UV-triggered Affinity Capture Identifies Interactions between the Plasmodium falciparum Multidrug Resistance Protein 1 (PfMDR1) and Antimalarial Agents in Live Parasitized Cells

• Published in: The Journal of biological chemistry Vol. 288; no. 31; pp. 22576 - 22583
• Main Authors: Brunner, Ralf, Ng, Caroline L., Aissaoui, Hamed, Akabas, Myles H., Boss, Christoph, Brun, Reto, Callaghan, Paul S., Corminboeuf, Olivier, Fidock, David A., Frame, Ithiel J., Heidmann, Bibia, Le Bihan, Amélie, Jenö, Paul, Mattheis, Corinna, Moes, Suzette, Müller, Ingrid B., Paguio, Michelle, Roepe, Paul D., Siegrist, Romain, Voss, Till, Welford, Richard W.D., Wittlin, Sergio, Binkert, Christoph
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.08.2013; American Society for Biochemistry and Molecular Biology
• Subjects: ACT-213615; Affinity Capture; Animals; Antimalarials - pharmacology; ATP Binding Cassette Transporter, Subfamily B, Member 1 - physiology; Drug Action; Mode of Action; Molecular Bases of Disease; Multidrug Transporters; PfMDR1; Photoaffinity Labeling; Plasmodium; Plasmodium falciparum - physiology; Protein Drug Interactions; Ultraviolet Rays; Mode of Action; Plasmodium; Photoaffinity Labeling; Protein Drug Interactions; ACT-213615; Drug Action; PfMDR1; Multidrug Transporters; Affinity Capture
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.453159

A representative of a new class of potent antimalarials with an unknown mode of action was recently described. To identify the molecular target of this class of antimalarials, we employed a photo-reactive affinity capture method to find parasite proteins specifically interacting with the capture compound in living parasitized cells. The capture reagent retained the antimalarial properties of the parent molecule (ACT-213615) and accumulated within parasites. We identified several proteins interacting with the capture compound and established a functional interaction between ACT-213615 and PfMDR1. We surmise that PfMDR1 may play a role in the antimalarial activity of the piperazine-containing compound ACT-213615. Background: We have previously identified potent novel antimalarial compounds with an unknown mode of action. Results: A photo-reactive affinity capture method was used to identify parasite proteins that interact with these antimalarials. Conclusion: ACT-213615 interacts with Plasmodium falciparum multidrug resistance protein 1 (PfMDR1). Significance: This photo-reactive affinity capture method can be generally used to identify drug targets in live cells.