Discovery of innovative drugs and diagnostic agents for neurodegenerative and protein conformational diseases.
Neurodegenerative diseases are illnesses associated with high morbidity and mortality, and few or no effective options are available for their treatment. A characteristic of many neurodegenerative diseases, which include stroke, amyotrophic lateral sclerosis (ALS), and Alzheimer’s disease (AD), is neuronal-cell death. AD is the leading cause of dementia among older people. Among the various therapeutic strategies explored, the use of reversible inhibitors of AChE is a viable and attractive therapeutic symptomatic approach. Four AChEI have been in fact approved to treat AD. Although some therapeutics are available, the lack of efficacious diagnostic agents is making difficult the early identification of this neurodegenerative disorder. Furthermore, no effective therapeutic and diagnostic agents are available to date for the Creutzfeldt-Jakob syndrome, an infectious disease which involves a limited number of patients worldwide. These diseases, together with other neurodegenerative syndromes belong to the class of pathologic conditions depending upon an abnormal folding of proteins (misfolding) and for this reason they have been named “Protein Conformational Diseases” (PCD). Neurodegenerative disorders as Parkinson’s and Alzheimer’s disease, Type II Diabetes, Amiotrophic Lateral Sclerosis, and Creutzfeldt-Jakob disease are associated with alfa-sinuclein, beta amiloid, amilyn, Cu,Zn,Superoxidismutase and prion protein respectively. The critical event in PCD relies on the change in the secondary and tertiary structure of the protein without any modification of its primary structure. This conformational change may develop the pathology either because of the increase of toxicity or of the loss of the normal physiological function of the native protein. The proteins involved in PCD do not share any homology in the primary sequence. Currently it is widely recognized that some proteins that contains irregular protein sequences or an abnormal secondary and/or tertiary structure may be stable to proteolytic activity and undergo assembling into insoluble aggregates of partially unfolded proteins, known as proteinaceous amyloid fibrils, in central and peripheral tissues (prion, beta-amyloid, hungtintin, sinucleine etc). Metal ions may play a critical role in the formation of insoluble proteinaceous aggregates, relevant to neurodegenerative disorders. An example of these aggregates are the fibrils of beta-amyloid protein. Beta-amyloid proteins (bA40-42), which are produced by the proteolysis of the amyloid precursor protein (APP) mediated by two key enzymes, gamma- and beta- secretases, are rich in beta-sheet conformation and under certain conditions aggregate with the formation of extracellular insoluble plaques, being the marker of neurodegenerative diseases such as AD. In the central nervous system the fibrils accumulated in the extracellular space are responsible for structural and functional damages to specific neuronal systems leading to neurodegeneration. AD is indeed characterized by aspecific degeneration of neuron populations in the brain. A protein that recently attracted the interest of the scientific community is the prion, a membrane protein that may undergo abnormal folding leading to PRPsc, which differs from the native protein in its secondary and tertiary structure. This misfolded pathological protein, rich in beta-sheet conformation, is more stable to proteolysis and may aggregate in insoluble proteinaceous aggregates, and these latter have been identified in many patients inflicted with prion diseases such as Alper syndrome, Creutzfeldt-Jakob disease (C-JD), bovine spongiform encephalopathy (BSE). In some cases, C-JD patients present amyloid plaques at the brain level. To date few methods are known for identifying, treating or inhibiting the aggregation of amyloid proteins or prions, and it is difficult to develop an imaging agent selective for only pathologic proteins and/or plaques. Furthermore, as in the case of AD and C-JD plaques are mainly localized in the brain and a molecule to be used in in vivo imaging should not only target amyloid and prion proteins, but should also cross the blood brain barrier.
NatSynDrugs research focus:
- • design and synthesis of small molecular heterocyclics and/or peptidomimetics to specifically inhibit beta-secretas
- • development of third generation inhibitors of cholinesterases;
- • analysis of the possible interaction sites linked to different conformational stages of prion and beta-amyloid proteins, through the integration of experimental data into molecular models and the use of molecular mechanic (MM) and molecular dynamic (MD) techniques.
Design and synthesis of specific ligands as novel diagnostic agents for in vitro and in vivo imaging for the early identification of proteinaceous plaques based on promising results obtained within the network ( Compounds and Methods for Diagnosing and Treating Amyloid-related Conditions, PCT WO02/24652 A1);
- • design and synthesis of novel compounds for the selective interference with the protein aggregating processes as potential therapeutic agents for pathological conditions such as AD and C-JD;
- • design and synthesis of glutamate reversed uptake inhibitors as novel neuroprotective agents;
- • development of AMPA receptor partial agonists and antagonists for the tretment of ALS.