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Harnessing Chaperones to Generate Small-Molecule Inhibitors of Amyloid ß Aggregation
Jason E. Gestwicki,Gerald R. Crabtree,Isabella A. Graef*
Protein aggregation is involved in the pathogenesis of neurodegenerativediseases and hence is considered an attractive target for therapeuticintervention. However, protein-protein interactions are exceedinglydifficult to inhibit. Small molecules lack sufficient stericbulk to prevent interactions between large peptide surfaces.To yield potent inhibitors of ß-amyloid (Aß)aggregation, we synthesized small molecules that increase theirsteric bulk by binding to chaperones but also have a moietyavailable for interaction with Aß. This strategy yieldspotent inhibitors of Aß aggregation and could leadto therapeutics for Alzheimer's disease and other forms of neurodegeneration.
Department of Pathology, Howard Hughes Medical Institute, Stanford University Medical School, Stanford, CA 94305, USA.
* To whom correspondence should be addressed. E-mail: graef{at}cmgm.stanford.edu
Phenol Red Interacts with the Protofibril-Like Oligomers of an Amyloidogenic Hexapeptide NFGAIL through Both Hydrophobic and Aromatic Contacts.
C. Wu, H. Lei, Z. Wang, W. Zhang, and Y. Duan (2006)
Biophys. J.
91, 3664-3672
|Abstract »|Full Text »|PDF »
Heat Shock Proteins 70 and 90 Inhibit Early Stages of Amyloid beta-(1-42) Aggregation in Vitro.
C. G. Evans, S. Wisen, and J. E. Gestwicki (2006)
J. Biol. Chem.
281, 33182-33191
|Abstract »|Full Text »|PDF »
Free energies of protein-protein association determined by electrospray ionization mass spectrometry correlate accurately with values obtained by solution methods..
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Protein Sci.
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|Abstract »|Full Text »|PDF »
Pharmacologic and genetic inhibition of hsp90-dependent trafficking reduces aggregation and promotes degradation of the expanded glutamine androgen receptor without stress protein induction.
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Hum. Mol. Genet.
15, 1876-1883
|Abstract »|Full Text »|PDF »
Inclusion-body myositis: A myodegenerative conformational disorder associated with A{beta}, protein misfolding, and proteasome inhibition.
Mutant Tamm-Horsfall Glycoprotein Accumulation in Endoplasmic Reticulum Induces Apoptosis Reversed by Colchicine and Sodium 4-Phenylbutyrate.
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J. Am. Soc. Nephrol.
16, 3006-3014
|Abstract »|Full Text »|PDF »
Reversal of amyloid-induced heart disease in desmin-related cardiomyopathy.
A. Sanbe, H. Osinska, C. Villa, J. Gulick, R. Klevitsky, C. G. Glabe, R. Kayed, and J. Robbins (2005)
PNAS
102, 13592-13597
|Abstract »|Full Text »|PDF »
Calpain Mediates Excitotoxic DNA Fragmentation via Mitochondrial Pathways in Adult Brains: EVIDENCE FROM CALPASTATIN MUTANT MICE.
J. Takano, M. Tomioka, S. Tsubuki, M. Higuchi, N. Iwata, S. Itohara, M. Maki, and T. C. Saido (2005)
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280, 16175-16184
|Abstract »|Full Text »|PDF »
Attacking Amyloid.
J. W. Kelly (2005)
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Drug Discovery in Neurodegenerative Diseases.
H. Geerts, J. Q. Trojanowski, and V. M.-Y. Lee (2005)
Sci. Aging Knowl. Environ.
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|Abstract »|Full Text »
Two Novel Approaches to Treating Alzheimer Disease.
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Journal Watch Psychiatry
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|Full Text »
Two Novel Approaches to Treating Alzheimer Disease.
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Journal Watch (General)
2004, 4
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