Award Abstract # 2223225
SBIR Phase I: Structure-guided design of anti-inflammatory modulators of protease-activated receptor 1 (PAR1)

NSF Org: TI
Translational Impacts
Recipient: FUNCTION THERAPEUTICS INC
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: FY 2023 = $274,710.00
History of Investigator:
  • Christopher Dockendorff (Principal Investigator)
    cdockendorff@function-therapeutics.com
Recipient Sponsored Research Office: FUNCTION THERAPEUTICS, INC.
1626 N PROSPECT AVE
MILWAUKEE
WI  US  53202-2437
(262)404-7496
Sponsor Congressional District: 04
Primary Place of Performance: FUNCTION THERAPEUTICS, INC.
1626 N. Prospect Ave. #1901
Milwaukee
WI  US  53202-2437
Primary Place of Performance
Congressional District:
04
Unique Entity Identifier (UEI): DMN7SCPC2TR5
Parent UEI:
NSF Program(s): SBIR Phase I
Primary Program Source: 01AB2324DB R&RA DRSA DEFC AAB
Program Reference Code(s): 6883
Program Element Code(s): 537100
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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DeRousse, Jacob T and Dockendorff, Chris "Characterizing Modulators of Protease-activated Receptors with a Calcium Mobilization Assay Using a Plate Reader" Journal of Visualized Experiments , 2024 https://doi.org/10.3791/66507 Citation Details

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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