Micael Silva's FWF ESPRIT project, "NMR-Guided Chemical Chaperones for Protein Misfolding", explores a potential new strategy for addressing protein misfolding, a process implicated in many neurodegenerative diseases. The project aims to identify small molecules, known as chemical chaperones, that bind to hydrophobic patches exposed on unfolded, misfolded, and intrinsically disordered proteins. By mimicking the protective role of molecular chaperones, these compounds could shift proteins away from toxic aggregation and towards more functional states. This approach may extend drug discovery beyond its conventional focus on stable, well-defined binding pockets.
Using solution-state nuclear magnetic resonance (NMR) spectroscopy, Silva will screen libraries of osmolytes, approved drugs, molecular fragments, and natural products for weak, transient protein-ligand interactions. 1D 1H ligand- and 19F protein-observed NMR experiments will identify candidate compounds. Promising hits will then be characterised at residue-level resolution using 2D 1H-15N protein NMR, alongside thermodynamic measurements, structure-activity relationship analyses, and thermal-denaturation and aggregation assays. Selected protein–ligand complexes will be investigated using an experimentally guided structural-ensemble approach that combines NMR data with artificial intelligence and machine-learning methods.
The project will focus on the marginally stable drkN SH3 domain and on α-synuclein, a protein associated with Parkinson's disease. By revealing how chemical chaperones bind to distinct protein states and reshape their conformational ensembles, the research aims to establish design principles for targeting transiently exposed protein surfaces that were previously considered "undruggable". In the longer term, these findings could inform the development of future therapies for neurodegenerative diseases.
Micael Silva completed his PhD in Molecular Biosciences at NOVA University Lisbon, Portugal, in 2021. His doctoral research used solution-state NMR spectroscopy to investigate how salts and ionic liquids affect protein structure, dynamics, and stability. After a postdoctoral position at the Weizmann Institute of Science, where he studied molecular chaperone-client recognition using advanced NMR methods, he joined Julien Orts's group in June 2024. His current research combines ligand screening with advanced NMR methods to investigate protein dynamics and allosteric regulation in oncogenic KRAS.
Beyond his research, Silva founded "Young Portuguese Biophysicists", recently organised the Austrian NMR Meeting 2026 in Vienna, and represents his department in the Faculty of Life Sciences' postdoctoral network.