# Multiplex discovery of synthetic host-protein combinations that inhibit HIV

> **NIH NIH R21** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $201,250

## Abstract

PROJECT SUMMARY
Decades of HIV research have yielded a panel of potent HIV drugs, but we need the help of new approaches
to eliminate the global HIV epidemic. Modern biotechnologies have opened new avenues toward developing
engineered proteins that target the remaining vulnerabilities in the virus life-cycle. Novel protein combinations
linking host-derived HIV binding peptides with effector domains that can mark the HIV protein for degradation
may potently interfere with infection without causing major cellular toxicity. Unfortunately, there are hundreds to
thousands of combinations that need to be tested, which is nearly impossible using traditional, one-by-one
approaches.
We propose to apply cutting edge synthetic biology tools for protein and cell engineering, harnessing multiplex,
library-based assays to identify the most promising designs. In the first aim, we will perform large-scale
pairwise fusions of known HIV binding peptides with different cellular ubiquitin ligase effector domains, to
identify the combinations that have the best therapeutic potentials. The second aim uses an unbiased,
genome-wide transposon insertional mutagenesis approach to uncover novel binders capable of inhibiting HIV
replication when fused to a ubiquitin ligase domain. Both approaches will harness novel combinations of
protein sequences already found and expressed in humans, avoiding immune responses to non-self peptide
antigens. This work will yield new lead therapeutics, advance rational protein design, and provide biological
insight into how the stoichiometries of HIV protein targets and the multimerization of the engineered
proteasomal degradation machinery provides the most accurate and specific antiviral responses.

## Key facts

- **NIH application ID:** 10136373
- **Project number:** 1R21AI156907-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Kenneth A Matreyek
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $201,250
- **Award type:** 1
- **Project period:** 2020-11-18 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136373

## Citation

> US National Institutes of Health, RePORTER application 10136373, Multiplex discovery of synthetic host-protein combinations that inhibit HIV (1R21AI156907-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10136373. Licensed CC0.

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