# Optimizing therapeutic peptide presentation within polymers

> **NIH NIH R35** · UNIVERSITY OF VIRGINIA · 2022 · $367,418

## Abstract

Project Summary
For a wide range of diseases, peptides could provide immense therapeutic benefit, however the short half-lives
of peptides in biological environments hinder their translation to clinical use. Immune system-mediated
clearance, renal filtration of structures smaller than 20 nm (such as peptides), and enzymatic degradation all
contribute to the short half-lives of peptides. Conjugating peptides to polymers can overcome many of these
obstacles and prolong half-life, similarly as in the case of PEG-INTRONTM, a star-shaped polymer decorated with
the protein therapeutic interferon alfa-2b that prolongs half-life of the protein and enables its use to treat cancer
and hepatitis, among other conditions. However, conjugation of peptides to polymers may also detract
substantially from the therapeutic function. For example, attachment of an antimicrobial peptide to one end of a
polymer reduces toxicity to mammalian cells, but also markedly reduces antimicrobial activity. On the other
hand, attaching multiple antimicrobial peptides to a polymer chain can improve activity by enabling multivalent
interactions of peptides with biological targets (e.g., pathogenic microbes), but may also cause undesired toxic
effects to mammalian cells. The overall goal of this proposal and a major thrust of my research group is to
leverage advances in polymer chemistry that enable precision control of polymer composition, molecular weight,
architecture, and supramolecular assembly to optimize presentation of therapeutic peptides. By varying the
density and number of peptides pendent to a water-soluble polymer chain, we aim to maximize the function and
therapeutic benefit of peptides designed to combat infectious disease and Amyotrophic Lateral Sclerosis. One
set of conjugates will feature antimicrobial peptides, and another will feature peptides we designed to bind and
sequester toxic poly(dipepetide)s implicated in Amyotrophic Lateral Sclerosis via stereochemistry-driven
interactions. We will characterize the size, morphology, surface charge, and stability of the polymer-peptide
conjugate variants, and interactions with biological targets to connect conjugate structure to these therapeutically
relevant biophysical properties. In other situations, chemical modification of peptides in any arrangement can
abrogate the intended function; in these cases, physical encapsulation of the peptides within polymer particles
provides an excellent alternative. By modulating both the percentage and arrangement of charge-neutral groups
in otherwise anionic polymers, we aim to control the stability, as well as the loading and release rates of cationic
therapeutic peptides. Together, these studies will provide critical insight regarding formulating peptides with
polymers to optimize therapeutic function and thereby accelerate the clinical implementation of this important
class of therapeutics.

## Key facts

- **NIH application ID:** 10501662
- **Project number:** 1R35GM147424-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Rachel Letteri
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $367,418
- **Award type:** 1
- **Project period:** 2022-07-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10501662

## Citation

> US National Institutes of Health, RePORTER application 10501662, Optimizing therapeutic peptide presentation within polymers (1R35GM147424-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10501662. Licensed CC0.

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