# Parasite-specific proteasome inhibitors to combat multi-drug resistant malaria

> **NIH NIH R33** · STANFORD UNIVERSITY · 2020 · $462,817

## Abstract

Project Summary
Multidrug-resistant forms of Plasmodium falciparum contribute directly to the massive global burden of malaria,
which, as of 2015, impacts nearly 200 million people and result in over 400,000 deaths per year. P. falciparum
resistance to the former first-line drugs chloroquine and pyrimethamine-sulfadoxine has now exacerbated the
emergence and spread of resistance to the current first-line drug artemisinin (ART) and some partner drugs
used in first line artemisinin (ART)-based combination therapies (ACTs). To achieve the stated goal of malaria
elimination, new therapeutic strategies are essential to eliminate multi-drug resistant parasites. Recent studies
of ART-resistant parasite strains suggest that they can resist drug-mediated killing by up-regulation of the
unfolded protein response (UPR), a process that depends on activation of the multi-catalytic proteasome
complex. Consequently, proteasome inhibitors have been shown to be highly synergistic with ART derivatives.
Unlike ART, these inhibitors are also active liver, gametocyte and oocyst stages. Therefore, compounds that
selectively target the Plasmodium proteasome have the potential to be curative while also blocking
transmission from human to insect vector and reducing the emergence of drug resistance. We hypothesize
that ART, as well as other classes of current anti-malarial drugs and preclinical candidates, induce
stress pathways in P. falciparum that depend on proteasomal activity to achieve resistance. We also
hypothesize that proteasome inhibitors have the potential to be broadly used to suppress the onset of
multidrug resistance in native parasite populations. This proposal is built around strong preliminary results
using substrate screening assays and our recently solved cryo-electron microscopy structure of the P.
falciparum 20S proteasome to design selective inhibitors of the parasite proteasome with nanomolar potency
that effectively clear rodent malaria infections in vivo. We find that proteasome inhibitors show a high degree of
synergism when combined with ART and are potent against ART-resistant field isolates. Our preliminary
results therefore establish the paradigm that the proteasome is a viable anti-malarial drug target. We propose
developing improved parasite-specific proteasome inhibitors that have enhanced potency, selectivity and
bioavailability while simultaneously defining the mechanism and conditions by which inhibitors can optimally
synergize with anti-malarial agents to prevent the spread of resistance.

## Key facts

- **NIH application ID:** 9840437
- **Project number:** 5R33AI127581-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Matthew Bogyo
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $462,817
- **Award type:** 5
- **Project period:** 2016-12-09 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840437

## Citation

> US National Institutes of Health, RePORTER application 9840437, Parasite-specific proteasome inhibitors to combat multi-drug resistant malaria (5R33AI127581-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9840437. Licensed CC0.

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