RRC ID 2029
Author Okada M, Itoh H, Hatakeyama T, Tokumitsu H, Kobayashi R.
Title Hsp90 is a direct target of the anti-allergic drugs disodium cromoglycate and amlexanox.
Journal Biochem J
Abstract Hsp90 (heat-shock protein 90) alone can act to prevent protein aggregation and promote refolding in vitro, but in vivo it operates as a part of a multichaperone complex, which includes Hsp70 and cohort proteins. Since the physiological function of Hsp90 is not yet fully understood, the development of specific antagonists might open new lines of investigation on the role of Hsp90. In an effort to discover Hsp90 antagonists, we screened many drugs and found that the anti-allergic drugs DSCG (disodium cromoglycate) and amlexanox target Hsp90. Both drugs were found to bind directly wild-type Hsp90 via the N- and C-terminal domains. Both drugs strongly suppressed the in vitro chaperone activity of native Hsp90 towards citrate synthase at 1.5-3.0 microM. Amlexanox suppressed C-terminal chaperone activity in vitro, but not N-terminal chaperone activity, and inhibited the association of cohort proteins, such as cyclophilin 40 and Hsp-organizing protein, to the C-terminal domain of Hsp90. These data suggest that amlexanox might disrupt the multichaperone complex, including Hsp70 and cohort proteins, both in vitro and in vivo. Although DSCG inhibited the in vitro chaperone activity of the N-terminal domain, the drug had no effect either on the C-terminal chaperone activity or on the association of the cohort proteins with the C-terminus of Hsp90. The physiological significance of these interactions in vivo remains to be investigated further, but undoubtedly must be taken into account when considering the pharmacology of anti-allergic drugs. DSCG and amlexanox may serve as useful tools for evaluating the physiological significance of Hsp90.
Volume 374(Pt 2)
Pages 433-41
Published 2003-9-1
DOI 10.1042/BJ20030351
PII BJ20030351
PMID 12803546
PMC PMC1223614
MeSH Amino Acid Sequence Aminopyridines / pharmacology* Animals Anti-Allergic Agents / metabolism Anti-Allergic Agents / pharmacology* Binding Sites / drug effects Binding Sites / genetics Brain Chemistry / drug effects Brain Chemistry / genetics Carrier Proteins / metabolism Cattle Cromolyn Sodium / metabolism Cromolyn Sodium / pharmacology* Cyclophilin D Cyclophilins* HSP70 Heat-Shock Proteins / metabolism HSP90 Heat-Shock Proteins / antagonists & inhibitors* HSP90 Heat-Shock Proteins / genetics HSP90 Heat-Shock Proteins / metabolism* Heat-Shock Proteins / metabolism Humans Macromolecular Substances Molecular Sequence Data Peptide Fragments / antagonists & inhibitors Peptide Fragments / genetics Peptide Fragments / metabolism Peptidylprolyl Isomerase / metabolism Protein Binding / drug effects Protein Binding / genetics Protein Folding Protein Structure, Tertiary / drug effects Protein Structure, Tertiary / genetics Rats Receptors, Drug / analysis* Receptors, Drug / chemistry Sequence Deletion Signal Transduction / drug effects Signal Transduction / genetics
IF 4.097
Times Cited 13
DNA material pHSP90 (RDB01127)