# Selective Plasmodium proteasome inhibitors as novel multi-stage antimalarials

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $737,380

## Abstract

Project Summary/Abstract
Proteasome inhibitors kill Plasmodium spp. However, lack of malaria-specific proteasome inhibitors that
spare human proteasomes has so far precluded treating malaria with drugs like bortezomib, carfilzomib
and ixazomib, which have significant toxicity. There is an urgent need to develop malaria-specific
proteasome inhibitors. Our past work, including substrate profiling, enzymology, structure-guided
rational design and high throughput screening, led to discovery of the first species-selective
proteasome inhibitors (active against mycobacterial proteasomes but not human proteasomes) as well
as highly isoform-selective proteasome inhibitors (active against the human immunoproteasome but not
the human constitutive proteasome). Informed by those experiences, we collaborated with Dr. Laura
Kirkman, parasitologist and co-PI, to identify a novel class of compounds that kill P. falciparum in vitro
but spare mammalian cells. These compounds inhibit the P. falciparum proteasome (Pf20S) ?5 subunit
potently, noncovalently. The chemophore, subunit specificity, noncovalent reactivity and noncompetitive
mode of inhibition of these compounds are distinctive compared to a Pf20S ?2 inhibitor recently
reported by Bogyo's team, thereby offering an independent shot on goal against a well validated target,
an opportunity to overcome resistance to one agent by using the other, and the possibility of synergistic
results from using both, if they each lead to drugs. Our inhibitors are highly potent in inhibiting growth of
P. falciparum at erythrocytic, liver, and gametocyte stages and are equally effective against P.
falciparum isolates that are sensitive or resistant to current drugs. We have formed a novel
organizational structure to pool the resources of the Lin chemistry/enzymology lab and the Kirkman
parasitology lab (for which this support is requested) with the expertise of two major drug companies,
each donating services through not-for-profit organizations (Tri-I Therapeutics Discovery Institute and
its partner, Takeda Pharmaceuticals, and Tres Cantos Open Lab Foundation and its partner,
GlaxoSmithKline). We now aim to continue our team approach to advance the development of malarial
proteasome inhibitors as antimalarial drugs by improving their selectivity, specificity and pharmaceutical
properties. Specific Aim 1 optimizes the hit compound series through rational design and concise and
parallel synthesis, then determines their in vitro potency and selectivity, tests their anti-Plasmodium
potency at erythrocytic, gametocytic, and liver stages, and improves their in vitro and in vivo
pharmaceutical properties. Aim 2 investigates the mechanism of resistance to Pf20S inhibitors and the
synergy of Pf20S inhibitors with other anti-malarial drugs.

## Key facts

- **NIH application ID:** 10404078
- **Project number:** 5R01AI143714-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Gang Lin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $737,380
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10404078

## Citation

> US National Institutes of Health, RePORTER application 10404078, Selective Plasmodium proteasome inhibitors as novel multi-stage antimalarials (5R01AI143714-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10404078. Licensed CC0.

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