Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Bimoclomol: A nontoxic, hydroxylamine derivative with stress protein-inducing activity and cytoprotective effects

Nature Medicine volume 3, pages 1150–1154 (1997)Cite this article

Abstract

Preservation of the chemical architecture of a cell or of an organism under changing and perhaps stressful conditions is termed homeostasis. An integral feature of homeostasis is the rapid expression of genes whose products are specifically dedicated to protect cellular functions against stress. One of the best known mechanisms protecting cells from various stresses is the heat-shock response which results in the induction of the synthesis of heat-shock proteins (HSPs or stress proteins)1–3. A large body of information supports that stress proteins — many of them molecular chaperones4–8 — are crucial for the maintenance of cell integrity during normal growth as well as during patho-physiological conditions9–11, and thus can be considered “homeostatic proteins.” Recently emphasis is being placed on the potential use of these proteins in preventing and/or treating diseases12–14. Therefore, it would be of great therapeutic benefit to discover compounds that are clinically safe yet able to induce the accumulation of HSPs in patients with chronic disorders such as diabetes mellitus, heart disease or kidney failure. Here we show that a novel cytoprotective hydroxylamine derivative, [2-hydroxy-3-(1-piperidinyl) propoxy]-3-pyridinecarboximidoil-chloride maleate, Bimoclomol15, facilitates the formation of chaperone molecules in eukaryotic cells by inducing or amplifying expression of heat-shock genes. The cytoprotective effects observed under several experimental conditions, including a murine model of ischemia and wound healing in the diabetic rat, are likely mediated by the coordinate expression of all major HSPs. This nontoxic drug, which is under Phase II clinical trials, has enormous potential therapeutic applications.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Ritossa, F.A. A new puffing pattern induced by temperature shock and DNP in Drosophila. Experientia 18, 571–573 (1962).

    Article  CAS  Google Scholar 

  2. Lindquist, S. The heat shock response. Annu. Rev. Biochem. 55, 1151–1191 (1986).

    Article  CAS  Google Scholar 

  3. Lindquist, S. & Craig, E.A. The heat shock proteins. Annu. Rev. Genet. 22, 631–677 (1988).

    Article  CAS  Google Scholar 

  4. Frydman, J., Nimmesgern, E., Ohtsuka, K. & Haiti, F.U. Folding of nascent polypeptide chains in a high molecular mass assembly with molecular chaperones. Nature 370, 111–117 (1994). see comments in Nature 370, 96–97 (1994).

    Article  CAS  Google Scholar 

  5. Hartl, F.U., Hlodan, R. & Langer, T. Molecular chaperones in protein folding: The art of avoiding sticky situations. Trends Biochem. Sci. 19, 20–25 (1994).

    Article  CAS  Google Scholar 

  6. Ostermann, J., Norwich, A.L., Neupert, W. & Hartl, U.F. Protein folding in mitochondria requires complex formation with hsp60 and ATP hydrolysis. Nature 34, 125–130 (1989).

    Article  Google Scholar 

  7. Kang, P.-J. et al. Requirement for hsp70 in the mitochondrial matrix for transloca-tion and folding of precursor proteins. Nature 348, 137–143 (1990).

    Article  CAS  Google Scholar 

  8. Hohfeld, J. & Hartl, F.U. Role of the chaperonin cofactor Hsp 10 in protein folding and sorting in yeast mitochondria. J. Cell Biol. 126, 305–315 (1994).

    Article  CAS  Google Scholar 

  9. Chopp, M. The roles of heat shock proteins and immediate early genes in central nervous system normal function and pathology. Curr. Opin. Neural. Neurosurg. 6, 6–10 (1993).

    CAS  Google Scholar 

  10. Bensaude, O. & Morange, M. Spontaneous high expression of heat-shock proteins in mouse embryonal carcinoma cells and ectoderm from day 8 mouse embryo. EMBO J. 2, 173–177 (1983).

    Article  CAS  Google Scholar 

  11. Lovis, C., Mach, F., Donati, Y.R., Bonventre, J.V. & Polla, B.S. Heat shock proteins and the kidney. Ren. Fail. 16, 179–192 (1994).

    Article  CAS  Google Scholar 

  12. Hutter, M.M., Sievers, R.E., Barbosa, V. & Wolfe, C.L. Heat-shock protein induction in rat hearts. A direct correlation between the amount of heat-shock protein induced and the degree of myocardial protection. Circulation 89, 355–360 (1994).

    Article  CAS  Google Scholar 

  13. Mestril, R. & Dillmann, W.H. Heat shock proteins and protection against myocardial ischemia. J. Mol. Cell. Cardiol. 27, 45–52 (1995).

    Article  CAS  Google Scholar 

  14. Marber, M.S. et al. Overexpression of the rat inducible 70-kD heat stress protein in a transgenic mouse increases the resistance of the heart to ischemic injury. J. Clin. Invest. 95, 1446–1156 (1995).

    Article  CAS  Google Scholar 

  15. O-(3-amino-2-hydroxypropyl)-hidroxamic acid halides and a process for preparing the same. Hungarian Patent no. 207988 (1988).

  16. Heads, R.J., Yellon, D.M. & Latchman, D.S. Differential cytoprotection against heat or hypoxia following expression of specific stress protein genes in myogenic cells. J. Mol. Cell Cardiol. 27, 1669–1678 (1995).

    Article  CAS  Google Scholar 

  17. Jaattela, M., Wissing, D., Bauer, P.A. & Li, G.C. Major heat shock protein hsp70 protects tumor cells from tumor necrosis factor cytotoxicity. EMBO J. 11, 3507–3512 (1992).

    Article  CAS  Google Scholar 

  18. Lee, B.S., Chen, J., Angelidis, C., Jurivich, D.A. & Morimoto, R.I. Pharmacological modulation of heat shock factor 1 by antiinflammatory drugs results in protection against stress-induced cellular damage. Proc. Natl. Acad. Sci. USA 92, 7207–7211 (1995).

    Article  CAS  Google Scholar 

  19. Kanei-lshii, C., Yasukawa, T., Morimoto, R. & Ishii, S. & Ishii, S. c-Myb-induced trans-activation by heat shock elements without sequence-specific DNA binding of c-Myb. J. Biol. Chem. 269, 15768–15775 (1994).

    Google Scholar 

  20. Jurivich, D.A., Sistonen, L., Sarge, K.D. & Morimoto, R.I. Arachidonate is a potent modulator of human heat shock gene transcription. Proc. Natl. Acad. Sci. USA. 91 2280–2284.(1994)

    Article  CAS  Google Scholar 

  21. Yellon, D.M. & Latchman, D.S. Stress proteins and myocardial protection. J. Mol. Cell. Cardiol. 24, 113–124 (1992).

    Article  CAS  Google Scholar 

  22. Plumier, J.-C. & Currie, R.W. Heat shock-induced myocardial protection against ischemic injury: A role for HSP70? Cell Stress Chaperones 1, 13–17 (1996).

    Article  CAS  Google Scholar 

  23. Plumier, J.-C. et al. Transgenic mice expressing the human hsp70 have improved post-ischemic myocardial recovery. J. Clin. Invest. 95, 1854–1860 (1995).

    Article  CAS  Google Scholar 

  24. Ferdinándy P. et al. KATP channel modulation in working rat hearts with coronary occlusion: Effects of cromakalim, cicletanine, and glibenclamide. Cardiovasc. Res. 30, 781–787 (1995).

    Article  Google Scholar 

  25. Maytin, E.V. Heat shock proteins and molecular chaperones: Implications for adaptive responses in the skin. J. Invest. Dermatol. 104, 448–155 (1995).

    Article  CAS  Google Scholar 

  26. Polla, B.S. Heat (shock) and the skin. Dermatologica 180, 113–117 (1990).

    Article  CAS  Google Scholar 

  27. Doxey, D.L., Ng, M.C., Dill, R.E. & lacopino, A.M. Platelet-derived growth factor levels in wounds of diabetic rats. Life Sci. 57, 1111–1123 (1995).

    Article  CAS  Google Scholar 

  28. Oberringer, M. et al. Differential expression of heat shock protein 70 in well healing and chronic human wound tissue. Biochem. Biophys. Res. Commun. 214, 1009–1014 (1995).

    Article  CAS  Google Scholar 

  29. Jaszlits, L. et al. Antiischaemic efficacy of BRLP-42. J. Mol. Cell. Cardiol. 25, (Suppl. 1), XIP 20 (1993).

    Google Scholar 

  30. Jednákovits, A. et al. Effect of BRLP-42 on vascular reactivity of diabetic arterial beds. Diabetologia 37 (Suppl. 1), 19 A7 (1994).

    Google Scholar 

  31. HegedOs, E. et al. Protective effect of BRLP-42 on experimental retinopathy. Diabetologia 37 (Suppl. 1), 137 A7 (1995).

    Google Scholar 

  32. Bíró, K., Jednákovits, A., Jaszlits, L., Heged^s, E. & Kukorelli, T. Improvement of streptozotocin-diabetic neuropathy by BRLP-42. Diabetologia 37 (Suppl. 1), 282 A73 (1994).

    Google Scholar 

  33. Nishizawa, J., Nakai, A., Higashi, T., Bau, T. & Nagata, K. Reperfusion causes a significant activation of heat-shock-factor-1 in ischemic rat-heart. Circulation 92, 3137–3143 (1996).

    Google Scholar 

  34. Knowlton, A.A. The role of heat shock proteins in the heart. J. Mol. Cell. Cardiol. 27, 121–131 (1995).

    Article  CAS  Google Scholar 

  35. Vígh, L., Los, D.A., Horváth, I. & Murata, N. The primary signal in the biological perception of temperature: Pd-catalyzed hydrogenation of membrane lipids stimulated the expression of the desA gene in Synechocystis PCC6803. Proc. Natl. Acad. Sci. USA 90, 9090–9094 (1993).

    Article  Google Scholar 

  36. Carratu, L. et al. Membrane lipid perturbation modifies the setpoint of the temperature of heat shock response in yeast. Proc. Natl. Acad. Sci. USA 93, 3870–3875 (1996).

    Article  CAS  Google Scholar 

  37. Torok, Z. et al. Evidence for a lipochaperonin: Association of active protein-folding GroESL oligomers with lipids can stabilize membranes under heat shock conditions. Proc. Natl. Acad. Sci. USA 94, 2192–2197 (1997).

    Article  CAS  Google Scholar 

  38. Piper, P.W. The heat shock response and ethanol stress responses of yeast exhibit extensive similarity and functional overlap. FEMS Microbiol. Lett. 134, 121–127 (1995).

    Article  CAS  Google Scholar 

  39. Sambrook, J., Fritsch, E.F., Maniatis, T. (eds.) Molecular Cloning, A Laboratory Manual. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989).

    Google Scholar 

  40. Mestril, R., Chi, S.-H., Sayen, M.R., O'Reilly, K. & Dillmann, W.H. Expression of inducible stress protein 70 in rat heart myogenic cells confers protection against simulated ischemia-induced injury. J. Clin. Invest. 93, 759–767 (1994).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Temesvári krt. 62, 6721, Szeged, Hungary

    László Vígh, Ibolya Horváth, Zsolt Török, Gábor Balogh, Attila Glatz, Eszter Kovács & Imre Boros

  2. BIOREX Research and Developing Co.,, P.O. Box 348, 8200, Veszprém-Szabadságpuszta, Hungary

    Péter N. Literáti, László Jaszlits, Andrea Jednákovits & László Korányi

  3. Department of Biochemistry,

    Péter Ferdinándy

  4. Department of Dermatology Albert Szent-Györgyi Medical University, Korányi fasor 6, 6720, Szeged, Hungary

    Beatrix Parkas

  5. International Institute of Genetics and Biophysics, Consiglio Nazionale delle Ricerche, Via Marconi 12, 80125, Naples, Italy

    Bruno Maresca

Authors
  1. László Vígh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Péter N. Literáti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ibolya Horváth
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zsolt Török
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gábor Balogh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Attila Glatz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eszter Kovács
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Imre Boros
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Péter Ferdinándy
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Beatrix Parkas
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. László Jaszlits
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Andrea Jednákovits
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. László Korányi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Bruno Maresca
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vígh, L., Literáti, P., Horváth, I. et al. Bimoclomol: A nontoxic, hydroxylamine derivative with stress protein-inducing activity and cytoprotective effects. Nat Med 3, 1150–1154 (1997). https://doi.org/10.1038/nm1097-1150

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1097-1150

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing