
NSF Org: |
TI Translational Impacts |
Recipient: |
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Initial Amendment Date: | March 7, 2023 |
Latest Amendment Date: | May 29, 2024 |
Award Number: | 2223225 |
Award Instrument: | Standard Grant |
Program Manager: |
Erik Pierstorff
epiersto@nsf.gov (703)292-0000 TI Translational Impacts TIP Directorate for Technology, Innovation, and Partnerships |
Start Date: | March 15, 2023 |
End Date: | August 31, 2024 (Estimated) |
Total Intended Award Amount: | $274,710.00 |
Total Awarded Amount to Date: | $274,710.00 |
Funds Obligated to Date: |
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History of Investigator: |
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Recipient Sponsored Research Office: |
1626 N PROSPECT AVE MILWAUKEE WI US 53202-2437 (262)404-7496 |
Sponsor Congressional District: |
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Primary Place of Performance: |
1626 N. Prospect Ave. #1901 Milwaukee WI US 53202-2437 |
Primary Place of
Performance Congressional District: |
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Unique Entity Identifier (UEI): |
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Parent UEI: |
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NSF Program(s): | SBIR Phase I |
Primary Program Source: |
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Program Reference Code(s): |
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Program Element Code(s): |
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Award Agency Code: | 4900 |
Fund Agency Code: | 4900 |
Assistance Listing Number(s): | 47.084 |
ABSTRACT
The broader impact of this Small Business Innovation Research (SBIR) Phase I project is that a deeper structural understanding will be developed of protease-activated receptor 1 (PAR1), an important target for promising new anti-thrombotic and anti-inflammatory drugs. The project will also support the development of new compounds targeting PAR1 with the potential for improved potency and safety profiles. Such compounds could represent a new drug class for the treatment of inflammation-related diseases, including kidney disease.
The proposed project involves the confirmation of the binding site on PAR1 of small molecule ligands called parmodulins. A detailed characterization of this binding site will support the rapid design, synthesis, and testing of new and improved parmodulins with superior properties as oral medications. A combination of computational, structural biology, and synthetic methods will be combined with PAR1 cell assays to confirm the binding site and develop more detailed structure-activity relationships of the parmodulins. It is also anticipated that novel parmodulins will be identified in this project with improved safety and stability profiles.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH
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PROJECT OUTCOMES REPORT
Disclaimer
This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.
In this project, several accomplishments were achieved that help to advance the development of anti-inflammatory compounds called parmodulins, small molecules that modulate the activity of protease-activated receptor 1 (PAR1).
First, an updated binding site model for parmodulins on PAR1 has been developed that is expected to support the faster identification of compounds with suitable properties for potential clinical investigation. This model is being used for computational docking studies to predict the activities of newly designed compounds. Second, methods were developed for the expression and purification of PAR1 for structural biology studies. Third, cell assays were developed to both greatly increase throughput and to measure the cytoprotective effects of parmodulins. The optimization of a plate reader calcium mobilization assay was completed, then this assay was translated to a plate imager to permit the rapid analysis of hundreds (optionally thousands) of compounds. Fourth, approximately 180 new and diverse parmodulins were designed, synthesized, and assayed in this grant project. Numerous synthetic methods were explored, and some were used for the preparation of analogs in an iterative process. Several lead compounds with nanomolar potency against PAR1 were identified, which also showed good solubility and metabolic stability. These and other parmodulins will be the subject of follow-up studies, including rodent pharmacokinetic measurements and testing in animal models of specific inflammatory diseases, including chronic kidney and liver diseases.
Last Modified: 09/22/2024
Modified by: Christopher Dockendorff
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