Title:Hydroximic Acid Derivatives: Pleiotropic Hsp Co-Inducers Restoring Homeostasis and Robustness
Volume: 19
Issue: 3
Author(s): Bianca J J M Brundel, Laszlo Vigh, Femke Hoogstra-Berends, Andre Heeres, Irma Kuipers, Lizette Loen, Jean-Paul Seerden, Deli Zhang, Roelien A M Meijering, Robert H Henning, Zsuzsanna Literati-Nagy, Harm H Kampinga, Laszlo Koranyi, Zoltan Szilvassy, Jozsef Mandl, Balazs Sumegi, Mark A Febbraio, Ibolya Horvath, Philip L Hooper, Laszlo Vigh, Imre Gombos, Noemi Toth, Stefano Piotto, Peter Literati-Nagy, Kalman Tory, Pierre Haldimann, Bernadett Kalmar, Linda Greensmith, Zsolt Torok, Gabor Balogh, Tim Crul, Federica Campana, Simona Concilio, Ferenc Gallyas, Gabor Nagy, Zoltan Berente, Burcin Gungor, Maria Peter, Attila Glatz and Akos Hunya
Affiliation:
Keywords:
Stress response, drug development, hydroximic acid derivatives, BGP-15, geranylgeranylacetone derivatives, insulin sensitizer, neuroprotection, atrial fibrillation, membrane sensor hypothesis, diabetes
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.
