Abstract: In this study ultrasound has been utilised for the Fischer glycosylation using free sugars and sulphuric acid immobilized on silica as catalyst. N-acetyl-D-glucosamine, N-acetyl-D-galactosamine, D-glucose, D-galactose, D-mannose, L-fucose, and lactose were glycosylated with propargyl alcohol or 2-azidoethanol affording the corresponding glycosides, with the production of the α-glycopyranoside as the dominant product. Remarkable acceleration of the glycosylation reactions (15 min-2 h compared to several hours) over reported procedures together with good yields were always observed.
Abstract: Natriuretic peptides (NP) are a family of structurally related but genetically distinct hormones/paracrine factors that regulate blood volume, blood pressure, ventricular hypertrophy, pulmonary hypertension, fat metabolism, and long bone growth. In this work we present computational structural analysis of the three human NP in solution, the synthesis and preliminary biological assays of a short fragment of CNP, I(14)GSM(17), together with one small mimetic, GGSM. Synthetic peptides IGSM, GGSM, and full length CNP were preliminary tested for their ability to influence cell growth of three human osteosarcoma cell lines. Synthetic peptides were shown to successfully mimic the biological activity of the full length natural peptide: their effects, although different upon the cell types used, are in accordance with the current literature, designating a possible role for CNP, and its derivatives, in skeletogenesis.
Abstract: Natriuretic peptides (NPs) are a family of structurally related hormone/paracrine factors (ANP, BNP and CNP), which mediate a broad array of physiological effects by interacting with specific guanylyl cyclase receptors (NPR) and have promising therapeutic and clinical applications. NPs are specific for different NPRs and share a common ring structure in which a disulfide bond between two conserved cysteine residues is formed. Residues within the cyclic loop are largely responsible for receptor selectivity. Structural features of free NPs in solution have not been investigated in details even if their characterization would be very useful in order to identify important aspects related to NPs function and receptor selectivity. In light of the above scenario, we carried out a 0.1 micros molecular dynamics investigation of NPs with the aim of providing a high-resolution atomistic view of specific of their conformational ensemble in solution. Our results clearly indicate that NP receptor-bound conformations are not stable solution structure and that induced-fit mechanisms are involved in the formation of NP-NPR complexes. Moreover, in agreement with the current view on strictly relationship between protein dynamics and protein function and activity, it turns out that differences in activity and NPR specificity of CNP and ANP/BNP might be correlated to different amino acid composition of the cyclic loop, propensity to form beta-sheet structures, flexibility patterns, dynamics properties and free conformations explored during the simulations.
Abstract: Several glycoprocessing enzymes and glycoreceptors have been recognized as important targets for therapeutic intervention. This concept has inspired the development of important classes of therapeutics, such as anti-influenza drugs inhibiting influenza virus neuraminidase, anti-inflammatory drugs targeting lectin-sialyl-Lewis X interaction and glycosidase inhibitors against HIV, Gaucher's disease, hepatitis and cancer. These therapeutics are mainly carbohydrate mimics in which proper modifications permit stronger interactions with the target protein, higher stability, better pharmacokinetic properties and easier synthesis. Furthermore, the conformational rigidity and polyfunctionality of carbohydrates stimulate their use as scaffolds for the generation of libraries by combinatorial decoration with different pharmacophores. This mini-review will present examples of how to exploit carbohydrates mimics and scaffolds in drug research.
Abstract: Small molecules altering protein functions as inhibitors, agonists or antagonists, find application in systems biology enabling an analysis of the in vivo consequences of these alterations. In this context carbohydrates are ideal tools, not only because they are involved in a variety of recognition phenomena of biological relevance, but also because they are ideal scaffolds to generate libraries of bioactive compounds. Examples of design, synthesis and biological assays of different carbohydrate based inhibitors or protein ligands are reported. Exploiting NMR methods, the binding between a small molecules (inhibitor or ligand) and a protein can be detected, the affinity measured, and the interaction topology defined. This set of information is useful not only to clarify the mechanism of protein-ligand interaction, but also to improve the design of new inhibitors/ligands. The multifunctionality and the conformational rigidity of carbohydrates make this class of compounds the ideal scaffolds to generate libraries exploiting the combinatorial approach. An example of solid phase combinatorial synthesis of a library of 37 compounds is reported.
