Sunday, May 18, 2025
5/18/2025
Natural-based therapies for sensory disorders - PROJECT SUMMARY Hearing loss is a major health concern in our society, affecting over 400 million people worldwide. Aminoglycoside therapy causes permanent hearing loss in 40-60% of treated patients. To date, no drugs have been approved by the Food and Drug Administration for protection from aminoglycoside- related hearing loss (AGIHL). Most candidate compounds currently in pre-clinical and clinical trials are related to antioxidants, vitamins, and glutathione metabolism. We have conducted a high-throughput screening of bioactive natural compounds employing zebrafish as our platform for aminoglycoside ototoxicity and identified piperlongumine, an alkaloid extracted from the long pepper Piper Longum L., as an important therapeutic molecule for aminoglycoside-induced hair cell death. Previous studies have shown that piperlongumine can allosterically modulate the transient receptor potential vanilloid 1 (TRPV1) channel at high doses. Our own studies in a mouse model for AGIHL demonstrated that piperlongumine can partially protect hearing function when given as a single dose for 17 consecutive days. The morphological assessment demonstrated that piperlongumine protects hair cells and their synapses. Given that TRPV1 is upregulated in the inner ear during inflammation, in this proposal we want to 1) design, synthesize and test piperlongumine derivatives with a better fit for TRPV1 allosteric pocket; 2) characterize the pharmacological and physicochemical properties and distribution of the top lead candidates; 3) establish efficacy and therapeutic window of the top candidates in an animal model that recapitulates AGHIL and endotoxemia; 4) establish the TRPV1-mediated mechanism(s) of action of the piperlongumine derivatives, and 5) confirm that piperlongumine derivatives do not antagonize with aminoglycoside anti-bacterial activity. By completing these studies, we will be able to obtain the necessary information to move piperlongumine derivatives forward toward future clinical trials. We have already established conversations with future collaborators involved in clinical research with cystic fibrosis patients and newborn intensive care unit patients. Moreover, I am one of the inventors on a patent for the use of piperlongumine to treat hearing loss filed by Ting Therapeutics LLC as a Patent Cooperation Treaty. Thus, this proposal has the potential to be a significant step forward for the treatment of AGIHL in patients with severe Gram-negative bacterial infections.
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