Hsp90 is a direct target of the anti-allergic drugs disodium cromoglycate and amlexanox.
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.
Okada
Miki
M
Department of Signal Transduction Sciences, Kagawa Medical University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
Itoh
Hideaki
H
Hatakeyama
Takashi
T
Tokumitsu
Hiroshi
H
Kobayashi
Ryoji
R
D000595:Amino Acid Sequence; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D018926:Anti-Allergic Agents / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics; D002352:Carrier Proteins / Q000378:metabolism; D002417:Cattle; D004205:Cromolyn Sodium / Q000378:metabolism / Q000494:pharmacology*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019696:Peptidylprolyl Isomerase / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D017510:Protein Folding; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000235:genetics; D051381:Rats; D011955:Receptors, Drug / Q000032:analysis* / Q000737:chemistry; D017384:Sequence Deletion; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D000631:Aminopyridines; D018926:Anti-Allergic Agents; D002352:Carrier Proteins; D000081406:Peptidyl-Prolyl Isomerase F; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D046911:Macromolecular Substances; D010446:Peptide Fragments; D011955:Receptors, Drug; C079373:STIP1 protein, human; C489790:Stip1 protein, rat; C045742:amlexanox; D021983:Cyclophilins; D019696:Peptidylprolyl Isomerase; D004205:Cromolyn Sodium