Spacer-modified disaccharide and pseudo-trisaccharide methyl glycosides that mimic maltotriose, as competitive inhibitors for pancreatic α-amylase

International audienc

Increasing selectivity of CC chemokine receptor 8 antagonists by engineering nondesolvation related interactions with the intended and off-target binding sites

The metabolic stability and selectivity of a series of CCR8 antagonists against binding to the hERGion channel and cytochrome Cyp2D6 are studied by principal component analysis. It is demonstrated that an efficient way of increasing metabolic stability and selectivity of this series is to decrease compound lipophilicity by engineering nondesolvation related attractive interactions with CCR8, as rationalized by three-dimensional receptor models. Although such polar interactions led to increased compound selectivity, such a strategy could also jeopardize the DMPK profile of compounds. However, once increased potency is found, the lipophilicity can be readjusted by engineering hydrophobic substituents that fit to CCR8 but do not fit to hERG. Several such lipophilic fragments are identified by two-dimensional fragment-based QSAR analysis. Electrophysiological measurements and site-directed mutagenesis studies indicated that the repulsive interactions of these fragments with hERG are caused by steric hindrances with residue F656. © 2009 American Chemical Society

Peptide-based molecules in angiogenesis.

Angiogenesis refers to the process of remodeling the vascular tissue characterized by the branching out of a new blood vessel from a pre-existing vessel. Angiogenesis is particularly active during embriogenesis, while during adult life it is quiescent and limited to particular physiological phenomena. Recently, the study of molecular mechanisms of angiogenesis has stirred renewed interest due to the recognition of the role played by angiogenesis in several pathologies of large social impact, such as tumors and cardiovascular disease, and due to the pharmacological interest rising from the possibility of modulating these phenomena. Antibodies, peptides and small molecules targeting active endothelial cells represent an innovative tool in therapeutic and diagnostic fields. In this article we reviewed the literature of peptide and peptidomimetics in angiogenesis and their potential applications. Two specific protein systems, namely the Vascular Endothelial Growth Factor (VEGF) and its receptor and Integrins, will be discussed in detail