# NIH grant: Development of covalent PI4K inhibitors to treat malaria (1R21AI201386-01) — retained record

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[original source ↗](https://reporter.nih.gov/project-details/1R21AI201386-01)

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NIH grant 1R21AI201386-01: Development of covalent PI4K inhibitors to treat malaria
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Daniel Patrick Flaherty. Award: $239023.
Start: 2026-08-21T00:00:00.
Project Summary:
 Malaria is caused by the eukaryotic protozoan Plasmodium parasites, transmitted to humans via Anopheles
mosquitoes. Despite mitigating strategies, malaria remains a global health problem. In 2021, there were an
estimated 247 million cases of malaria worldwide, resulting in 619,000 deaths. A major barrier to malaria
elimination and eradication is decreased antimalarial therapeutic efficacy due to parasite-mediated drug
resistance. Alarmingly, Plasmodium parasites have gained resistance to every clinically-used antimalarial,
including dihydroartemisinin, the most potent antimalarial in our therapeutic armamentarium. Thus, there is a
significant need for novel therapeutic targets and molecular scaffolds with uncompromised modes of action for
antimalarial drug discovery. PI4KIIIβ was validated as an antimalarial therapeutic target with previous drug
discovery campaigns developing reversible small molecule inhibitors, some that reached clinical testing. Our
team has identified a molecular scaffold that inhibits PI4KIIIβ via an irreversible mechanism of action and
discovered that the Plasmodium PI4KIIIβ contains a nucleophilic cysteine residue that can be exploited for drug
design. This proposal will capitalize on this discovery to carry out hit-to-lead optimization of high priority scaffolds
against Plasmodium species. We hypothesize that the alternative mechanism of action of the irreversible
inhibitors will be able to overcome liabilities observed from the aforementioned reversible inhibitors that made it
to clinical trials, including lack of off-target kinase selectivity. The project will evaluate the ability of covalent
irreversible PI4KIIIβ inhibitors to evade resistance and also solve the PI4KIIIβ crystal structure for the first time.
Ultimately, the project will seek to nominate up to two lead molecules to be evaluated for in vivo efficacy to
validate the novel mechanism of action for new antimalarials.
```



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