Hsp90 Modulators Preventing Axonal Degeneration
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Solution Overview
Problem
Current therapies are ineffective in preventing nerve degeneration in neurodegenerative disorders such as chemotherapy-induced peripheral neuropathy, diabetes-induced peripheral neuropathy, and amyotrophic lateral sclerosis, with heat shock proteins contributing to both normal cellular functions and disease progression.
Innovation Solution
Administration of compounds like ethoxyquin (EQ) and its derivatives, which modulate the activity of heat shock protein 90 (hsp90) without affecting its ATPase activity, providing neuroprotection by preventing distal axonal degeneration and reducing neurotoxicity caused by stressors like paclitaxel.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If heat shock proteins are increased to protect neurons from stress, then neuroprotection is improved, but tumor cell survival is enhanced
Solution Approach 1:
The compound selectively modulates hsp90 activity in neural tissues to provide neuroprotection while avoiding the systemic enhancement of tumor cell survival. This is achieved through targeted action on hsp90's chaperone function in neurons without broadly stabilizing aberrant signaling proteins in cancer cells.
Solution Approach 2:
The compound changes the functional state of hsp90 by modulating its chaperone activity parameter while leaving ATPase activity unchanged. This selective parameter modification allows neuroprotection through stabilized neuronal proteins without the harmful effect of enhanced tumor cell survival that occurs with broad hsp90 upregulation.
2Reliability
If hsp90 activity is modulated to prevent nerve degeneration, then neuroprotection is improved, but ATPase activity is affected
Solution Approach 1:
The invention segments the functional aspects of hsp90 by selectively modulating only the chaperone activity while leaving the ATPase activity untouched. This allows independent control of the protective chaperone function from the energy-consuming ATP hydrolysis function, achieving neuroprotection without interfering with normal energy metabolism.
Solution Approach 2:
The compound changes specific functional parameters of hsp90 - specifically modulating chaperone activity while maintaining ATPase activity at normal levels. This selective parameter modification enables neuroprotection through altered protein folding assistance without disrupting the energy consumption cycle of hsp90.
Data Source
AI summary
Compounds and methods for treating or preventing a neurodegenerative disease, disorder or condition associated with the overall activity of hsp90 but not with the ATPase activity of hsp90, including peripheral neuropathy, such as peripheral neuropathy caused by chemotherapy or diabetes, disorders 5 of the central nervous system, such as Alzheimer's disease and Parkinsons disease, and motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), in a subject are provided.