# Compounds that force Plasmodium falciparum to produce its own inhibitors

> **NIH NIH R21** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $211,875

## Abstract

Project Summary/Abstract
Though curable, malaria is a persistent global health crisis, with over 200 million debilitating cases a
year and half a million deaths, mostly in children under five. Plasmodium falciparum (Pf) has developed
resistance to all antimalarials, including the mainstay artemisinins (ARTs). ART and its semi-synthetic
analogs are considered essential for malaria treatment. ART resistance is widespread in Southeast
Asia and there are increasing reports of ART resistance in Africa. Combination therapy is a backbone
for treatment of tuberculosis, cancer, HIV and malaria. Despite the huge success of the combination
therapy, its efficaciousness can be derailed as a two-drug combination can become de facto
monotherapy under certain unavoidable situations. Moreover, extended exposure of Pf to ART induces
multidrug tolerance. We recently showed that inhibitors specific for Pf proteasome (Pf20S) can kill Pf in
each stage of its life cycle and synergize with ART, overcoming ART resistance. In this proposal, we
hypothesize that what we call an artezomib (ATZ) – a covalent hybrid of an ART analogue and a Pf20S
inhibitor – can enhance ART action and minimize the emergence of resistance to both components. We
predict that Pf will active the ART component of ATZ, which, like ART itself, will bind to Pf proteins;
Pf20S will generate ATZ-modified oligopeptides; and the peptides' extended contact with the Pf20S
active site will augment the binding of the Pf20S inhibitor component of ATZ and overcome the
decreased binding that might result from Pf20S point mutations. Consistent with this, we have
synthesized ATZs that are more potent Pf20S inhibitors than their component Pf20S inhibitor, and
these ATZs are potent against wild type, Pf20S inhibitor-resistant and ART-resistant K13 Pf. We now
aim to explore the mechanism of action of AZTs and develop more drug-like AZTs with a long
residence time on target so as to kill parasites when they exit the stage of their life cycle in which they
are intrinsically resistant to ARTs.

## Key facts

- **NIH application ID:** 10037851
- **Project number:** 1R21AI153485-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Gang Lin
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $211,875
- **Award type:** 1
- **Project period:** 2020-05-22 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10037851

## Citation

> US National Institutes of Health, RePORTER application 10037851, Compounds that force Plasmodium falciparum to produce its own inhibitors (1R21AI153485-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10037851. Licensed CC0.

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