A5094192100- Protein Structure and Dynamics
- Alzheimer's disease research and treatments
- Parkinson's Disease Mechanisms and Treatments
- Nanopore and Nanochannel Transport Studies
- RNA Research and Splicing
- Advanced Fluorescence Microscopy Techniques
- Peptidase Inhibition and Analysis
- Biochemical and biochemical processes
- Computational Drug Discovery Methods
- biodegradable polymer synthesis and properties
University of Cambridge
2024
Abstract Machine learning methods hold the promise to reduce costs and failure rates of conventional drug discovery pipelines. This issue is especially pressing for neurodegenerative diseases, where development disease-modifying drugs has been particularly challenging. To address this problem, we describe here a machine approach identify small molecule inhibitors α-synuclein aggregation, process implicated in Parkinson’s disease other synucleinopathies. Because proliferation aggregates takes...
Oligomeric species arising during the aggregation of α-synuclein are implicated as a major source toxicity in Parkinson's disease, and thus potential drug target. However, both their mechanism formation role largely unresolved. Here we show that, at physiological pH absence lipid membranes, aggregates form by secondary nucleation, rather than simple primary that this process is enhanced agitation. Moreover, using combination single molecule bulk level techniques, identify nucleation on...
Abstract Segments of proteins with high β-strand propensity can self-associate to form amyloid fibrils implicated in many diseases. We describe a general approach bind such segments and β-hairpin conformations using de novo designed scaffolds that contain deep peptide-binding clefts. The designs their cognate peptides vitro nanomolar affinities. crystal structure protein−peptide complex is close the design model, NMR characterization reveals how cleft protected apo state. use binders...
Abstract The complex kinetics of disease-related amyloid aggregation proteins such as α-Synuclein (α-Syn) in Parkinson’s disease and Aβ42 Alzheimer’s include primary nucleation, fibril elongation secondary nucleation. latter can be a key accelerator the process. It has been demonstrated that chaperone domain BRICHOS interfere with nucleation process Aβ42. Here, we explore mechanism inhibition lung surfactant protein (proSP-C) against α-Syn formation. We determine 3D NMR structure an inactive...