# Interrogating plasmodial endocytosis with mefloquine-based affinity probes

> **NIH NIH R21** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2020 · $228,271

## Abstract

ABSTRACT
The human malaria parasite Plasmodium falciparum imports and catabolizes
massive amounts of host erythrocyte cytosol (mainly hemoglobin) during its
asexual replication cycle. The mechanism and regulation of hemoglobin uptake,
which occurs through a specialized protozoan structure termed the cytostome, is
poorly understood. Here, we present new data which, together with prior
published work, strongly suggests that the anti-malarial action of mefloquine
(MQ) is closely associated with the inhibition of hemoglobin endocytosis. In this
proposal, we will test the hypothesis that MQ binds to a protein target that plays a
key role in the parasite’s endocytosis of host erythrocyte hemoglobin. In Aim 1,
we will synthesize a library of photoaffinity probes that are based on the MQ
pharmacophore. Probe design will focus on the incorporation of “all-in-one”
moieties that enable the introduction of photoactivatable and affinity groups with
minimal structural perturbation. Phenotypic and parasite viability assays will be
employed to characterize probe potency and to verify retention of MQ’s mode of
action. In Aim 2, these probes will be used to irreversibly label the protein target
of MQ. Specificity of labeling will be assessed by competition with unmodified
MQ and the characterization of purified enantiomers of selected probes. Putative
targets will be affinity purified, identified by mass spectrometry, and validated
using a suite of complementary approaches. These studies hold great promise to
address the long-standing questions of the molecular mechanisms of hemoglobin
endocytosis and of the mode of action of MQ, thereby identifying a potentially
high-value anti-malarial target.

## Key facts

- **NIH application ID:** 9876321
- **Project number:** 1R21AI149190-01
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Paul R Carlier
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $228,271
- **Award type:** 1
- **Project period:** 2020-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9876321

## Citation

> US National Institutes of Health, RePORTER application 9876321, Interrogating plasmodial endocytosis with mefloquine-based affinity probes (1R21AI149190-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9876321. Licensed CC0.

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