Hydroximic acid derivatives

Pleiotropic Hsp co-inducers restoring homeostasis and robustness

Tim Crul, Noemi Toth, Stefano Piotto, Peter Literati-Nagy, K. Tory, Pierre Haldimann, Bernadett Kalmar, Linda Greensmith, Z. Török, G. Balogh, I. Gombos, Federica Campana, Simona Concilio, F. Gallyas, Gabor Nagy, Z. Berente, Burcin Gungor, Maria Peter, A. Glatz, Akos Hunya & 20 others Zsuzsanna Literati-Nagy, Laszlo Vigh, Femke Hoogstra-Berends, André Heeres, Irma Kuipers, Lizette Loen, Jean Paul Seerden, Deli Zhang, Roelien A M Meijering, Robert H. Henning, Bianca J J M Brundel, Harm H. Kampinga, Laszlo Koranyi, Z. Szilvássy, J. Mandl, B. Sümegi, Mark A. Febbraio, I. Horváth, Philip L. Hooper, L. Vígh

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

According to the "membrane sensor" hypothesis, the membrane's physical properties and microdomain organization play an initiating role in the heat shock response. Clinical conditions such as cancer, diabetes and neurodegenerative diseases are all coupled with specific changes in the physical state and lipid composition of cellular membranes and characterized by altered heat shock protein levels in cells suggesting that these "membrane defects" can cause suboptimal hsp-gene expression. Such observations provide a new rationale for the introduction of novel, heat shock protein modulating drug candidates. Intercalating compounds can be used to alter membrane properties and by doing so normalize dysregulated expression of heat shock proteins, resulting in a beneficial therapeutic effect for reversing the pathological impact of disease. The membrane (and lipid) interacting hydroximic acid (HA) derivatives discussed in this review physiologically restore the heat shock protein stress response, creating a new class of "membrane-lipid therapy" pharmaceuticals. The diseases that HA derivatives potentially target are diverse and include, among others, insulin resistance and diabetes, neuropathy, atrial fibrillation, and amyotrophic lateral sclerosis. At a molecular level HA derivatives are broad spectrum, multi-target compounds as they fluidize yet stabilize membranes and remodel their lipid rafts while otherwise acting as PARP inhibitors. The HA derivatives have the potential to ameliorate disparate conditions, whether of acute or chronic nature. Many of these diseases presently are either untreatable or inadequately treated with currently available pharmaceuticals. Ultimately, the HA derivatives promise to play a major role in future pharmacotherapy.

Original languageEnglish
Pages (from-to)309-346
Number of pages38
JournalCurrent Pharmaceutical Design
Volume19
Issue number3
Publication statusPublished - 2013

Fingerprint

Heat-Shock Proteins
Homeostasis
Acids
Membranes
Membrane Lipids
Pharmaceutical Preparations
Lipids
Heat-Shock Response
Amyotrophic Lateral Sclerosis
Therapeutic Uses
Neurodegenerative Diseases
Atrial Fibrillation
Insulin Resistance
Cell Membrane
Gene Expression
Drug Therapy
Neoplasms
Therapeutics

Keywords

  • Atrial fibrillation
  • BGP-15
  • Drug development
  • Geranylgeranylacetone derivatives
  • Hydroximic acid derivatives
  • Insulin sensitizer
  • Neuroprotection
  • Stress response

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology

Cite this

Hydroximic acid derivatives : Pleiotropic Hsp co-inducers restoring homeostasis and robustness. / Crul, Tim; Toth, Noemi; Piotto, Stefano; Literati-Nagy, Peter; Tory, K.; Haldimann, Pierre; Kalmar, Bernadett; Greensmith, Linda; Török, Z.; Balogh, G.; Gombos, I.; Campana, Federica; Concilio, Simona; Gallyas, F.; Nagy, Gabor; Berente, Z.; Gungor, Burcin; Peter, Maria; Glatz, A.; Hunya, Akos; Literati-Nagy, Zsuzsanna; Vigh, Laszlo; Hoogstra-Berends, Femke; Heeres, André; Kuipers, Irma; Loen, Lizette; Seerden, Jean Paul; Zhang, Deli; Meijering, Roelien A M; Henning, Robert H.; Brundel, Bianca J J M; Kampinga, Harm H.; Koranyi, Laszlo; Szilvássy, Z.; Mandl, J.; Sümegi, B.; Febbraio, Mark A.; Horváth, I.; Hooper, Philip L.; Vígh, L.

In: Current Pharmaceutical Design, Vol. 19, No. 3, 2013, p. 309-346.

Research output: Contribution to journalArticle

Crul, T, Toth, N, Piotto, S, Literati-Nagy, P, Tory, K, Haldimann, P, Kalmar, B, Greensmith, L, Török, Z, Balogh, G, Gombos, I, Campana, F, Concilio, S, Gallyas, F, Nagy, G, Berente, Z, Gungor, B, Peter, M, Glatz, A, Hunya, A, Literati-Nagy, Z, Vigh, L, Hoogstra-Berends, F, Heeres, A, Kuipers, I, Loen, L, Seerden, JP, Zhang, D, Meijering, RAM, Henning, RH, Brundel, BJJM, Kampinga, HH, Koranyi, L, Szilvássy, Z, Mandl, J, Sümegi, B, Febbraio, MA, Horváth, I, Hooper, PL & Vígh, L 2013, 'Hydroximic acid derivatives: Pleiotropic Hsp co-inducers restoring homeostasis and robustness', Current Pharmaceutical Design, vol. 19, no. 3, pp. 309-346.
Crul, Tim ; Toth, Noemi ; Piotto, Stefano ; Literati-Nagy, Peter ; Tory, K. ; Haldimann, Pierre ; Kalmar, Bernadett ; Greensmith, Linda ; Török, Z. ; Balogh, G. ; Gombos, I. ; Campana, Federica ; Concilio, Simona ; Gallyas, F. ; Nagy, Gabor ; Berente, Z. ; Gungor, Burcin ; Peter, Maria ; Glatz, A. ; Hunya, Akos ; Literati-Nagy, Zsuzsanna ; Vigh, Laszlo ; Hoogstra-Berends, Femke ; Heeres, André ; Kuipers, Irma ; Loen, Lizette ; Seerden, Jean Paul ; Zhang, Deli ; Meijering, Roelien A M ; Henning, Robert H. ; Brundel, Bianca J J M ; Kampinga, Harm H. ; Koranyi, Laszlo ; Szilvássy, Z. ; Mandl, J. ; Sümegi, B. ; Febbraio, Mark A. ; Horváth, I. ; Hooper, Philip L. ; Vígh, L. / Hydroximic acid derivatives : Pleiotropic Hsp co-inducers restoring homeostasis and robustness. In: Current Pharmaceutical Design. 2013 ; Vol. 19, No. 3. pp. 309-346.
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AU - Literati-Nagy, Peter

AU - Tory, K.

AU - Haldimann, Pierre

AU - Kalmar, Bernadett

AU - Greensmith, Linda

AU - Török, Z.

AU - Balogh, G.

AU - Gombos, I.

AU - Campana, Federica

AU - Concilio, Simona

AU - Gallyas, F.

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AU - Berente, Z.

AU - Gungor, Burcin

AU - Peter, Maria

AU - Glatz, A.

AU - Hunya, Akos

AU - Literati-Nagy, Zsuzsanna

AU - Vigh, Laszlo

AU - Hoogstra-Berends, Femke

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AU - Loen, Lizette

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AU - Zhang, Deli

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AU - Henning, Robert H.

AU - Brundel, Bianca J J M

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AU - Koranyi, Laszlo

AU - Szilvássy, Z.

AU - Mandl, J.

AU - Sümegi, B.

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AU - Vígh, L.

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