Carbohydrate Chemistry

Group coordinator: Amélia Pilar Grases Santos Silva Rauter

The Carbohydrate Chemistry Group was founded in 2001 [RG-CHEM-LVT-Lisboa-612-640] as a group of FCUL Center of
Chemistry and Biochemistry. The research carried out led to results totally original focusing on applications in domains of organic
and biomolecular chemistry. The Group (partner 40) was a Center of Excellence of the European Science Foundation funded
network "Euroglycoforum" (2009-2014). Highly committed in international networking, the Group created FCUL Consortium at the
European Innovation Partnership on Active and Healthy Ageing- Action Group A3 with more than 30 national and international
members from academia, industry and policy makers.
Based on a sustainable model, starting from sugars or natural resources towards new functional food ingredients/drug leads for
food/pharmaceutical industries, the research of this Group aims to provide economic and social benefits for a healthy life, focusing
on problem-solving approaches of societal challenges.

Antibiotic resistance is a major concern in our society and the discovery of antibiotics with new mechanisms of action remains
mandatory. A new family of carbohydrate-based bactericides has been developed, particularly active over Bacillus anthracis, and
exploited their novel mechanism of action in the quest for innovative agents for health and biosecurity.
Inspired by nature, new structures to prevent disease and retard ageing have been designed and new leads developed for
parasitic diseases, cystic fibrosis, tuberculosis, cancer and other degenerative diseases, namely those involving amyloid
disorders, e.g. diabetes and Alzheimer disease. Engaged in projects in collaboration with national and international companies,
the Group is also devoted to advanced training and outreach activities, namely the creation of the website for
the general public, and the organization of international scientific meetings, e.g. the 29th International Carbohydrate Symposium
in 2018.

The formation of beta-amyloid plaques in AD is associated with butyrylcholinesterase (BChE ) in the cerebral cortex, where BChE
is not normally found in quantity. In an AD mouse model with BChE gene knocked, 70% fewer fibrillar Abeta brain plaques have
been detected, suggesting that selective BChE inhibitors may lead to a curative approach to AD. We have discovered a new
family of potent and selective nanomolar inhibitors of BChE, structurally based on purine nucleosides. Interestingly, within the
synthesized compounds, some were cytotoxic to cancer cell lines, at similar level as that of anticancer drugs. Their mode of action
relies on induction of cell cycle arrest and apoptosis, quite distinct from that of clinically-used nucleosides, thus suggesting their
importance to overcome chemotherapy resistance.
Nucleosides acting as selective divalent copper ion chelators were also generated by purine benzoylation. These chelators are
required to circumvent systemic copper dyshomeostasis altering neurotransmission, a new approach to treat AD. This research,
carried out in collaboration with Eli Lilly UK and Biofordrug, has been funded by a European project (ca.400k euro) for developing
drugs against AD.


According to the International Diabetes Federation, type 2 diabetes accounts for at least 90% of all cases of diabetes, affecting
over 415 million people worldwide. Research in this area conducted to the generation of a library of antidiabetic agents by Cglucosylation
of dihydrochalcones, transforming the latter in nanomolar inhibitors of sodium glucose co-transporter 2 (SGLT2),
much more active than the aglycones or the O-glucosides, and highly selective for SGLT2 over SGLT1. Both enzymes promote
glucose reabsorption in the kidneys but SGLT1 also transports galactose, which inhibition causes considerable side effects in this
new approach to treat diabetes type 2. These C-glucosides are promising molecular entities with a low toxicity, that do not
interfere with glucose transport by GLUTs.

Bacterial resistance represents a serious threat to patient safety worldwide. Exploiting new approaches to tackle antibiotic
resistance is therefore mandatory. The Group discovered the first sugar-based antimicrobials responsible for specific
carbohydrate-phospholipid interactions, causing phosphatidylethanolamine lamellar to hexagonal membrane phase transition and
acting over B. anthracis strains as potent and selective bactericides. Complete bacteria cell death in 10 min, bacteria eradication
after induced spore germination, and disruption of cellular envelope, shown by atomic force spectroscopy, corroborate
antimicrobials effect over lipid polymorphism, as confirmed by fluorescence anisotropy. The absence of bacterial resistance further
supported this mechanism of action, triggering innovation on membrane-targeting antimicrobials, in particular against anthrax.