the side chain of peptides enabling peptide ligation. With this method, the side chain-to-side chain cyclic peptide, branched/bridged peptides, tailed cyclic peptides and multi-cyclic peptides have been designed and successfully synthesized with native peptidic linkages at the ligation sites. This strategy has provided an alternative strategic opportunity for synthetic peptide development. It also serves as an inspiration for the structural design of PPI inhibitors with new modalities.

Integrated microRNA and mRNA expression profile analysis of tumor-associated macrophages after exposure to single-dose irradiation.

BACKGROUND: Radiotherapy (RT) is a common approach that accounts for nearly 50% of cancer patient treatment and has the potential for long-term tumor control. Recently, we published a research article on gene expression profiling of tumor-associated macrophages (TAM) that were exposed to ionizing radiation (IR). Single-dose irradiation of tumors could initiate differentially expressed genes in TAM as a time series from irradiated tumors that are associated with the immune response. It is also well known that human cancers are associated with microRNA (miRNA) alterations that are involved in cancer progression. However, the role of miRNA on TAM after exposure to irradiation remains unclear. RESULTS: In this study, miRNA expression profiles from microarrays were used to identify the key miRNAs and correlating pathways involved in the role of TAMs in tumor progression and recurrence after RT. Using a mouse tumor model, we identified miRNA pattern changes over time in response to irradiation. Based on our results, we hypothesize that miRNA expression in the irradiated tumor may be used as a distinguishing marker to indicate the best time for therapeutic intervention to prevent tumor recurrence after RT. CONCLUSIONS: We established a murine model irradiated with a single dose of 25 Gy that could initiate temporal changes in the expression of miRNAs associated with cell proliferation and the immune response, as evidenced by macrophages directly extracted from irradiated tumors after two weeks of IR. Statistical analyses were conducted by comparing the miRNA expression in macrophages from non-irradiated versus irradiated tumors. Thus, our study could lead to a better understanding of the function of miRNA expressions, which changed temporally in an irradiated tumor microenvironment.

Automatic and quantitative measurement of laryngeal video stroboscopic images.

The laryngeal video stroboscope is an important instrument for physicians to analyze abnormalities and diseases in the glottal area. Stroboscope has been widely used around the world. However, without quantized indices, physicians can only make subjective judgment on glottal images. We designed a new laser projection marking module and applied it onto the laryngeal video stroboscope to provide scale conversion reference parameters for glottal imaging and to convert the physiological parameters of glottis. Image processing technology was used to segment the important image regions of interest. Information of the glottis was quantified, and the vocal fold image segmentation system was completed to assist clinical diagnosis and increase accuracy. Regarding image processing, histogram equalization was used to enhance glottis image contrast. The center weighted median filters image noise while retaining the texture of the glottal image. Statistical threshold determination was used for automatic segmentation of a glottal image. As the glottis image contains saliva and light spots, which are classified as the noise of the image, noise was eliminated by erosion, expansion, disconnection, and closure techniques to highlight the vocal area. We also used image processing to automatically identify an image of vocal fold region in order to quantify information from the glottal image, such as glottal area, vocal fold perimeter, vocal fold length, glottal width, and vocal fold angle. The quantized glottis image database was created to assist physicians in diagnosing glottis diseases more objectively.

Enabling N-to-C Ser/Thr Ligation for Convergent Protein Synthesis via Combining Chemical Ligation Approaches.

In this article, Ser/Thr ligation(on/off) has been realized to enable N-to-C successive peptide ligations using a salicylaldehyde semicarbazone (SAL(off)) group by in situ activation with pyruvic acid of the peptide SAL(off) ester into the peptide salicylaldehyde (SAL(on)) ester. In addition, a peptide with a C-terminal thioester and N-terminal Ser or Thr as the middle peptide segment can undergo one-pot Ser/Thr ligation and native chemical ligation in the N-to-C direction. The utility of this combined ligation strategy in the N-to-C direction has been showcased through the convergent assembly of a human cytokine protein sequence, GlcNAcylated interleukin-25.

Serine/threonine ligation for natural cyclic peptide syntheses.

Covering: 2000 to 2014Cyclic peptides are a class of abundant natural products, often exhibiting attractive biological activities. The challenges in the total synthesis of cyclic peptides lie in the preparation of unnatural amino acids if present and the peptide cyclization. Cyclization is an entropy-disfavoured process, with competition between intermolecular and intramolecular reactions. Biological methods can utilize the pre-organized conformation of the side chain unprotected peptide, which brings the reacting termini into proximity, while chemical synthesis requires protecting groups, often large-size and hydrophobic in nature. In this regard, performing peptide cyclization can be an arbitrary and trial-and-error practice. In this highlight, we discuss the application of chemoselective ligation-mediated peptide cyclization in the total synthesis of natural cyclic peptides.

Serine/threonine ligation for the chemical synthesis of proteins.

Advances in the development of efficient peptide ligation methods have enabled the total synthesis of complex proteins to be successfully undertaken. Recently, a Ser/Thr ligation has emerged as a new tool in synthetic protein chemistry. The chemoselective reaction between an N-terminal serine or threonine of an unprotected peptide segment and a C-terminal salicylaldehyde ester of another unprotected peptide segment gives rise to an N,O-benzylidene acetal linked product, which upon acidolysis produces a native peptide bond at the site of ligation. Ser/Thr ligation has been used for the synthesis of the human erythrocyte acylphosphatase protein and MUC1 glycopeptide segments, semisynthesis of peptoid/PEG-RNase S protein hybrids, and cyclic peptide synthesis including cyclic tetrapeptides, cyclomontanin B, yunnanin C, mahafacyclin B, and daptomycin.

Protein chemical synthesis by serine and threonine ligation.

An efficient method has been developed for the salicylaldehyde ester-mediated ligation of unprotected peptides at serine (Ser) or threonine (Thr) residues. The utility of this peptide ligation approach has been demonstrated through the convergent syntheses of two therapeutic peptides--ovine-corticoliberin and Forteo--and the human erythrocyte acylphosphatase protein (∼11 kDa). The requisite peptide salicylaldehyde ester precursor is prepared in an epimerization-free manner via Fmoc-solid-phase peptide synthesis.

A three-component reaction toward the synthesis of 1-carboxamido-isoindoles.

An efficient three-component reaction toward the facile synthesis of structurally diverse 1-carboxamido-isoindoles has been developed. The resultant isoindoles can be used in Diels-Alder reactions.