Developing a Novel Therapeutic for Laryngopharyngeal Reflux Disease

Mentor 1

Alexander Arnold

Location

Union Wisconsin Room

Start Date

24-4-2015 10:30 AM

End Date

24-4-2015 11:45 AM

Description

Laryngopharyngeal Reflux Disease (LPRD), an extension of gastroesophageal reflux disease (GERD) occurs when gastric contents are refluxed past the esophagus into the larynx, pharynx, and even the middle ear. Current acid suppression therapy with proton pump inhibitors (PPIs) has proven ineffective because unlike GERD, pepsin is the mechanism behind damaging of healthy tissues, not stomach acid. When pepsin is refluxed extraesophageally it can actively digest healthy tissues, damaging cells, leading to mutations and causing subsequent cancers. The objective of this research is to identify new pepsin inhibitors to completely and irreversibly inhibit pepsin’s activity when present in these tissues. Previous work in the project includes three different fluorescence assays, which were developed using labeled pepstatin, casein, and peptide probes to indicate varying levels of inhibition of the pepsin enzyme. These assays were then used to screen the Library of Pharmacologically Active Compounds (LOPAC) to determine if any compounds inhibited pepsin. Fortunately, each assay turned up only a few hit compounds, allowing our research to focus in on these specific hits. In order to verify that these hits were specific and selective to pepsin, an additional fluorescence assay was designed using a different aspartic protease, Cathepsin-D. The Cathepsin-D assay will be used to again screen the LOPAC library for hit compounds to determine if the previous hits were in fact specific to pepsin. Once target compounds have been identified, they will be subjected to cell based assays to assess their viability as drug candidates in vivo.

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Apr 24th, 10:30 AM Apr 24th, 11:45 AM

Developing a Novel Therapeutic for Laryngopharyngeal Reflux Disease

Union Wisconsin Room

Laryngopharyngeal Reflux Disease (LPRD), an extension of gastroesophageal reflux disease (GERD) occurs when gastric contents are refluxed past the esophagus into the larynx, pharynx, and even the middle ear. Current acid suppression therapy with proton pump inhibitors (PPIs) has proven ineffective because unlike GERD, pepsin is the mechanism behind damaging of healthy tissues, not stomach acid. When pepsin is refluxed extraesophageally it can actively digest healthy tissues, damaging cells, leading to mutations and causing subsequent cancers. The objective of this research is to identify new pepsin inhibitors to completely and irreversibly inhibit pepsin’s activity when present in these tissues. Previous work in the project includes three different fluorescence assays, which were developed using labeled pepstatin, casein, and peptide probes to indicate varying levels of inhibition of the pepsin enzyme. These assays were then used to screen the Library of Pharmacologically Active Compounds (LOPAC) to determine if any compounds inhibited pepsin. Fortunately, each assay turned up only a few hit compounds, allowing our research to focus in on these specific hits. In order to verify that these hits were specific and selective to pepsin, an additional fluorescence assay was designed using a different aspartic protease, Cathepsin-D. The Cathepsin-D assay will be used to again screen the LOPAC library for hit compounds to determine if the previous hits were in fact specific to pepsin. Once target compounds have been identified, they will be subjected to cell based assays to assess their viability as drug candidates in vivo.