CyanoMetAl-Descoberta de agentes quelantes de metais de origem cianobacteriana: uma solução multifuncional para a doença de Alzheimer

IIn Europe, 14.1 million people suffer from dementia, with AD accounting >60% of cases, placing significant socioeconomic strains on societies, with dementia healthcare expenses totaling 392 billion €[12]. According to OECD, Portugal has the 4th highest number of dementia cases per 1000 inhabitants[13]. Given these figures and the lack of effective AD drugs, prioritizing discovery of new and more effective anti-AD drugs is crucial to improve the quality of life and well-being of our societies. The complex pathogenesis of AD, combined with numerous hypotheses surrounding its onset and progression, along with limitations of existing single-target drugs, provide a compelling rationale for adopting multifunctional strategies in the AD drug discovery pipeline[4]. CyanoMetAl aims to deliver cyanobacterial compounds capable of sequestering metal ions as well as inhibit Aß aggregation (through BACE1 or AchE inhibition), and/or mitigating oxidative damage, and glutamate excitotoxicity. Chelating agents coordinate with metal through multiple points of attachment, typically involving electronegative atoms in chemical groups such as thiols, disulfides, amines, and hydroxyls[7]. Cyanobacterial compounds, particularly non-ribosomal peptides (NRP), ribosomally synthesized and post-translationally modified peptides (RiPP), polyketides (PK), and PK/NRP hybrids, are an excellent source of these moieties[14]. Given their chemical properties (chemical functions and low molecular weight), as well as ability to cross membranes[15], cyanobacterial metallophores have many natural advantages for success as promising multifunctional anti-AD compounds. Our innovative approach begins with mapping the genes encoding metallophore biosynthesis in selected LEGEcc cyanobacteria. While advanced genome mining tools predict the chemical structures of these gene products, the low homology to known biosynthetic gene clusters (BGC) in cyanobacterial metabolites may only allow partial substructure rationalization. Another hurdle in cyanobacterial natural products discovery is that the presence of a BCG does not guaranteed its expression under the standard cultivation conditions (BGC may be silent or cryptic)[16]. To validate the production of metallophores at an early stage, we will analyze the strains’ metabolome using mass spectrometry-based substructure discovery tools. If metallophores remain undetected, strategies will be employed to activate these BGCs by altering cultivation parameters, especially metal concentrations. In parallel, applying a medium-throughput screening of our cyanobacterial natural products library will expedite the discovery of BACE1 and AChE inhibitors devoid of unwanted toxicity. Positive hits will undergo untargeted metabolomics, aiding compound dereplication and unveiling metallophoric substructures. Integration of these modern methodologies will ensure sustainability and scalability, guiding the selection of 3 cyanobacterial strains for large-scale cultivation and subsequent compound isolation. 5 robust lead compounds will be achieved by characterizing their potential multifunctionality, encompassing metal ion sequestration and inhibition of AD targets, alongside in silico target validation and assessment of blood-brain barrier permeability. This pioneer project will be implemented through 8 Tasks (Annex I), engaging a multidisciplinary team of experts, putting CyanoMetAl at the forefront of cyanobacterial natural products research for AD drugs.