COORDINATION AND PARTICIPATION IN RESEARCH PROJECTS

The Group research has been funded by EU research projects, FCT projects and other international projects as shown below:

I. EU funded research projects

1. "Diagnostic and Drug Discovery Initiative for Alzheimer's Disease", Industry-Academia Partnerships and Pathways (IAPP), FP7-PEOPLE-2013-IAPP, Project Nr. 612347, 2014-2018, coordinated by the University of Sheffield (UK), with the participant institutions Faculdade de Ciências - Universidade de Lisboa, Eli Lilly and Company (UK), Amorfix Life Sciences Ltd (Canada) and Biofordrug (Italy) PI FCUL: A. P. Rauter

Alzheimer's disease (AD) is the major cause of dementia with more than 35 million patients suffering from this disease, which has no cure. In this project a long-term partnership will be established between academia and companies to better understand the role of prion protein in AD and to develop new molecular entities for diagnostic and therapeutic applications.

2. "PERsonalised ICT supported Service for Independent Living and Active Ageing", Small or medium-scale focused research project (STREP), FP7-ICT-2013-10, Project Nr. 610359, 2013-2016, coordinated by Universiteit Twente (The Netherlands), with the participant Institutions Fundação da Faculdade de Ciências e Faculdade de Ciências Universidade de Lisboa (third party), Roessingh Research and Development (The Netherlands), Azienda Ospedaliera Universitaria Federico II (Italy), University College Cork, National University of Ireland (Ireland), Universidad Politecnica de Madrid (Spain), Fundacio Privada Institut de Neurorehabilitacio Guttmann (Spain) and Nexera (Italy), PI FFCUL-FCUL and workpackage 3 leader: A. P. Rauter

This project combines a consortium from social, medical, and technological sciences with industry, academia and end user organisations, with the primary objective of developing an information and communications technology (ICT) based platform to identify and manage community dwelling older adults at risk of functional decline and frailty. Within this project, our major activities adhere to the tenants of our commitment at the European Innovation Partnership of Active and Healthy Ageing Action Group 3 related to nutrition, in particular to the development of an interative website for nutrition.

II. Stem Cells, Prion Proteins and Alzheimer's Disease: A Prion Chemical Biology Network (PCBNet) funded projects

3. "Detoxification of toxic oligormers using natural products", 2012-2013, coordinated by The University of Sheffield, with FCUL as the participating institution, PI FCUL: A. P. Rauter

4. "Towards the development of molecular probes for investigating drug targets in amyloid diseases", 2011-2012, coordinated by The University of Sheffield, with FCUL as the participating institution, PI FCUL: A. P. Rauter

III. National StrategicFramework's Program (QREN) and Foundation for Science and Technology (FCT) funded projects

5. "Synthesis of nucleotide mimics as potential antitumor agents targeting cyclin-dependent kinases", FCT Exploratory Project within the FCT Investigator Programme, 2014-2018, PI: N. M. Xavier

This project deals with the design, synthesis and biological evaluation of new potential antitumor agents intended to inhibit cyclin-dependent kinases, which are ATP-dependent enzymes that regulate cell cycle progression and whose abnormal activity or overexpression play a crucial role in the development of cancer.

6. "New drugs from sugars against infection caused by pathogenic Bacillus species (FACIB)", funded by QREN within the Incentive System to Research & Technological Development to companies projects in co-promotion (QREN SI I&DT Co-Promotion program), Lisboa-01-0202-FEDER-021547, 2011-2014, extended to February 2015, coordinated by CIPAN-Industrial Company for the Production of Antibiotics, in co-promotion with FCUL, PI FCUL: A. P: Rauter

In this project a new family of antibacterial glycosides is explored, that have shown a selective activity against Bacillus species, in particular against Bacillus anthracis, the cause of anthrax, a primarily disease of hoofed herbivores and a bioterrorism agent. In this project, bridging of chemistry and biology leads to novel molecular entities with new mechanisms of action, currently under investigation.

7. "Halophytes: a precious resource for nutritional elements and bioactive compounds (XtremeBio)", funded by FCT, PTDC/MAR-EST/4346/2012, 2013-2015, coordinated by CCMar/CIMAR Universidade do Algarve and the participant institution was Fundação da Faculdade de Ciências da Universidade de Lisboa (FFCUL), PI FFCUL: A. P. Rauter

The project aims to determine the chemical and nutritional profiles, as well as the antioxidant, antitumoral and neuroprotective properties of halophytes from the Algarve. Valorization of halophytes in terms of the biological properties already found in the halophytes studied, will be based on their potential application as food additives.

8. "New antidiabetic agents from Genista tenera Isolation, structural characterization, synthesis and mechanisms of action", funded by FCT, PTDC/QUI/67165/2006, 2008-2011, extended until August 2012, coordinated by FFCUL, with Escola Superior Agrária do Instituto Politécnico de Santarém as participant Institution, PI: A. P. Rauter

The main goal of this project dealt with the valorization of the plant Genista tenera, an antidiabetic medicinal plant from Madeira Island, by identifying its active principles for nutraceutical/medicinal purposes. Investigation of various plant extracts regarding their antidiabetic, antioxidant and anticholinesterase activities, toxicity and phytochemical studies led to the selection of the most potent extract, in which the plant active principle was identified as 8-β-D-glucosylgenistein. Its synthesis, biological studies and absence of toxicity, together with the results obtained regarding its interaction with amyloid peptides identified this compound as a promising lead for diabetes and the frequently associated Alzheimer's disease.

9. "Total synthesis and stereochemical elucidation of Miharamycins A and B. carbohydrate-based generation of analogues and bioactivity studies", funded by FCT, POCI/PPCDT/QUI/59672/2004, 2005-2008, coordinated by FFCUL, with Escola Superior Agrária do Instituto Politécnico de Santarém as participant Institution, PI: A. P. Rauter.

The natural products Miharamycins are potent inhibitors of the fungus Pyricularia oryzae, that destroys rice cultures and is considered a bioterrorism agent. These molecules are structurally quite complex, embodying a nucleoside with a 2-aminopurine N9-β-linked to a bicyclic saccharide moiety, elongated to an amino acid of unknown stereochemistry, N-linked to L-arginine (Miharamycin B) or its hydroxy derivative (miharamycin A). The greatest challenge of this project was based on the assignment of the unknown stereochemistry of these molecules and the first synthesis of its core structure. These goals were fully achieved and a small library of compounds was also generated aiming to access new compounds structurally more simple than the natural products for structure/activity relationship studies. The anticholinesterase activity of the new intermediate nucleosides was evaluated and the N9-β-linked structures were not active, as desired for their investigation as pesticide leads. Interestingly, the N7-β-linked nucleosides exhibited, some of them, a selective and potent butyrylcholinesterase (BChE) inhibition, opening a new line of research based on these structures for the production of new molecular entities to study the progression of Alzheimer's disease in late stages, where acetylcholinesterase levels have decreased and BChE levels increased considerably. The project was carried out in collaboration with the Université Pierre et Marie Curie within a joint Ph.D. program (Filipa Marcelo).

10. "Study of Salvia species crop production aiming at the evaluation of their constituents for the potential control of Alzheimer's disease", funded by FCT, PTDC/AGR-AAM/66414/2006, 2007-2010, coordinated by Escola Superior Agrária do Instituto Politécnico de Santarém with FFCUL as participant Institution, PI of FFCUL: A. P. Rauter

Salvia sclareoides is an Iberian endemism which extracts demonstrated unique properties as acetylcholinesterase inhibitors, more potent than rivastigmine, a drug marketed for the treatment of AD in the early disease stages. The phytochemical study of the plant identified the triterpene and phenolic components. Amongst the latter group of compounds, the major product, rosmarinic acid, has anticholinesterase activity and recently, in 2013, we could demonstrate by NMR a new binding site for this compound, opening the way to a new line of research based on these findings. This research was developed in collaboration with Dr. Filipa Marcelo (Universidade Nova de Lisboa) and Prof. Jesus Jimenez Barbero (Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Científicas, in Spain).This plant also showed a significant antiproliferative effect on human neuroblastome cells (collaboration with Prof. Margarida Meireles, CQB-FCUL) and stabilized the normal and soluble Prion protein by preventing its conformational changes, that cause the formation of plaques and vacuoles in the brain occurring in transmissible spongiform encephalopathies (TSEs), also known as prion diseases, in humans and animals, for which no therapy is available. The latter study was conducted in collaboration with The Sheffield University in UK, within PCBNet approved projects with the Carbohydrate Chemistry Group.The biological properties of the plant and identified components, and the absence of toxicity of its extracts, encouraged further research, up to the present time, including the Ph.D. research program on this plant of Dr. Isabel Branco (Ph. D., UL).

11. "Sugar derivatives containing α,β-unsaturated γ-lactones as potential non-toxic environmentally friendly pesticides", funded by FCT, POCI/PPCDT/AMB/58116/2004, 2005-2008, coordinated by coordinated by Escola Superior Agrária do Instituto Politécnico de Santarém with FFCUL as participant Institution, PI of FFCUL: A. P. Rauter

Our contribution to this project was based on the generation of a small library of biologically active sugar derivatives by synthesis, and elucidation of their structure for structure/activity relationship studies. The most promising results were patented in Europe and in USA.

12. "Synthesis, chemistry and photophysics of nanoencapsulated anthocyanins. Development of a new concept of food dyes with anthocyanins", funded by FCT, POCTI/QUI/38884/2001, 2001-2004, coordinated by Instituto Superior Técnico of Universidade Técnica de Lisboa, with Fundação da Faculdade de Ciências da Universidade de Lisboa as participant Institution, PI of FFCUL: A. P. Rauter

Within this project, we have synthesized a small library of new anthocyanins, highly reactive and unstable, which structure could be characterized by NMR.

13. "Structure and reactivity of flavonoid glycosides and synthetic analogues: a fundamental research by Mass Spectrometry Techniques", PRAXIS - 2/2.1/QUI/119/94, 1998-2001, approved by POCTI, 2001 2003, coordinated by FCUL, FCUL team member: A. P. Rauter

Our contribution to this project relied mainly on flavonoid structure elucidation, particularly for those flavonoids that were isolated from natural resources.