Rational steering of insulin binding specificity by intra-chain chemical crosslinking

Insulin is a key hormone of human metabolism with major therapeutic importance for both types of diabetes. New insulin analogues with more physiological profiles and better glycemic control are needed, especially analogues that preferentially bind to the metabolic B-isoform of insulin receptor (IR-B). Here, we aimed to stabilize and modulate the receptor-compatible conformation of insulin by covalent intra-chain crosslinking within its B22-B30 segment, using the Cu I -catalyzed Huisgen 1,3-dipolar cycloaddition reaction of azides and alkynes. This approach resulted in 14 new, systematically crosslinked insulin analogues whose structures and functions were extensively characterized and correlated. One of the analogues, containing a B26-B29 triazole bridge, was highly active in binding to both IR isoforms, with a significant preference for IR-B. Our results demonstrate the potential of chemistry-driven modulation of insulin function, also shedding new light on the functional importance of hormones B-chain C-terminus for its IR-B specificity

Supercooled liquids with enhanced orientational order

The nature of the glass transition, the transformation of a liquid into a disordered solid, still remains one of the most intriguing unsolved problems in materials science. Recent models rationalize crucial features of vitrification with the presence of medium-range ordered regions coexisting with the isotropic liquid. Here, in line with this prediction, we report an extraordinary enhancement in bond orientational order in ultrathin films of supercooled polyols, grown by physical vapour deposition. By varying the deposition conditions and the molecular size, we could tune the kinetic stability of the liquid phase enriched in bond orientational order towards conversion into the ordinary liquid phase. We observed a strong increase in the dielectric strength with respect to the ordinary supercooled liquid and slower structural dynamics, suggesting the existence of a metastable liquid phase with improved orientational correlations.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Synthetic and structural routes for the rational conversion of peptides into small molecules

The demand for modified peptides with improved stability profiles and pharmacokinetic properties is driving extensive research effort in this field. The conversion of peptides into organic molecules, as traditional drugs, is a long and puzzled way. Many and versatile approaches have been described for designing peptide mimetics: the substitution of natural residues with modified amino acids and the rigidification and modification of the backbone are the main structural and chemical routes walked in medicinal chemistry. All of these strategies have been successfully applied to obtain active new compounds in molecular biology, drug discovery and design. Here we propose a panoramic review of the most common methods for the preparation of modified peptides and the most interesting findings of the last decade

Triggers and cues that activate antibiotic production by actinomycetes

Microbial Biotechnolog