# Advancing Fast-acting Antimalarials that Disrupt Na+ Homeostasis in Parasites

> **NIH NIH R01** · DREXEL UNIVERSITY · 2022 · $741,091

## Abstract

Project Summary
For a foreseeable future antimalarial drugs will remain a mainstay for the management of malaria worldwide.
While the pipeline of new antimalarial compounds has begun to look promising in recent years, the specter of
drug resistance is always looming. This fact demands continued efforts to discover and develop new
antimalarial drugs. Among the promising new antimalarial compounds to emerge in recent years are those
that disrupt Na+ homeostasis in Plasmodium falciparum. Two of these compounds (a spiroindolone and a
dihydroisoquinolone) have progressed to Phase II clinical trials and have shown to be highly potent against P.
falciparum and P. vivax infections with in vivo parasite clearance times that are even faster than artemisinin,
the fastest acting antimalarial drug in use. Remarkably, at least 20 distinct chemical classes of compounds,
comprising ~8% of all antimalarials present in the Malaria and Pathogen Boxes distributed by Medicines for
Malaria Venture (MMV), also have the propensity to disrupt Na+ homeostasis in P. falciparum. Several lines of
evidence support the notion that all these compounds inhibit a parasite-encoded Na+-pumping P-type ATPase
named PfATP4. Thus, PfATP4 presents a highly attractive target for a very broad range of small molecules.
Extraordinarily fast clearance of parasites in vivo by PfATP4-active compounds holds the promise for these
compounds to emerge as potential replacement for artemisinin, something the world needs to be prepared for
given the potential spread of artemisinin treatment failures. While two PfATP4-active compounds have
advanced to clinical trials, the history of drug development advises prudence to explore back-up compounds to
account for pipeline attrition and mitigating chances of failure against a valuable target. It is with this
background that we are proposing here to conduct a medicinal chemistry campaign that would deliver
additional preclinical candidates that meet the stringent criteria advocated by MMV. Over the past decade we
have carried out extensive medicinal chemistry campaign to identify highly potent PfATP4-active compounds
that belong to different chemical classes than the two compounds under clinical investigations. We aim to
identify a pre-clinical candidate compound guided by potency, metabolic stability, physicochemical and
pharmacokinetic properties, in vivo efficacy in a humanized mouse model of P. falciparum infection and safety
studies. These studies will be allied with PK/PD simulations to ensure a compound that meets safety and
single dose criteria. We also propose to investigate the possibility of minimizing resistance emergence by
exploring the effects of targeting two different domains of PfATP4 by combination of distinct chemical scaffolds.

## Key facts

- **NIH application ID:** 10455481
- **Project number:** 5R01AI154499-03
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** Sandhya Kortagere
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $741,091
- **Award type:** 5
- **Project period:** 2020-08-12 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10455481

## Citation

> US National Institutes of Health, RePORTER application 10455481, Advancing Fast-acting Antimalarials that Disrupt Na+ Homeostasis in Parasites (5R01AI154499-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10455481. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*