Allosteric, Small-Molecule Ligands of PAR1 for the Treatment of Diabetic Nephropathy
Abstract
This collaborative project targets the 2021 PRMRP topic area of diabetes, specifically diabetic nephropathy (diabetic kidney disease). New options for the treatment of acute and chronic kidney disease are urgently needed. Fifteen percent of U.S. adults are estimated to suffer from chronic kidney disease, with ~0.5 million suffering from end-stage renal disease that requires dialysis or transplant. The majority of these cases are caused by diabetes and/or high blood pressure. Despite numerous effective drugs for the management of high blood pressure, these are only able to slow the decline of kidney function in many cases. Current drugs have not been broadly successful in halting the progression of diabetic nephropathy for many patients. Therefore, new treatments to specifically target diabetic nephropathy and chronic kidney disease are urgently needed. This project will help to validate the utility of a new class of small molecules called parmodulins for the treatment of diabetic nephropathy. These target a cell surface receptor called PAR1. Unlike proteins, parmodulins are small organic compounds with the potential for oral dosing. They bind to a different region of PAR1 than other known compounds, and in so doing have unique anti-inflammatory and protective effects. Excitingly, unpublished results from our labs demonstrate that parmodulins have the potential to protect kidney cells under stress, and a published parmodulin called ML161 demonstrated excellent improvement of kidney function in a mouse model of diabetic nephropathy. New parmodulins with improved properties, especially oral activity, could be extremely desirable for the treatment of chronic kidney disease. In Aim 1 of this project, a collection of novel parmodulins will be synthesized to address specific deficiencies of published compounds. In Aim 2, these compounds will be screened in an iterative fashion to confirm PAR1 activity and measure protective activity in a range of assays, including with kidney cells. Promising examples will also be measured in a battery of selectivity and drug-like profiling assays. In Aim 3, optimal compounds demonstrating protective effects with the potential for oral activity will undergo pharmacokinetic studies (measuring concentrations of drug, and the time the drug is present before being cleared). Additional selectivity screening will be performed to avoid potential compounds with potential toxicity issues. Finally, the top analogs will progress to a rodent diabetic nephropathy study. We anticipate that these studies will help to validate that PAR1 is a promising target for diabetic nephropathy and kidney disease in general. The objective is to identify orally active parmodulins with the properties and performance to justify future development efforts, including toxicology and advanced efficacy studies that are required prior to clinical studies. We hypothesize that examples can be identified with the potential to halt the dangerous spiral towards renal failure suffered by diabetes patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210185
Entities
People
- Christopher Dockendorff
Organizations
- United States Army