# Selective Plasmodium proteasome inhibitors as novel multi-stage antimalarials

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $845,899

## Abstract

Project Summary/Abstract
Malaria control efforts are currently facing substantial challenges, primarily due to increasing drug resistance,
including the first-line drugs artemisinins. From 2018 to 2021, there was a noticeable increase in new malaria
cases, with the count rising from 237 million to 254 million, and the annual death toll surged from 567,000 to
617,000 in 2021. Over 90% of these cases and 96% of these deaths occurred in Sub-Saharan Africa, as
reported by the World Health Organization (WHO). Tragically, 80% of the mortalities were children under the
age of five. There is an urgent need for enhanced vector control measures and antimalarial drugs that are
prophylactic, therapeutic, and transmission blocking. The proteasome plays a crucial role in regulating various
cellular functions by degrading regulatory and damaged proteins. The proteasome is a well-established drug
target for cancer treatment, with three FDA-approved drugs, and for certain infectious diseases, with two in
clinical development. Malaria proteasome inhibitors have shown promise with killing activity against
Plasmodium parasites at multiple stages of their life cycle, including the challenging transmission and liver
stages. Therefore, a P. falciparum proteasome (Pf20S) inhibitor has potential to be a therapeutic, prophylactic,
and transmission-blocking agent. Moreover, Pf20S inhibitors demonstrate synergistic effects when combined
with artemisinins, making them even more appealing for malaria treatment. However, the development of orally
bioavailable Pf20S inhibitors that can minimize the emergence of resistance while maintaining high selectivity
for Pf20S over both the human constitutive proteasome and immunoproteasome presents a challenge. We
have achieved significant progress in pursuit of these goals for antimalarial proteasome inhibitors.
Furthermore, we have solved multiple cryo-EM structures of Pf20S with a β5 inhibitor, a β2 inhibitor, and a
nonpeptide inhibitor, providing valuable insights into structure-activity relationships, mechanisms of resistance
and collateral sensitivity. This application seeks to build upon these achievements by advancing our
development program for both peptide-based and nonpeptide-based proteasome inhibitors, with a focus on
enhancing potency, selectivity, and in vitro and in vivo pharmacokinetic properties to achieve oral
bioavailability. We will conduct iterative structure-activity relationship (SAR) studies for both peptide- and
nonpeptide-based Pf20S inhibitor series and assess their antimalarial activities at different parasite stages in
vitro, as well as their parasitemia-reducing capabilities in animal models of malarial infection.

## Key facts

- **NIH application ID:** 10981978
- **Project number:** 2R01AI143714-06
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Gang Lin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $845,899
- **Award type:** 2
- **Project period:** 2019-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981978

## Citation

> US National Institutes of Health, RePORTER application 10981978, Selective Plasmodium proteasome inhibitors as novel multi-stage antimalarials (2R01AI143714-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10981978. Licensed CC0.

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