Hsp90 is a direct target of the anti-allergic drugs disodium cromoglycate and amlexanox

Miki Okada, Hideaki Itoh, Takashi Hatakeyama, Hiroshi Tokumitsu, Ryoji Kobayashi

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 μM. 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.

Original languageEnglish
Pages (from-to)433-441
Number of pages9
JournalBiochemical Journal
Volume374
Issue number2
DOIs
Publication statusPublished - Sep 1 2003
Externally publishedYes

Fingerprint

HSP90 Heat-Shock Proteins
Anti-Allergic Agents
Cromolyn Sodium
Pharmaceutical Preparations
Proteins
Protein C
amlexanox
Citrate (si)-Synthase
Agglomeration
In Vitro Techniques
Pharmacology

Keywords

  • Amlexanox
  • Anti-allergic drug
  • Chaperone
  • Citrate synthase
  • Cohort protein
  • Disodium cromoglycate
  • Hsp90
  • Rhodanese

ASJC Scopus subject areas

  • Biochemistry

Cite this

Hsp90 is a direct target of the anti-allergic drugs disodium cromoglycate and amlexanox. / Okada, Miki; Itoh, Hideaki; Hatakeyama, Takashi; Tokumitsu, Hiroshi; Kobayashi, Ryoji.

In: Biochemical Journal, Vol. 374, No. 2, 01.09.2003, p. 433-441.

Research output: Contribution to journalArticle

Okada, Miki ; Itoh, Hideaki ; Hatakeyama, Takashi ; Tokumitsu, Hiroshi ; Kobayashi, Ryoji. / Hsp90 is a direct target of the anti-allergic drugs disodium cromoglycate and amlexanox. In: Biochemical Journal. 2003 ; Vol. 374, No. 2. pp. 433-441.
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