Maria J. Matos
“Nothing in life is to be feared; it is only to be understood.” Marie Curie
Research Projects
From small molecules to targeted therapies
Targeted therapies as a promising approach for neurodegenerative diseases
Neurodegenerative diseases are becoming increasingly prevalent with the aging of the general population. The twentieth century witnessed a significant demographic change in the human population of the industrialized world that is currently followed by a similar shift of life expectancy to upper age ranges in developing countries.Understanding some of the molecular changes associated to these ubiquitous and widespread diseases, has stimulated efforts to develop drugs that specially target key proteins involved in the development of a given type of it. Knowledge on biochemical processes brings the opportunity to provide treatments that are potentially less toxic and more effective than previous therapeutic approaches. Targeted drug delivery is a very promising concept, which still needs improvements for better clinical outcomes.
The effectiveness of a drug is dependent on accumulation at the site of action at therapeutic levels, however, challenges such as rapid renal clearance, degradation or non-specific accumulation requires drug delivery enabling technologies. Access for drugs to the central nervous system (CNS) is highly restricted due to the presence of the blood–brain barrier (BBB). Utilizing the existing carrier proteins for nutrient delivery across the BBB is a promising option to achieve or increase availability in the brain. Adsorptive-mediated endocytosis (AME) is a transport mechanism that has gained significant importance recently. The underlying principle of AME based transport is the electrostatic interaction between a positively charged substance.
Design, synthesis and pharmacological study of small molecules as potential drug candidates
Over the last few years, molecular hybridization has emerged as an interesting approach in drug discovery that involves agglutination of two or more pharmacophores (or parts of them) in one single molecule in order to develop hybrid multifunctional molecules. This approach can increase several biological properties, modulating selectivity profiles, bringing together different or similar modes of action, and/or reducing side effects. Such molecules can be further modified to exhibit increased pharmacokinetics and oral bioavailability. Our research group have been designing and synthesizing hybrid coumarins, with heterogeneous bioactive chemical entities such as stilbenes (resveratrol), thiophene, carboxamides, and chalcones. More than 700 compounds were obtained, and some of them present interesting enzymatic inhibition activities (MAO-B, AChE, BuChE and BACE1), cytotoxicity, human adenosine receptors modulation, tyrosinase inhibition, antioxidant and anti-inflammatory activities. In particular, arylcoumarins can be highlighted, both because their synthetic versatility and their pharmacological properties. They are structurally coumarin-resveratrol hybrids, and were designed due to their multitargetproperties, an approach that is being explored in the field of multifactorial pathologies, as neurodegenerative diseases.