Rational design of potent human transthyretin amyloid disease inhibitors
| Autor: | T, Klabunde, H M, Petrassi, V B, Oza, P, Raman, J W, Kelly, J C, Sacchettini |
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| Rok vydání: | 2000 |
| Předmět: |
Models
Molecular Binding Sites Diclofenac Anti-Inflammatory Agents Non-Steroidal Molecular Sequence Data Hydrogen Bonding Amyloid Neuropathies Crystallography X-Ray Structure-Activity Relationship Flurbiprofen Resveratrol Drug Design Oxazines Stilbenes Humans Prealbumin Thermodynamics Dicarboxylic Acids ortho-Aminobenzoates Amino Acid Sequence Cardiomyopathies Protein Structure Quaternary Benzofurans |
| Zdroj: | Nature structural biology. 7(4) |
| ISSN: | 1072-8368 |
| Popis: | The human amyloid disorders, familial amyloid polyneuropathy, familial amyloid cardiomyopathy and senile systemic amyloidosis, are caused by insoluble transthyretin (TTR) fibrils, which deposit in the peripheral nerves and heart tissue. Several nonsteroidal anti-inflammatory drugs and structurally similar compounds have been found to strongly inhibit the formation of TTR amyloid fibrils in vitro. These include flufenamic acid, diclofenac, flurbiprofen, and resveratrol. Crystal structures of the protein-drug complexes have been determined to allow detailed analyses of the protein-drug interactions that stabilize the native tetrameric conformation of TTR and inhibit the formation of amyloidogenic TTR. Using a structure-based drug design approach ortho-trifluormethylphenyl anthranilic acid and N-(meta-trifluoromethylphenyl) phenoxazine 4, 6-dicarboxylic acid have been discovered to be very potent and specific TTR fibril formation inhibitors. This research provides a rationale for a chemotherapeutic approach for the treatment of TTR-associated amyloid diseases. |
| Databáze: | OpenAIRE |
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