# Systematic Design of Histone-Derived Antimicrobial Peptides

> **NIH NIH R15** · WELLESLEY COLLEGE · 2022 · $455,312

## Abstract

Project Summary
Bacteria that have developed resistance to conventional antibiotics are an increasing public health
concern, and antimicrobial peptides (AMPs) represent a potential alternative to combat these
bacteria. One intriguing family of AMPs is the histone-derived antimicrobial peptides (HDAPs).
HDAPs have been isolated from natural sources, and the mechanisms for many of these peptides
have been determined experimentally. However, relatively little focus has been given to the
rational optimization and design of HDAPs to engineer more active peptides. This proposal aims
to address this gap through purposeful and design-motivated investigations of three additional
factors that we hypothesize will impact HDAP activity: peptide truncations, the formation of hybrid
peptides, and combination therapy with antibiotic+AMP cocktails.
We are employing a carefully selected set of four representative HDAPs, BF2 and three designed
peptides DesHDAP1, DesHDAP2 and DesHDAP3A. These peptides were chosen to span the two
broad categories for AMP interaction with cell membranes—peptides that translocate across
plasma membranes (BF2 and DesHDAP1) and those that induce significant membrane
permeabilization (DesHDAP2 and DesHDAP3A). These peptides also reflect a range of initial
antibacterial activities. Thus, we feel that they provide a tractable sample size that nonetheless
provide sufficient molecular diversity to identify trends. Our methods include a combination of
bacterial and eukaryotic assays, confocal microscopy, spectroscopic measurements, and
molecular dynamics simulations.
After elucidating trends for our three proposed factors that affect HDAP activity with our
representative set of four peptides, we will combine this information to create a novel series of
peptides identified from histone sequences through a library-based approach that optimizes the
individual factors for peptide activity. We can thus assess the generalizability of our trends to
validate whether this is a useful approach for peptide design in HDAPs.
These studies will promote the development of HDAPs as potential therapeutic agents and
provide insights into HDAP structure-function relationships that potentially can be expanded to
other AMP families. In addition to these scientific goals, this research also has a strong emphasis
on training as the work will be carried out by several undergraduate researchers and a few recent
graduates at Wellesley College, an undergraduate-only women’s college.

## Key facts

- **NIH application ID:** 10438240
- **Project number:** 1R15AI169210-01
- **Recipient organization:** WELLESLEY COLLEGE
- **Principal Investigator:** Donald E. Elmore
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $455,312
- **Award type:** 1
- **Project period:** 2022-04-08 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10438240

## Citation

> US National Institutes of Health, RePORTER application 10438240, Systematic Design of Histone-Derived Antimicrobial Peptides (1R15AI169210-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10438240. Licensed CC0.

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