# Targeted Modification of Membrane Lipids

> **NIH NIH R01** · BOSTON COLLEGE · 2021 · $313,000

## Abstract

Targeted Modification of Membrane Lipids
Project Summary
 The lipid composition of membranes has critical ramifications in biology. It has been long known that
bacterial and mammalian cells harbor a different set of lipids in their membranes. While a mammalian cell
membrane is largely composed of zwitterionic lipids, bacterial cells typically display anionic lipids in large
quantities. Taking advantage of this difference, many organisms have evolved cationic host defense peptides
(HDPs), which serve as the frontline of the innate immunity to fend off invading bacterial pathogens. For
example, human neutrophils rely on cationic defensins for bacterial cell killing and clearance. To acquire
resistance against cationic HDPs, selected bacterial species synthesize the lipid Lys-PG, which carries a net
positive charge. We hypothesize that synthetic molecules that bind Lys-PG and consequently mask its net
charge will re-sensitize the bacterial cells to killing by HDPs. To test the hypothesis, we will develop synthetic
modifiers of Lys-PG by introducing reversible covalent warheads into well-structured scaffolds. Further we will
test the efficacy of Lys-PG modification in vitro and in mouse infection models. The specific aims are: 1) we will
use a known, foldable cyclic peptide scaffold to assemble multiple side chains for Lys-PG modification.
Computational modeling will be integrated with experimental characterization to optimize for Lys-PG binding; 2)
we will develop potent and specific modifiers of Lys-PG by screening novel bicyclic peptide libraries. This part
of the proposal will be based on a powerful peptide bicyclization strategy recently developed by our group; 3)
the Lys-PG modifiers developed in 1) and 2) will be tested for their capability to potentiate the bactericidal
activity of several HDPs and neutrophils. Their efficacy to facilitate bacterial clearance will be further examined
in mouse models of infection. With success, the proposed work will yield a novel strategy to fight against the
drug-resistance strains of bacterial pathogens. Although the proposed work focuses on Lys-PG, the
methodology developed here should be extendable to other lipid modifications of biological significance.

## Key facts

- **NIH application ID:** 10176514
- **Project number:** 5R01GM102735-09
- **Recipient organization:** BOSTON COLLEGE
- **Principal Investigator:** Jianmin Gao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $313,000
- **Award type:** 5
- **Project period:** 2012-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10176514

## Citation

> US National Institutes of Health, RePORTER application 10176514, Targeted Modification of Membrane Lipids (5R01GM102735-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10176514. Licensed CC0.

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