Scuotto, Maria (2014) Exploring physical and biological properties of TBA by site specific chemical modifications. [Tesi di dottorato]

Maria Scuotto Phd.pdf

Download (4MB) | Preview
[error in script] [error in script]
Item Type: Tesi di dottorato
Resource language: English
Title: Exploring physical and biological properties of TBA by site specific chemical modifications.
Date: 28 March 2014
Number of Pages: 133
Institution: Università degli Studi di Napoli Federico II
Department: Farmacia
Scuola di dottorato: Scienze farmaceutiche
Dottorato: Scienza del farmaco
Ciclo di dottorato: 26
Coordinatore del Corso di dottorato:
D'Auria, Maria
Date: 28 March 2014
Number of Pages: 133
Keywords: Thrombin Binding Aptamer, acyclic nucleosides, thrombin inhibitors, G-quadruplex
Settori scientifico-disciplinari del MIUR: Area 03 - Scienze chimiche > CHIM/06 - Chimica organica
Aree tematiche (7° programma Quadro): SALUTE e TUTELA DEL CONSUMATORE > Biotecnologie, strumenti e tecnologie generiche per la salute umana
Date Deposited: 07 Apr 2014 08:53
Last Modified: 26 Jan 2015 12:11

Collection description

Coagulation is the process responsible for the transformation of blood into a solid mass formed by fibrin, platelet and blood cell, namely clot. The normal functioning of this process named Homeostasis produces the repair of an injury. Disorders of coagulation can lead to an increased risk of obstructive clotting (thrombosis), that is, in severe cases, lethal for the organism. Despite its phenomenal success, current anticoagulation therapy still suffers from the risk toward serious bleeding. A direct correlation exists between the intensity of anticoagulation and severity of bleeding. The need for safer and more effective antithrombotic agents clearly exists. During the last twenty years, aptamer technology is efficiently employed toward the development of therapeutic anticoagulants, by selecting thrombin-binding-oligonucleotides. The term aptamers is generally referred to single-stranded oligonucleotides that bind to a selected protein and specifically inhibits one or more of its functions. The TBA (Thrombin-Binding-Aptamer), isolated via SELEX , is a 15-nucleotide consensus sequence that binds thrombin and inhibits its coagulant activity. TBA adopts a monomolecular chair-like G-quadruplex structure consisting of two G-tetrads connected by two lateral TT and a central TGT loops. Biological and structural results indicate that TBA exerts its anticoagulant activity competing with fibrinogen at the exosite I on the thrombin. Despite an high number of scientific results concerning the structure and the biological properties of TBA and its analogues were published during the last years, today still, the exact mechanism of action by which TBA exerts its antithrombin activity is an open question. In the frame of different multidisciplinary studies, I synthesized and I characterized for their tridimensional structures as well as for their biological behavior, different libraries of new TBA analogues, with the aim to acquire new information about the differences in the mechanism of action of TBA and its synthetic analogues. Furthermore, since TBA is a very promising tool for DNA-functionalized biosensors, I also synthesized new heterochiral TBA mutants with the aim to make stable the phosphodiester bonds of this molecule in biological environment. These new molecules were studied for their ability to fold in stable G-quadruplexes using different spectroscopic techniques.


Downloads per month over past year

Actions (login required)

View Item View Item