INVESTIGADORES
MENACHO MÁRQUEZ Mauricio Ariel
congresos y reuniones científicas
Título:
Binding modes and anti-amyloid effects of small molecules: Advances in the design of novel compounds for neurodegenerative diseases
Autor/es:
GENTILI I; CHESTA ME; VALIENTE-GABIOUD A; FARCHI F; MAURICIO MENACHO MÁRQUEZ; CLAUDIO O. FERNÁNDEZ
Lugar:
Carlos Paz
Reunión:
Congreso; Alexander von Humboldt Kolleg Current Advances on Neurodegeneration: from Molecular Biology to Translational Medicine.; 2017
Institución organizadora:
Alexander von Humboldt Kolleg
Resumen:
Neurodegenerative diseases such as Alzheimer?s disease (AD), Parkinson?s disease (PD), and Creutzfled−Jakob?s disease (CJD) share a common pathological mechanism that involves the formation of aggregated protein species including toxic oligomers and amyloid fibrils. The aggregation of alpha-synuclein (αS) in PD and the amyloid beta peptide (Aβ) and tau protein in AD results in neuronal death and disease onset. In the case of CJD, the misfolding of the physiological prion protein (PrP) induces a chain reaction that results in accumulation of particles that elicit brain damage. Currently, there is no preventive therapy for these diseases and the available therapeutic approaches are based on the treatment of the symptoms rather than the underlying causes of the disease. Accordingly, the aggregation pathway of these proteins represents a useful target for therapeutic intervention. Therefore, understanding the mechanism of amyloid formation and its inhibition is of high clinical importance.The design of small molecules that efficiently inhibit the aggregation process and/or neutralize its associated toxicity constitutes a promising tool for the development of therapeutic strategies against these disorders. In this work, we will show our advances on the anti-amyloid activity of a series of chemical compounds that belong to the family of porphyrinoids and their potential use as drug candidates in neurodegeneration. These tetrapyrrolic compounds modulate the amyloid assembly of αS, tau, Aβ, and the PrP in vitro, and protect cells from the toxic effects of amyloid aggregates. The structural basis for the inhibitory effect of these compounds will be discusssed together with their structure−activity relationship. Because the structural and molecular basis for the anti-amyloid effects of these molecules is starting to emerge, combined efforts from the fields of structural, cellular, and animal biology will result critical for the rational design and discovery of new drugs for the treatment of amyloid related neurological disorders.