Cyclopeptide analogs for generating new molecular and 3D diversity

6noCyclic peptides have been often utilized as metabolically stable, conformationally restricted mimics of different kinds of biologically active peptides, including peptide antibiotics, endogenous opioid peptides, integrin inhibitors, peptide hormones, anticancer peptides, and so on. And in particular, cyclic compounds which can mimic important secondary structure elements such as β-turns are of outstanding importance. Since greater chemical and structural diversity are primary features to pursue for finding novel leads for pharmacological and biotechnological applications, we explored the potential utility of the retro-inverso modification. We introduced this modification into the sequence of 13-membered cyclotetrapeptides, which can be regarded as easily available, conformationally stable analogs of cyclotetrapeptides composed of all α-residues. In this paper we describe the synthesis of a selected mini-library of partially modified retro-inverso cyclic peptides as conformationally homogeneous scaffolds for medicinal chemistry applications. The different compounds have been obtained by simple scramble of the same residues. Finally, we discuss the conformational features of such molecules as turn mimics. The comparison suggests that the retro-inverso modification allows a higher degree of three-dimensional diversity than normal peptides. © 2009 Bentham Science Publishers Ltd.reservedopenGentilucci L.; Cardillo G.; Tolomelli A.; Squassabia F.; De Marco R.; Chiriano G.Gentilucci, L.; Cardillo, G.; Tolomelli, A.; Squassabia, F.; De Marco, R.; Chiriano, G

Design of ligands with a high affinity to PrPC.

Prion diseases, also known as transmissible spongiform encephalopathies (TSE), are fatal neurodegenerative disorders of the central nervous system. The main molecular mechanism underlining TSE is based on the aberrant misfolding of the cellular form of the prion protein (PrPC) into its pathological counterpart denominated PrPSc. To date there are no identified therapies. One therapeutic strategy against this disease is focused on the stabilization of the PrPC in order to prevent its conversion to PrPSc . Designing ligands targeting PrPC with a high binding affinity might augment its stability and prevent its misfolding. Here, we have set-up a computational protocol aiming at addressing this issue

DESIGN OF LIGANDS WITH A HIGH AFFINITY TO PrPC

Prion diseases, also known as transmissible spongiform encephalopathies (TSE), are fatal neurodegenerative disorders of the central nervous system. The main molecular mechanism underlining TSE is based on the aberrant misfolding of the cellular form of the prion protein (PrPC) into its pathological counterpart denominated PrPSc. To date there are no identified therapies. One therapeutic strategy against this disease is focused on the stabilization of the PrPC in order to prevent its conversion to PrPSc . Designing ligands targeting PrPC with a high binding affinity might augment its stability and prevent its misfolding. Here, we have set-up a computational protocol aiming at addressing this issue

Sequential Virtual Screening Approach to the Identification of Small Organic Molecules as Potential BACE-1 Inhibitors

In this letter, we report on the sequential application of two different in silico screening approaches combined with bioassays aimed at the identification of small organic molecules as potential BACE-1 inhibitors. Two hits endowed of micromolar inhibitory potency were selected, and the binding mode of the most potent compound was further characterized through docking simulations

A small chemical library of 2-aminoimidazole derivatives as BACE-1 inhibitors: Structure-based design, synthesis, and biological evaluation

In this work, we report a rational structure-based approach aimed at the discovery of new 2- aminoimidazoles as b-secretase inhibitors. Taking advantage of a microwave-assisted synthetic protocol, a small library of derivatives was obtained and biologically evaluated. Two compounds showed promising activities in both enzymatic and cellular assays. Moreover, one of them exhibited the capa- bility to cross the bloodebrain barrier as assessed by the parallel arti\u2423cial membrane permeability assay

Synthesis of Monomeric Derivatives To Probe Memoquin's Bivalent Interactions

Eight monomeric congeners, related to the multitarget lead candidate memoquin, were prepared and evaluated at multiple targets to determine their profile against Alzheimer's disease. 2-4 bind to AChE with similar low nanomolar affinities and function as effective inhibitors of amyloid aggregation. The most potent monovalent ligand 2 also inhibits BACE-1 in vitro and APP metabolism in primary chicken telencephalic neurons