# Chemical Inhibition PTPN22 to boost anti-viral immunity

> **NIH NIH P20** · UNIVERSITY OF KANSAS LAWRENCE · 2024 · $89,107

## Abstract

The overall goal of this project is to boost anti-viral immunity by inhibiting the protein tyrosine phosphatase 
non receptor 22 (PTPN22/Ptpn22) encoded enzyme Lyp (PEP in mice). Our hypothesis is that targeting 
Lyp/PEP C-terminal binding domain rather than the N-terminal enzymatic pocket will; 1- increase specificity 
and 2- chemically replicate the altered function caused by a commonly expressed PTPN22 allele 
(rs24766010), which causes an arginine (Arg) to tryptophan (Trp) amino acid substitution in the C-terminal 
region of Lyp/PEP and disrupts binding. In myeloid cells, N-terminal mutations rendering eenzymatically 
deadf Lyp/PEP compared to the health-relevant mutation in the C-terminal binding domain (rs24760010) 
can have different biological impact. We have previously shown that mice harboring this PEP Arg¨Trp Cterminal 
mutation have enhanced anti-viral immunity and can clear persistent virus infection. Now, we aim 
to therapeutically target PEP to achieve a comparable phenotype. This project utilizes the use of multiple 
CoBRE funded and non-CoBRE funded cores at the University of Kansas (KU). In brief, we will employ the 
protein production group to purify full length, N-terminal, and C- Terminal region of PEP. Then, the 
Infectious Disease Assay Development (IDAD) core will screen a compound library against these various 
PEP constructs. After identifying the compound of interest, this data will be submitted to the Computational 
Chemical Biology (CCB) core to computationally define these potential inhibitors. Further, the CCB core will 
work to rationally design a peptide based on the available structure of the P1 binding domain of PEP to 
binding partner Csk. Alongside these computational analyses, my lab will biologically validate the 
compounds evaluating anti-viral function in various immune cells, such as cytokine production, using 
spectral flow cytometry in the new Immunology Core. We will also molecularly assess the binding capacity 
of PEP to common protein partners. Future studies will submit the top compound(s) to the Synthetic 
Chemical Biology (SCB) core to be chemically stabilized and modified for in vivo experiments addressing 
anti-viral immunity. Discovery of such compounds results in a novel tool to further understand the role of 
Lyp/PEP during disease and potentially lead to a new therapeutic to better treat individualfs suffering from 
chronic infectious diseases.

## Key facts

- **NIH application ID:** 10870106
- **Project number:** 5P20GM113117-09
- **Recipient organization:** UNIVERSITY OF KANSAS LAWRENCE
- **Principal Investigator:** Robin C. Orozco
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $89,107
- **Award type:** 5
- **Project period:** 2016-05-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10870106

## Citation

> US National Institutes of Health, RePORTER application 10870106, Chemical Inhibition PTPN22 to boost anti-viral immunity (5P20GM113117-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10870106. Licensed CC0.

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