DSpace Collection:
https://hdl.handle.net/10171/19284
2024-03-28T22:16:58ZNovel pharmacological maps of protein lysine methyltransferases: key for target deorphanization
https://hdl.handle.net/10171/65384
Title: Novel pharmacological maps of protein lysine methyltransferases: key for target deorphanization
Abstract: Epigenetic therapies are being investigated for the treatment of cancer, cognitive disorders, metabolic alterations and
autoinmune diseases. Among the diferent epigenetic target families, protein lysine methyltransferases (PKMTs), are
especially interesting because it is believed that their inhibition may be highly specifc at the functional level. Despite
its relevance, there are currently known inhibitors against only 10 out of the 50 SET-domain containing members of
the PKMT family. Accordingly, the identifcation of chemical probes for the validation of the therapeutic impact of
epigenetic modulation is key. Moreover, little is known about the mechanisms that dictate their substrate specifcity and ligand selectivity. Consequently, it is desirable to explore novel methods to characterize the pharmacological similarity of PKMTs, going beyond classical phylogenetic relationships. Such characterization would enable the
prediction of ligand of-target efects caused by lack of ligand selectivity and the repurposing of known compounds
against alternative targets. This is particularly relevant in the case of orphan targets with unreported inhibitors. Here,
we frst perform a systematic study of binding modes of cofactor and substrate bound ligands with all available SET
domain-containing PKMTs. Protein ligand interaction fngerprints were applied to identify conserved hot spots and
contact-specifc residues across subfamilies at each binding site; a relevant analysis for guiding the design of novel,
selective compounds. Then, a recently described methodology (GPCR-CoINPocket) that incorporates ligand contact
information into classical alignment-based comparisons was applied to the entire family of 50 SET-containing proteins
to devise pharmacological similarities between them. The main advantage of this approach is that it is not restricted
to proteins for which crystallographic data with bound ligands is available. The resulting family organization from the
separate analysis of both sites (cofactor and substrate) was retrospectively and prospectively validated. Of note, three
hits (inhibition>50% at 10 µM) were identifed for the orphan NSD1.2018-01-01T00:00:00ZBrain aging and Parkinson's disease: new therapeutic approaches using drugs delivery systems
https://hdl.handle.net/10171/40096
Title: Brain aging and Parkinson's disease: new therapeutic approaches using drugs delivery systems
Abstract: ABSTRACT
The etiology and pathogenesis of Parkinson’s disease (PD) is unknown, aging being the
strongest risk factor for brain degeneration. Understanding PD pathogenesis and how
aging increases the risk of disease would aid the development of therapies able to slow
or prevent the progression of this neurodegenerative disorder. In this review we provide
an overview of the most promising therapeutic targets and strategies to delay the loss of
dopaminergic neurons observed both in PD and aging. Among them, handling alphasynuclein
toxicity, enhancing proteasome and lysosome clearance, ameliorating
mitochondrial disruptions and modifying the glial environment are so far the most
promising candidates. These new and conventional drugs may present problems related
to their labile nature and to the difficulties in reaching the brain. Thus, we highlight the
latest types of drug delivery system (DDS)-based strategies for PD treatment, including
DDS for local and systemic drug delivery. Finally, the ongoing challenges for the
discovery of new targets and the opportunities for DDS-based therapies to improve and
efficacious PD therapy will be discussed.2015-01-01T00:00:00ZSox-2 positive neural progenitors in the primate striatum undergo dynamic changes after dopamine denervation
https://hdl.handle.net/10171/35411
Title: Sox-2 positive neural progenitors in the primate striatum undergo dynamic changes after dopamine denervation
Abstract: The existence of endogenous neural progenitors in the nigrostriatal system could represent a powerful tool for restorative therapies in Parkinson's disease. Sox-2 is a transcription factor expressed in pluripotent and adult stem cells, including neural progenitors. In the adult brain Sox-2 is expressed in the neurogenic niches. There is also widespread expression of Sox-2 in other brain regions, although the neurogenic potential outside the niches is uncertain. Here, we analyzed the presence of Sox-2+ cells in the adult primate (Macaca fascicularis) brain in naïve animals (N = 3) and in animals exposed to systemic administration of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine to render them parkinsonian (N = 8). Animals received bromodeoxyuridine (100 mg/kg once a day during five consecutive days) to label proliferating cells and their progeny. Using confocal and electron microscopy we analyzed the Sox-2+ cell population in the nigrostriatal system and investigated changes in the number, proliferation and neurogenic potential of Sox-2+ cells, in control conditions and at two time points after MPTP administration. We found Sox-2+ cells with self-renewal capacity in both the striatum and the substantia nigra. Importantly, only in the striatum Sox-2+ was expressed in some calretinin+ neurons. MPTP administration led to an increase in the proliferation of striatal Sox-2+ cells and to an acute, concomitant decrease in the percentage of Sox-2+/calretinin+ neurons, which recovered by 18 months. Given their potential capacity to differentiate into neurons and their responsiveness to dopamine neurotoxic insults, striatal Sox-2+ cells represent good candidates to harness endogenous repair mechanisms for regenerative approaches in Parkinson's disease2013-01-01T00:00:00Z