# A Potent and Specific Approach to Targeting B-Cell Lymphoma: Disrupting Malignant Protein-Protein Interactions Using CD19-Targeted Stapled Peptide Amphiphile Nanoparticles

> **NIH NIH F30** · UNIVERSITY OF CHICAGO · 2021 · $51,036

## Abstract

PROJECT SUMMARY/ABSTRACT
This project seeks to engineer a potent, specific, and clinically relevant treatment platform to target B-cell
lymphoma, which is often refractory to chemotherapeutic treatments. To accomplish that goal, this project
develops a peptide-based nanoparticle platform for disrupting oncogenic protein-protein interactions (PPIs) and
inducing cell death specifically in lymphoma B cells without targeting other cells. Cancer cells often upregulate
pro-survival PPIs to sequester and inactivate tumor suppressor proteins and evade programmed cell death,
which is one of the hallmarks of cancer. Despite intensive pharmacologic efforts to target and disrupt
oncogenic PPIs, only one FDA-approved small-molecule drug exists to do so. Synthetic peptides, in contrast,
have emerged as promising tools for disrupting PPIs because they more accurately mimic the large, alpha-
helical binding domains known to be crucial for many PPIs. However, major barriers remain to successful in
vivo delivery of therapeutic peptides to their intracellular targets, including: (i) short circulation half-lives, (ii)
non-specific cellular targeting, (iii) poor cellular penetration, and (iv) poor binding affinity due to loss of alpha-
helical secondary structure. Two molecular engineering approaches, hydrocarbon “stapled” peptides and
peptide-amphiphile (PA) nanoparticles, have been used to overcome subsets of these obstacles, though
neither overcomes them all simultaneously. Hydrocarbon stapled peptides are formed by adding a
hydrocarbon “staple” across alpha-helical turns of a peptide to physically lock it in an alpha-helical
conformation and more accurately mimic the structure of the native protein and improve binding affinity to its
target. PA nanoparticles, meanwhile, enhance therapeutic peptide circulation times, serum stability, and
cellular uptake, and can be functionalized with targeting moieties to actively target specific cell types. This
project seeks to simultaneously overcome the barriers to therapeutic peptide delivery by combining
hydrocarbon stapled peptides and PA nanoparticles. This work aims to do so in three ways. First, synthesize
and characterize a p53-mimicking stapled PA (p53-sPA) designed to reactivate tumor suppressor protein p53
and reinstate cell death in diffuse large B cell lymphoma (DLBCL), a cancer in which most clinical cases have
wildtype p53 inactivated by aberrant PPIs. Second, deliver p53-reactivating nanoparticles specifically to
malignant DLBCL cells using antibody single-chain variable fragments (scFvs) specific for B-cell surface
antigen CD19. Lastly, combat chemotherapeutic resistance in DLBCL using mixed PA nanoparticles to
spatially constrain the delivery of synergistic peptide therapeutics targeting the p53 and BCL2 pro-survival
PPIs. The success of these aims will create a new treatment paradigm for potently and specifically killing
cancer cells while avoiding the development of chemotherapeutic resistance.

## Key facts

- **NIH application ID:** 10187524
- **Project number:** 5F30CA221250-05
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Mathew Ryan Schnorenberg
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10187524

## Citation

> US National Institutes of Health, RePORTER application 10187524, A Potent and Specific Approach to Targeting B-Cell Lymphoma: Disrupting Malignant Protein-Protein Interactions Using CD19-Targeted Stapled Peptide Amphiphile Nanoparticles (5F30CA221250-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10187524. Licensed CC0.

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