# Elucidating the molecular basis of piperaquine resistance in Plasmodium falciparum

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $504,920

## Abstract

PROJECT SUMMARY
Plasmodium falciparum (Pf) malaria cases have recently surged, with an estimated 627,000 deaths in 2020,
mostly in young African children. Efforts to reduce the burden of disease in Africa include both chemoprevention
strategies to protect vulnerable populations and treatment of symptomatic infections with effective artemisinin-
based combination therapies. Clinical studies have identified piperaquine (PPQ) as an ideal chemoprevention
and treatment partner drug due to its potency against asexual blood stage parasites, long plasma half-life, and
good safety profile in children and pregnant women. However, both drugs in the first-line combination of
dihydroartemisinin-PPQ have encountered widespread resistance in Southeast Asia. Given the recent
emergence in Rwanda and Uganda of artemisinin-resistant Pf parasites, there is a pressing need to investigate
whether PPQ resistance can emerge and spread in Africa, identify its genetic mediators, and develop new ways
to neutralize resistance. In Aim 1, our studies will focus on novel mutations that emerged on the background of
chloroquine-resistant isoforms of the Pf chloroquine resistance transporter PfCRT, as well as the amplification
of plasmepsins 2 and 3 (pm2/3), both of which contribute to PPQ resistance and treatment failure in Southeast
Asia. Using gene editing and overexpression approaches, we will determine whether PPQ resistance can be
generated in African lines by introducing individual mutations into African-specific PfCRT isoforms and assessing
whether increased pm2/3 copy numbers augment resistance. We will also assess whether pm2/3 amplifications
afford a fitness benefit to PfCRT mutant parasites, which could help establish and maintain PPQ resistance in
high-transmission African settings. In Aim 2, we will examine the role of inhibition of heme detoxification and
concentration-dependent drug efflux in PPQ action and resistance, respectively. Our studies will also test the
hypothesis that PPQ-resistant PfCRT isoforms perturb intracellular hemoglobin-derived peptide levels, which
may be corrected by pm2/3 amplification. In Aim 3, we propose that directly targeting PfCRT-mediated
resistance represents a high-value approach to retaining PPQ efficacy. Leveraging insights regarding opposing
selective pressures, we will test whether combining PPQ with other quinoline-based drugs (chloroquine,
amodiaquine or mefloquine) can eliminate PPQ-resistant parasites and prevent the recrudescence of resistant
variants. We will also screen for inhibitors that reverse resistance by blocking PPQ efflux via mutant PfCRT.
Assays will include ZY19489, an antimalarial in human clinical trials that inhibits PfCRT-mediated drug efflux and
hypersensitizes Pf parasites to PPQ. Concurrently, we will conduct a high-throughput screen designed to identify
novel PPQ resistance reversal agents. This proposal, which aligns with NIAID’s priority of supporting research
on antimicrobial drug resistance, is desi...

## Key facts

- **NIH application ID:** 10740858
- **Project number:** 5R01AI124678-07
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** David A Fidock
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $504,920
- **Award type:** 5
- **Project period:** 2016-02-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10740858

## Citation

> US National Institutes of Health, RePORTER application 10740858, Elucidating the molecular basis of piperaquine resistance in Plasmodium falciparum (5R01AI124678-07). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10740858. Licensed CC0.

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