# Discovery of Novel Antimalarial Leads Targeting Translational Repression in Plasmodium parasites

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $239,484

## Abstract

Abstract
The malaria parasite Plasmodium falciparum is responsible for an estimated 200 million cases of disease and
nearly 500,000 deaths annually, while Plasmodium vivax infects another 70-390 million people annually and is
associated with relapsing infection. While antimalarial drug discovery has seen increased attention in recent
years, a serious threat is posed by multi-drug resistant parasites, and particularly the artemisinin-resistant, K13
mutant strains observed clinically in Southeast Asia. Our long-term objective is to develop new antimalarial
agents that target translation repression in Plasmodium parasites to counter these emerging threats.
In Plasmodium parasites, as in higher eukaryotes, translation repression is conferred by the phosphorylated
form of the initiation factor PfeIF2 (i.e., PfeIF2α-P) which inhibits its own guanine exchange factor PfeIF2B.
Translation repression is required for blood stages to complete the erythrocytic cycle and has recently been
shown to play a role in the enhanced stress response observed in K13 mutant ring stages. Beyond this,
translation repression is required for latency in sporozoites, and likely also in dormant, liver-stage hypnozoites
that cause relapsing infection by P. vivax. Unfortunately, a general lack of useful pharmacological tools has
hampered studies of these wider-ranging effects of translation repression in relevant cellular and animal
models. Here we propose a lead identification effort focused on two complementary targets in the parasite
stress response pathway, the PfeIF2α kinase PfPK4 and the guanine exchange factor PfeIF2B (the predicted
GEF for PfeIF2α). Based on strong preliminary data, we predict that either PK4 inhibition or GEF activation
will inhibit translation repression and that these two pharmacologies will be synergistic in the pathway.
The expected outcome of the project is specific PK4 inhibitors and PfeIF2B activators with bona fide on-
pathway activity in parasites. In addition to providing tractable lead compounds for further lead discovery
efforts, the project will generate crucial pharmacological tools that can be used to study the broader-ranging
roles of translation repression in malaria infectivity, dormancy, and transmission outside the scope of this
project.

## Key facts

- **NIH application ID:** 9857532
- **Project number:** 5R21AI135495-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Adam R Renslo
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $239,484
- **Award type:** 5
- **Project period:** 2019-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857532

## Citation

> US National Institutes of Health, RePORTER application 9857532, Discovery of Novel Antimalarial Leads Targeting Translational Repression in Plasmodium parasites (5R21AI135495-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9857532. Licensed CC0.

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