ArchivIA Collezione:
http://hdl.handle.net/10761/32
2024-03-28T22:48:16ZStudi di Binding e Relazioni Struttura-Affinità di Potenziali Ligandi Sigma-1/Sigma-2.
http://hdl.handle.net/10761/2741
Titolo: Studi di Binding e Relazioni Struttura-Affinità di Potenziali Ligandi Sigma-1/Sigma-2.
Autori: Sanfilippo, Mariangela
Abstract: -2007-03-12T23:00:00ZPorphyrin derivatives as versatile proteasome modulators
http://hdl.handle.net/10761/3828
Titolo: Porphyrin derivatives as versatile proteasome modulators
Autori: Cunsolo, Alessandra
Abstract: The ubiquitin proteasome system (UPS) is the primary degradation system in eukaryotic cells, with high selectivity for a myriad of soluble proteins, and perturbations in the UPS are associated with numerous human disorders. For this reason the proteasome has become a pharmacological target for cancer and neurodegenerative diseases where opposite effects are desirable, inhibition and activation respectively.
Interestingly, accumulation of the ubiquitin-conjugated proteins, which have been tagged for degradation, but not efficiently degraded have been observed at advanced age in many tissues. Similar phenomena have been observed in many diseases such as Alzheimer, Parkinson, and other neurodegenerative disorders. In-line with these data the efficiency of the UPS and the proteasome in particular decrease with age, which suggests a link between neurodegenerative diseases and UPS dysfunction. Ubiquitinylated protein accrual has also been observed in senescent cells (which accumulate with age) and maybe caused by dysfunction of the proteasome or the ubiquitinating/deubiquitinating machinery. It has been suggested that activation of the proteasome core might be a potential strategy to minimize protein homeostasis deficiencies underlying aggregation-related diseases, such as Alzheimer s and Huntington s disease. Therefore, stimulating proteasome activity seems to be very promising as a therapeutic strategy for this type of pathology.
It is also known that multiple hallmarks of cancer such as replicative immortality, apoptosis resistance, and increased proliferation, are clearly dependent on the proteasome and UPS. For this reason proteasome inhibition is a very promising anti-cancer therapy yet there are very few drugs available for this use.
It is known that cationic porphyrins behave as proteasome inhibitors and their potency depends on the number of positive charges. During this PhD study, we have worked towards a deeper understanding of the molecular mechanisms responsible for the interactions between proteasome and the tetra cationic porphyrin H2T4. Moreover, other porphyrin, porphyrinoid derivatives and bio-inspired molecules have been studied for their potential roles in modulating proteasome function. Surprisingly, the tetra anionic porphyrin H2TPPS has an unexpected activator quality on 20S proteasome in both cell based assays and purified 20S CP.
From these studies emerge a new scenario where these macrocyclic molecules, thanks to their inhibitory action on the proteasome, are becoming increasingly rich multi-target molecules for oncological applications.
This research has also uncovered novel porphyrin molecules capable of activating the proteasome suggesting that they are capable of not just inhibition but proteasomal modulation and, if correctly designed, they are able to interact with the electrostatic access code of proteasome s core particle allowing for biological activities.2017-03-12T23:00:00ZDesign and synthesis of novel compounds as fatty acids binding protein inhibitors and as gallium-68 chelators for positron emission tomography
http://hdl.handle.net/10761/4168
Titolo: Design and synthesis of novel compounds as fatty acids binding protein inhibitors and as gallium-68 chelators for positron emission tomography
Autori: Floresta, Giuseppe
Abstract: Finding new small molecules targets as well as improving the diagnosis methodologies are two of the most important areas in which the researchers are spending efforts to improve our arsenal to fight cancer and other diseases. In this thesis, two different chapters are discussed. In the first one, the design of new Fatty acid binding protein 4 inhibitors is discussed. In the second one, the design of two targeting peptide bioconjugates for the detection of cancers is reported.
Fatty acid binding proteins are a class of proteins involved particularly in the transport of fatty acids in human. Recently it comes out that the Fatty acid binding proteins are an interesting molecular target for the treatment of type 2 diabetes, other metabolic diseases and some type of cancers. In this chapter (first), three new molecules inhibitors of the Fatty acid binding protein 4 are designed, using computer-aided drug design methodologies, and synthesized. The three molecules, AST_1 3, were synthesized and tested against the target protein and showed an IC50 between 3.70 and 5.59 uM. Moreover, a huge number of different other molecules were theorized to be as effective as the three synthesized. Among them, some are derived from a virtual screening of an FDA approved drugs database and some from the bioisosteric scaffold-hopping analysis of a note inhibitor of the fatty acid binding protein 4 (BMS309403).
In the second chapter, two different targeting peptides, against two proteins involved in particular types of cancer (c-Met and GLP-1), were synthesized and then conjugated to a small molecule able to chelate gallium, for their potential applicability as PET tracers. The two compounds were then evaluated as effective 68-gallium chelating compounds and the result showed their capability in the binding of the 68Ga.2018-11-30T23:00:00ZProteomic analysis of the metabolic fractions in modern and old wheat genotypes: a qualitative and quantitative comparison
http://hdl.handle.net/10761/4167
Titolo: Proteomic analysis of the metabolic fractions in modern and old wheat genotypes: a qualitative and quantitative comparison
Autori: Di Francesco, Antonella
Abstract: Wheat, due to its adaptability to a wide range of environments and for the unique functional properties of its flour, represents the most widely grown, processed, and consumed cereal by humankind of temperate regions. Most of the modern wheat genotypes are derived from old wheats and have appreciable properties in terms of grain yield. Wheat is also the causing factors of many adverse reactions, such as celiac disease, allergies and non-celiac wheat sensitivity (NCWS) in susceptible people. This has led to an increasing interest for the old wheat genotypes which are generally considered better tolerated than the modern ones, but without any scientific evidence. The aim of the present work is the qualitative and quantitative comparison by a proteomic approach of the metabolic protein fractions extracted from the mature kernel of two old Sicilian durum wheat landraces (Russello and Timilia reste bianche), and Simeto, an improved durum wheat variety, widely spread in Italy and other Mediterranean countries, chosen as representative of the most widely commercial cultivars. The qualitative comparison of the protein composition revealed a remarkable similarity between old and modern cultivar. The quantitative evaluation of the identified proteins shows that some proteins are differentially expressed in old and modern varieties.2019-11-30T23:00:00Z