Hydroximic acid derivatives: pleiotropic HSP co-inducers restoring homeostasis and robustness

Tim Crul, Noemi Toth, Stefano Piotto, Peter Literati-Nagy, Kalman Tory, Pierre Haldimann, Bernadett Kalmar, Linda Greensmith, Zsolt Torok, Gabor Balogh, Imre Gombos, Federica Campana, Simona Concilio, Ferenc Gallyas, Gabor Nagy, Zoltan Berente, Burcin Gungor, Maria Peter, Attila 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, Zoltan Szilvassy, Jozsef Mandl, Balazs Sumegi, Mark A Febbraio, Ibolya Horvath, Philip L Hooper, Laszlo Vigh

Research output: Contribution to journalArticleAcademicpeer-review

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)309-46
JournalCurrent pharmaceutical design
Volume19
Issue number3
Publication statusPublished - 2013

Keywords

  • animals
  • genetic pleiotropy
  • heat-shock proteins
  • heat-shock response
  • homeostasis
  • humans
  • membrane lipids
  • oximes

Cite this

Crul, T., Toth, N., Piotto, S., Literati-Nagy, P., Tory, K., Haldimann, P., ... Vigh, L. (2013). Hydroximic acid derivatives: pleiotropic HSP co-inducers restoring homeostasis and robustness. Current pharmaceutical design, 19(3), 309-46.
Crul, Tim ; Toth, Noemi ; Piotto, Stefano ; Literati-Nagy, Peter ; Tory, Kalman ; Haldimann, Pierre ; Kalmar, Bernadett ; Greensmith, Linda ; Torok, Zsolt ; Balogh, Gabor ; Gombos, Imre ; Campana, Federica ; Concilio, Simona ; Gallyas, Ferenc ; Nagy, Gabor ; Berente, Zoltan ; Gungor, Burcin ; Peter, Maria ; Glatz, Attila ; 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 ; Szilvassy, Zoltan ; Mandl, Jozsef ; Sumegi, Balazs ; Febbraio, Mark A ; Horvath, Ibolya ; Hooper, Philip L ; Vigh, Laszlo. / Hydroximic acid derivatives : pleiotropic HSP co-inducers restoring homeostasis and robustness. In: Current pharmaceutical design. 2013 ; Vol. 19, No. 3. pp. 309-46.
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Crul, T, Toth, N, Piotto, S, Literati-Nagy, P, Tory, K, Haldimann, P, Kalmar, B, Greensmith, L, Torok, 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, J-P, Zhang, D, Meijering, RAM, Henning, RH, Brundel, BJJM, Kampinga, HH, Koranyi, L, Szilvassy, Z, Mandl, J, Sumegi, B, Febbraio, MA, Horvath, I, Hooper, PL & Vigh, L 2013, 'Hydroximic acid derivatives: pleiotropic HSP co-inducers restoring homeostasis and robustness' Current pharmaceutical design, vol. 19, no. 3, pp. 309-46.

Hydroximic acid derivatives : pleiotropic HSP co-inducers restoring homeostasis and robustness. / Crul, Tim; Toth, Noemi; Piotto, Stefano; Literati-Nagy, Peter; Tory, Kalman; Haldimann, Pierre; Kalmar, Bernadett; Greensmith, Linda; Torok, Zsolt; Balogh, Gabor; Gombos, Imre; Campana, Federica; Concilio, Simona; Gallyas, Ferenc; Nagy, Gabor; Berente, Zoltan; Gungor, Burcin; Peter, Maria; Glatz, Attila; 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; Szilvassy, Zoltan; Mandl, Jozsef; Sumegi, Balazs; Febbraio, Mark A; Horvath, Ibolya; Hooper, Philip L; Vigh, Laszlo.

In: Current pharmaceutical design, Vol. 19, No. 3, 2013, p. 309-46.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Hydroximic acid derivatives

T2 - pleiotropic HSP co-inducers restoring homeostasis and robustness

AU - Crul, Tim

AU - Toth, Noemi

AU - Piotto, Stefano

AU - Literati-Nagy, Peter

AU - Tory, Kalman

AU - Haldimann, Pierre

AU - Kalmar, Bernadett

AU - Greensmith, Linda

AU - Torok, Zsolt

AU - Balogh, Gabor

AU - Gombos, Imre

AU - Campana, Federica

AU - Concilio, Simona

AU - Gallyas, Ferenc

AU - Nagy, Gabor

AU - Berente, Zoltan

AU - Gungor, Burcin

AU - Peter, Maria

AU - Glatz, Attila

AU - Hunya, Akos

AU - Literati-Nagy, Zsuzsanna

AU - Vigh, Laszlo

AU - Hoogstra-Berends, Femke

AU - Heeres, André

AU - Kuipers, Irma

AU - Loen, Lizette

AU - Seerden, Jean-Paul

AU - Zhang, Deli

AU - Meijering, Roelien A M

AU - Henning, Robert H

AU - Brundel, Bianca J J M

AU - Kampinga, Harm H

AU - Koranyi, Laszlo

AU - Szilvassy, Zoltan

AU - Mandl, Jozsef

AU - Sumegi, Balazs

AU - Febbraio, Mark A

AU - Horvath, Ibolya

AU - Hooper, Philip L

AU - Vigh, Laszlo

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

KW - animals

KW - genetic pleiotropy

KW - heat-shock proteins

KW - heat-shock response

KW - homeostasis

KW - humans

KW - membrane lipids

KW - oximes

KW - biochemie

M3 - Article

VL - 19

SP - 309

EP - 346

JO - Current pharmaceutical design

JF - Current pharmaceutical design

SN - 1381-6128

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Crul T, Toth N, Piotto S, Literati-Nagy P, Tory K, Haldimann P et al. Hydroximic acid derivatives: pleiotropic HSP co-inducers restoring homeostasis and robustness. Current pharmaceutical design. 2013;19(3):309-46.