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G-quadruplex unfolding in higher-order DNA structures
No full textG-quadruplex unfolding within a sequence of two quadruplex units was characterized by gel electrophoresis, calorimetry and spectroscopy. The obtained results suggest that the kinetics and thermodynamics of the individual quadruplex unfolding are affected by its interaction with other DNA secondary structural elements
Nuovi ligandi per G-quadruplex: un approccio chimico-fisico nella terapia anti-cancro
No full textIn tutte le cellule eucariotiche umane il DNA telomerico è costituito da una sequenza altamente ripetuta 5’TTAGGG3’. Ad ogni ciclo replicativo il DNA telomerico si riduce a partire dall’estremità 3’ costituita da singolo filamento fino ad una lunghezza critica che conduce la cellula all'apoptosi. Nell’80-85% delle cellule tumorali si osserva la sovraespressione della telomerasi, un enzima che catalizza l’allungamento del DNA telomerico determinando una proliferazione incontrollata delle cellule tumorali. Qualsiasi strategia capace di inibire la telomerasi può essere considerata una potenziale terapia anti-cancro. Le sequenze TTAGGG ricche di guanine presenti alle estremità telomeriche a singolo filamento hanno la capacità di ripiegarsi su se stesse formando delle strutture note come quadruple eliche. La formazione di tali strutture è in grado di inibire l’attività della telomerasi. E’ di estremo interesse lo studio di composti in grado di legare in maniera specifica le quadruple eliche e dei fattori che regolano gli equilibri in gioco. La conoscenza degli aspetti chimico-fisici che regolano l’interazione tra quadrupla elica e ligando rappresenta un punto chiave in vista di future applicazioni biomediche. Lo studio dell’energetica d’interazione tra nuovi ligandi e le strutture target ha permesso di chiarire la natura delle forze che guidano il processo di binding e di far luce sugli elementi strutturali utili ad ottimizzare le proprietà di legame, fornendo le basi strutturali per una futura progettazione razionale di nuove classi di farmaci ad attività anti-tumorale
Chitosan-based nanoparticles studied by isothermal titration calorimetry
No full textIn the last decade, there has been a growing interest on chitosan-based nanomaterials. Chitosan is a polymer exceptionally versatile, biodegradable, biocompatible and with good capacity of mucoadhesivity and permeation-enhancing effect. These features make chitosan a perfect material for the fabrication of polymeric nanoparticles for a variety of applications in the field of pharmaceutics, nutraceutics or cosmetics. This paper discuss on the role of isothermal titration calorimetry (ITC) in the creation of protocols for the preparation of chitosan-based nanoparticles, as well as the role of calorimetry to find chitosan-coating conditions to offer to nanoparticles the desired proprieties for the delivery of drugs, biologics and vaccines. Although several papers of the current literature show the employment of ITC in chitosan-based nanosystems, most of them lack a thermodynamic description. Here, we highlight on two types of systems: chitosan-coating nanoparticles and chitosan-containing nanoparticles. The thermodynamic properties and the energetic aspects of the overall interactions are discussed
Biophysical study of the human telomeric quadruplexes-drugs interaction: a good starting point for anti cancer agents
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Binding properties of human telomeric quadruplex multimers: a new route for drug design.
No full textHuman telomeric G-quadruplex structures are known to be promising targets for an anticancer therapy. In the past decade, several research groups have been focused on the design of new ligands trying to optimize the interactions between these small molecules and the G-quadruplex motif. In most of these studies, the target structures were the single quadruplex units formed by short human DNA telomeric sequences (typically 21-26 nt). However, the 3'-terminal single-stranded human telomeric DNA is actually 100-200 bases long and can form higher-order structures by clustering several consecutive quadruplex units (multimers). Despite the increasing number of structural information on longer DNA telomeric sequences, very few data are available on the binding properties of these sequences compared with the shorter DNA telomeric sequences. In this paper we use a combination of spectroscopic (CD, UV and fluorescence) and calorimetric techniques (ITC) to compare the binding properties of the (TTAGGG)(8)TT structure formed by two adjacent quadruplex units with the binding properties of the (AG(3)TT)(4) single quadruplex structure. The three side-chained triazatruxene derivative azatrux and TMPyP4 cationic porphyrin were used as quadruplex ligands. We found that, depending on the drug, the number of binding sites per quadruplex unit available in the multimer structure was smaller or greater than the one expected on the basis of the results obtained from individual quadruplex binding studies. This work suggests that the quadruplex units along a multimer structure do not behave as completely independent. The presence of adjacent quadruplexes results in a diverse binding ability not predictable from single quadruplex binding studies. The existence of quadruplex-quadruplex interfaces in the full length telomeric overhang may provide an advantageous factor in drug design to enhance both affinity and selectivity for DNA telomeric quadruplexes
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