Dual Modulator of ASIC Channels and GABA Receptors from Thyme Alters Fear-Related Hippocampal Activity.

Acid-sensing ion channels (ASICs) are proton-gated ion channels that mediate nociception in the peripheral nervous system and contribute to fear and learning in the central nervous system. Sevanol was reported previously as a naturally-occurring ASIC inhibitor from thyme with favorable analgesic and anti-inflammatory activity. Using electrophysiological methods, we found that in the high micromolar range, the compound effectively inhibited homomeric ASIC1a and, in sub- and low-micromolar ranges, positively modulated the currents of α1β2γ2 GABA receptors.

Structure elucidation of Keroplatus (Diptera:Keroplatidae) fungus gnat oxyluciferin.

Bioluminescence of insects is a well-known natural phenomenon in the focus of interest of scientific research. While the mechanisms of bioluminescence in Coleoptera have been extensively studied, there is a lack of information about the chemistry of light emission in Diptera species. Here we report the Keroplatus spp.

Total Synthesis of Racemic Thieno[3,2-]thiochromene Tricarboxylate, a Luciferin from Marine Polychaeta .

We report the first total synthesis of racemic luciferin, a thieno[3,2-]thiochromene tricarboxylate comprising a 6-6-5-fused tricyclic skeleton with three sulfur atoms in different electronic states. The key transformation is based on tandem condensation of bifunctional thiol-phosphonate, obtained from dimethyl acetylene dicarboxylate, with benzothiophene-6,7-quinone. The presented convergent approach provides the synthesis of the target compound with a previously unreported fused heterocyclic core in 11 steps, thus allowing for unambiguous confirmation of the chemical structure of luciferin by 2D-NMR spectroscopy.

Novel platform for the preparation of synthetic orally active peptidomimetics with hemoregulating activity. II. Hemosuppressor activity of 2,5-diketopiperazine-based cyclopeptides.

The novel chemical platform formed by the branched piperazine-2,5-dione peptide derivatives (2,5-diketopiperazines) for creating non-invasive biologically active peptidomimetics has been developed. A successful application of this approach to orally available hemostimulatory peptidomimetics was demonstrated for all-L cyclopeptide from the Glu-Trp-peptide family. In the 1980s, we have separated and characterized a number of dipeptides from the thymus homogenate.

Novel side reaction accompanying cyclization of Glu(R1)-Glu(R2) dipeptides via lactamization of the Glu(R1) residue.

A series of linear peptides with the general formula H-Glu(R1)-Glu(R2)-OH was subjected to cyclization under standard conditions. Formation of respective 2,5-diketopiperazines was accompanied by transformation of the N-terminal Glu(R1) to pyroglutamic acid residue. Even in the case R1 is an amino acid residue attached to the N-terminal γ-carboxyl group, lactamization leads to its elimination.

Chemical Platform for the Preparation of Synthetic Orally Active Peptidomimetics with Hemoregulating Activity.

A novel chemical platform based on branched piperazine-2,5-dione derivatives (2,5-diketopiperazines) for creating orally available biologically active peptidomimetics has been developed. The platform includes a diketopiperazine scaffold with "built-in" functionally active peptide fragments covalently attached via linkers. The concept was applied to two hemostimulatory drugs, the dipeptide thymogen (GluTrp) and the tripeptide stemokin (IleGluTrp).

beta-Actin-derived peptides isolated from acidic extract of rat spleen suppress tumor cell growth.

Twenty-two fragments of beta-actin and beta-actin-related protein were isolated from the acidic extracts of rat spleen tissue. beta-Actin fragments (75-90), (78-89), and (78-88), 0.01-1 microM, decreased live cell number of L929 murine tumor fibroblasts by 80-90%, with maximal cytotoxic effect of 30-40%.

Peptidomics: a logical sequel to proteomics.

Rapid progress of separation techniques as well as methods of structural analysis provided conditions in the past decade for total screening of complex biologic mixtures for any given class of biomolecules. The present review updates the reader with the modern state of peptidomics, a chapter of chemical biology that deals with structure and biologic properties of sets of peptides present in biologic tissues, cells or fluids. Scope and limitations of currently employed experimental techniques are considered and the main results are outlined.

Generation of peptides by human erythrocytes: facts and artifacts.

Previously reported data on peptide composition of human erythrocyte lysate were obtained under conditions that did not exclude proteolytic degradation of hemoglobin in the process of peptide isolation. Comparative chromatographic analysis of the diluted erythrocyte lysate incubated in acidic conditions with or without proteolytic enzyme inhibitors showed that several peptides earlier identified as intraerythrocyte ones in fact result from hemoglobin degradation by erythrocyte acidic protease(s) during incubation of the lysate. A rational scheme excluding postlysis proteolysis was developed for isolation of peptide fraction.

Family of hemorphins: co-relations between amino acid sequences and effects in cell cultures.

Hemorphins, i.e. endogenous fragments of beta-globin chain segment (32-41) LVVYPWTQRY(F) suppress the growth of transformed murine fibroblasts L929 cell culture, the effect is due to cytotoxicity and inhibition of cell proliferation.

Peptides comprising the bulk of rat brain extracts: isolation, amino acid sequences and biological activity.

Chromatographic separation of rat brain extracts followed by automatic Edman sequencing of the major individual components resulted in identification of 61 endogenous peptides derived from known functional proteins (hemoglobin, myelin basic protein, cytochrome-c oxidase, etc.) or unknown precursors. The results are compared with the data obtained earlier for bovine brain.

LVV- and VV-hemorphins: comparative levels in rat tissues.

Screening of hemorphins in extracts of rat lung, brain, heart and spleen was carried out. The threshold for detection of hemorphins was 0.01 nmol for spleen and 0.

Neokyotorphin and neokyotorphin (1-4): secretion by erythrocytes and regulation of tumor cell growth.

Human erythrocytes release neokyotorphin, the 137-141 fragment of hemoglobin alpha-chain into the supernatant of red blood cells primary culture. However, the neokyotorphin fragment 1-4 that is formed together with neokyotorphin inside the red blood cells and in various tissues is not found in the supernatant. Both neokyotorphin and its 1-4 fragment were shown to stimulate proliferation of L929 tumor cells.

Cytotoxic activity of acetylcholine receptor ligands.

Acetylcholine receptor ligands were studied for cytotoxicity in K562 human erythroid leukemia tumor cells. Cytotoxicity of carbachol, an agonist of acetylcholine receptors, atropine, an antagonist of muscarinic acetylcholine receptor, neurotoxin 11 (NT II) from Naja naja oxiana cobra venom and tubocurarine, antagonists of acetylcholine receptor of nicotinic type was exhibited in the 10-7-10-5 M concentration range. Several cytolytic processes, two for carbachol and three for other ligands, corresponding to different concentrations of each ligand were detected.

Different pathways of the release of cytotoxic proteins in LAK cells.

Human LAK cells were shown to release cytotoxic proteins by both Ca(2+)-dependent and Ca(2+)-independent mechanisms. CD3+ CD8+ CD16- and CD16+ CD8+ CD3- LAK cells were co-incubated with target cells in the presence of 4 mM EGTA. Although EGTA inhibited the exocytosis of cytolytic granules, supernatants obtained were cytotoxic for target cells.

Neokyotorphin and neokyotorphin (1-4): cytolytic activity and comparative levels in rat tissues.

The content of biologically active hemoglobin fragment neokyotorphin (TSKYR) as well as that of neokyotorphin fragment (1-4) (TSKY) were determined in extracts of lung, heart, and brain tissue of rats. The content of both peptides as well as the neokyotorphin/neokyotorphin(1-4) ratio differed significantly from each other in these tissues. The respective parameters deviate considerably from those of erythocytes where these peptides are originally formed.