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Hydroximic Acid Derivatives: Pleiotropic Hsp Co-Inducers Restoring Homeostasis and Robustness

[ Vol. 19 , Issue. 3 ]

Author(s):

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, Zsuzsanna Literati-Nagy, Laszlo Vigh, Femke Hoogstra-Berends, Andre 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 and Laszlo Vigh   Pages 309 - 346 ( 38 )

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.

Keywords:

Stress response, drug development, hydroximic acid derivatives, BGP-15, geranylgeranylacetone derivatives, insulin sensitizer, neuroprotection, atrial fibrillation, membrane sensor hypothesis, diabetes

Affiliation:

Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, 6726-Szeged, Temesvari krt. 62, Hungary.



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