Serdecznie zapraszam na czwarty wykład z serii AMU Invited Lecture Series in Structural Biology.
30 marca br. (czwartek) o godz. 17:00 (godzinę później niż zwykle) wykład pt.
Structure-based discovery of small molecules that disaggregate amyloid fibrils
wygłosi (za pośrednictwem platformy teams) prof. David S. Eisenberg,z University of California Los Aangeles, CA, USA
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Informacja o wykładowcy i wykładzie.
David S. Eisenberg.*Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, USA*Department of Biological Chemistry, UCLA, Los Angeles, CA, USA*UCLA-DOE Institute, Los Angeles, CA, USA*Molecular Biology Institute, UCLA, Los Angeles, CA, USA*Howard Hughes Medical Institute, Los Angeles, CA, USA.
Short abstract:
Alzheimer’s disease (AD) is the consequence of neuronal death and brainatrophy associated with the aggregation of protein tau into fibrils. Thus disaggregationof tau fibrils could be a therapeutic approach to AD. The smallmolecule EGCG, abundant in green tea, has long been known to disaggregatetau and other amyloid fibrils, but EGCG has poor drug-like properties, failing tofully penetrate the brain. Here we have cryogenically trapped an intermediateof brain-extracted tau fibrils on the kinetic pathway to EGCG-induced disaggregationand have determined its cryoEM structure. The structure revealsthat EGCG molecules stack in polar clefts between the paired helical protofilamentsthat pathologically define AD. Treating the EGCG binding position asa pharmacophore, we computationally screened thousands of drug-likecompounds for compatibility for the pharmacophore, discovering several thatexperimentally disaggregate brain-derived tau fibrils in vitro. This work suggeststhe potential of structure-based, small-molecule drug discovery foramyloid diseases.