# Identification of antimalarial drugs and bradykinin as ligands of the Plasmodium membrane protein PfSR10

## TL;DR

This study identifies PfSR10 as a receptor for antimalarial drugs and bradykinin, revealing its role in malaria drug action and host-parasite communication.

## Contribution

The novel contribution is the discovery that PfSR10 is a dual receptor for antimalarial drugs and host peptides, with implications for malaria treatment.

## Key findings

- Antimalarial drugs like chloroquine and artemisinin activate PfSR10 signaling.
- Bradykinin is an endogenous agonist of PfSR10.
- Key residues in PfSR10 are defined for drug binding.

## Abstract

Malaria caused by Plasmodium falciparum remains a public health issue, yet direct targets of antimalarial drugs remain elusive. Membrane proteins in Plasmodium are potential drug targets and may contribute to pathophysiological processes in malaria. Recent studies show that the serpentine receptor SR10 is essential for coordinating host rhythms during parasite development. In this study, we found that antimalarial drugs including chloroquine (CQ), dihydroartemisinin (DHA), piperaquine-tetraphosphatetetrahydrate (PIP-TT), and primaquine diphosphate (PQ) are PfSR10 agonists that induce coupling with human Gi/Gq proteins, confirmed through biochemical reconstitution and cryo-EM analysis. Using proteomic profiling, we also identified bradykinin as an endogenous agonist activating PfSR10. Ligand binding and conformational changes were characterized via mutagenesis and FlAsH-BRET assays. These results establish PfSR10 as a receptor for both antimalarials and host peptides, highlighting its dual role in drug action and host-parasite communication, with broad implications in understanding malaria pathogenesis and developing new therapeutics.

•PfSR10 constitutively couples with human Gi and Gq proteins•Diverse antimalarial drugs directly activate PfSR10 signaling•Key PfSR10 residues defined for antimalarial drug binding•Host-derived bradykinin is identified as an endogenous agonist of PfSR10

PfSR10 constitutively couples with human Gi and Gq proteins

Diverse antimalarial drugs directly activate PfSR10 signaling

Key PfSR10 residues defined for antimalarial drug binding

Host-derived bradykinin is identified as an endogenous agonist of PfSR10

Natural sciences; Biological sciences; Biochemistry; Microbiology