Disulfide Bond Replacement with 1,4- and 1,5-Disubstituted [1,2,3]-Triazole on C-X-C Chemokine Receptor Type 4 (CXCR4) Peptide Ligands: Small Changes that Make Big Differences

Here we investigated the structural and biological effects ensuing from the disulfide bond replacement of a potent and selective C-X-C chemokine receptor type 4 (CXCR4) peptide antagonist, with 1,4- and 1,5- disubstituted 1,2,3-triazole moieties. Both strategies produced candidates that showed high affinity and selectivity against CXCR4. Notably, when assessed for their ability to modulate the CXCL12-mediated cell migration, the 1,4-triazole variant conserved the antagonistic effect in the low-mid nanomolar range, while the 1,5-triazole one displayed the ability to activate the migration, becoming the first in class low-molecular-weight CXCR4 peptide agonist. By combining NMR and computational studies, we provided a valuable model that highlighted differences in the interactions of the two peptidomimetics with the receptor that could account for their different functional profile. Finally, we envisage that our findings could be translated to different GPCR-interacting peptides for the pursuit of novel chemical probes that could assist in dissecting the complex puzzle of this fundamental class of transmembrane receptors.     

Growth and remodeling in highly stressed solid tumors

Meccanica - Growing biological media develop residual stresses to make compatible elastic and inelastic growth-induced deformations, which in turn remodel the tissue properties modifying the actual...     

Misenine,a Novel Macrocyclic Alkaloid with an Unusual Skeleton from the Mediterranean Sponge Reniera sp

PolycycJic marine alkaloids containing 3-alkylpyridine or partially reduced 3-alkylpyridine as basic building blocks represent an emerging and intriguing group of bioactive natural products from marine sponges. Since halitoxin,² the first example of this kind of alkaloid, was reported in 1978, many related alkaloids have been discovered from sponges of the order Haplosclerida. All of these alkaloids, in spite of formally exhibiting quite different frameworks, could biogeneticaliy derive from bis-3-alkylpyridine or reduced bis-3-alkylpyridine units. In the last decade, the knowledge of this fascinating group of compounds has increased remarkably. A recent review has exhaustively studied occurrence, distribution, plausible biogenetic origin and relatedness, as well as biological activities, of 3-alkylpyridine derived marine alkaloids.³     

Thermal analysis of milling products and its implications in self-ignition

Thermal degradation of soft wheat, durum wheat, and maize as well as native starch and maize dextrin used to make fireworks, under nitrogen atmosphere, was studied by differential scanning calorimetry and thermogravimetric analysis. The results indicate that bran-free products give rise to a decomposition via transglycosylation-volatilization. On the contrary, wheat products containing bran or ligno-cellulosic residues decompose via exothermic reaction of dehydration-charring. For each product, the curve is determined as a function of its physical form, i.e., flour, ground product, and grain. The comparison of the conversion calculated as a first-order kinetics and the experimental, exhibits a very low mean square error. On this basis, the pyrolysis was assumed to obey first-order kinetics. The kinetic results were then used to estimate the temperature of spontaneous combustion, when these products are stored in silos. In particular, Frank-Kamenetskii theory is applied to prove how the products, under particular conditions, can become extremely explosive.     

Structure of Nanobody Nb23

Background: Nanobodies, or VHHs, are derived from heavy chain-only antibodies (hcAbs) found in camelids. They overcome some of the inherent limitations of monoclonal antibodies (mAbs) and derivatives thereof, due to their smaller molecular size and higher stability, and thus present an alternative to mAbs for therapeutic use. Two nanobodies, Nb23 and Nb24, have been shown to similarly inhibit the self-aggregation of very amyloidogenic variants of β2-microglobulin. Here, the structure of Nb23 was modeled with the Chemical-Shift (CS)-Rosetta server using chemical shift assignments from nuclear magnetic resonance (NMR) spectroscopy experiments, and used as prior knowledge in PONDEROSA restrained modeling based on experimentally assessed internuclear distances. Further validation was comparatively obtained with the results of molecular dynamics trajectories calculated from the resulting best energy-minimized Nb23 conformers. Methods: 2D and 3D NMR spectroscopy experiments were carried out to determine the assignment of the backbone and side chain hydrogen, nitrogen and carbon resonances to extract chemical shifts and interproton separations for restrained modeling. Results: The solution structure of isolated Nb23 nanobody was determined. Conclusions: The structural analysis indicated that isolated Nb23 has a dynamic CDR3 loop distributed over different orientations with respect to Nb24, which could determine differences in target antigen affinity or complex lability.     

Nondenaturing polyacrylamide gel electrophoresis to study the dissociation of the p53·MDM2/X complex by potentially anticancer compounds

A new analytical method to study the dissociation of the complexes between the oncosuppressor p53 and its negative modulators murine double‐minute protein 2 (MDM2) or MDMX, is proposed. This technique is reliable to determine the dissociative power exerted by small molecules on the complex taking advantage of the appearance of migrating MDM2 or MDMX in a native polyacrylamide gel, when inhibitors are added to the complex mixture. Therefore, we propose this new approach to easily screen library of compounds, with potential pharmacological anticancer activity.