Viability Screen of LOPAC1280 Reveals Tyrosine Kinase Inhibitor Tyrphostin A9 as a Novel Partner Drug for Artesunate Combinations to Target the Plasmodium falciparum Ring Stage [Experimental Therapeutics]

The emergence of artemisinin-resistant P. falciparum poses a major threat to current frontline artemisinin combination therapies. Artemisinin resistance is widely associated with mutations in the PfKelch13 propeller region leading to delayed parasite clearance and increased survival of early ring stage parasites. There is therefore a need to discover novel drugs that are effective against artemisinin-resistant P. falciparum. In view of this, our study aims to identify compounds from the Library of Pharmacologically Active Compounds¹²⁸⁰ (LOPAC¹²⁸⁰) that could increase the efficacy of artesunate and be used as a potential partner drug for treatment against artemisinin-resistant falciparum malaria. By using a modified ring stage survival assay, we performed a high throughput screening of 1280 compounds from the LOPAC library in combination with artesunate against P. falciparum IPC 5202 field isolate harboring R539T mutation at the PfKelch13 propeller region. The potencies of the hits were determined through dose-dependent isobologram analyses against both IPC 5202 and CamWT_C580Y field isolates; the latter with more prevalent C580Y mutation characteristic of artemisinin resistance. We identified tyrphostin A9 with synergistic and additive activity against both parasite strains when dosed in combination with artesunate. These findings provide promising novel artesunate combinations that can target the P. falciparum artemisinin resistant ring stage and insights that may aid in a better understanding of the mechanism involved in ART resistance.

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