Manipulation of Nitric Oxide Levels via a Modified Hydroxyethyl Starch Molecule.

Introduction: Although the improving effect of nitric oxide (NO) donors has experimentally been demonstrated in shock, there are still no NO donor medications clinically available. Thiol-nitrosothiol-hydroxyethyl starch (S-NO-HES) is a novel molecule consisting of NO coupled to a thiolated derivative of hydroxyethyl starch (HES). It was aimed to assess the ability of S-NO-HES to serve as an NO donor under a variety of in vitro simulated physiologic conditions, which might be the first step to qualify this molecule as a novel type of NO donor-fluid.

Sequence-specific peptide synthesis by an artificial small-molecule machine.

The ribosome builds proteins by joining together amino acids in an order determined by messenger RNA. Here, we report on the design, synthesis, and operation of an artificial small-molecule machine that travels along a molecular strand, picking up amino acids that block its path, to synthesize a peptide in a sequence-specific manner. The chemical structure is based on a rotaxane, a molecular ring threaded onto a molecular axle.

Breaking the dogma of the metal-coordinating carboxylate group in integrin ligands: introducing hydroxamic acids to the MIDAS to tune potency and selectivity.

A suitable substitute: All integrin receptors bind their ligands, which contain an aspartate residue, in the metal-ion- dependent adhesion site (MIDAS). So far all attempts to replace the carboxyl group of aspartate with other, pharmacologically favorable isosteric groups have failed. Now it has been shown that a hydroxamic acid group can replace the carboxyl group; the resulting ligand retains its high binding activity.

Rational design of highly active and selective ligands for the alpha5beta1 integrin receptor.

The inhibition of integrin function is a major challenge in medicinal chemistry. Potent ligands are currently in different stages of clinical trials for the antiangiogenic therapy of cancer and age-related macula degeneration (AMD). The subtype alpha5beta1 has recently been drawn into the focus of research because of its genuine role in angiogenesis.

Design and chemical synthesis of integrin ligands.

The design and synthesis of peptidic and nonpeptidic integrin ligands derived from the most abundant natural tripeptide sequence, RGD, are described in this article. Special emphasis is placed on the activity and selectivity of the ligands to integrin subtypes. Two approaches are described-ligand- and structure-oriented design.

The RGD motif in fibronectin is essential for development but dispensable for fibril assembly.

Fibronectin (FN) is secreted as a disulfide-bonded FN dimer. Each subunit contains three types of repeating modules: FN-I, FN-II, and FN-III. The interactions of alpha5beta1 or alphav integrins with the RGD motif of FN-III repeat 10 (FN-III10) are considered an essential step in the assembly of FN fibrils.

Ligand binding analysis for human alpha5beta1 integrin: strategies for designing new alpha5beta1 integrin antagonists.

We report a three-dimensional model of the alpha5beta1 integrin headgroup bound to the most potent and selective ligand (SJ749) known to date. The model was built using the comparative protein modeling method, and it is consistent with experimental data. From this study, we identified two potentially important regions in the alpha5beta1 receptor that are peculiar to this integrin and might be worth considering for drug targeting.

Orientational properties of stretched polystyrene gels in organic solvents and the suppression of their residual 1H NMR signals.

While residual dipolar couplings (RDCs) are an established method in high-resolution biomolecular NMR, their use for structure determination of small molecules in organic solvents is limited by the alignment media available. Only recently stretched polystyrene (PS) gels were introduced for the measurement of RDCs on small compounds that allowed urgently needed free scalability of the induced anisotropy. Here, the properties of such stretched PS gels in different organic solvents as well as for different magnetic field strengths and temperatures are studied and practical NMR-spectroscopic aspects are discussed.