Development of Semisynthetic Blasticidin S Analogs with Potent and Fast-Killing Antimalarial Activity

Protein synthesis represents an attractive target space for the development of antimalarials with novel modes of action. Natural-product inhibitors of the eukaryotic 80S ribosome can have potent antimalarial activity but are often poorly selective due to mammalian cytotoxicity. Blasticidin S is a microbially produced natural product that broadly inhibits prokaryotic and eukaryotic protein synthesis by binding to the ribosomal peptidyl transferase center. In this study, we explored the potential for improving the antimalarial potency and selectivity of the blasticidin S scaffold with semisynthetic analogs that are modified at the C6' and C4 sites. The two best analogs were 2 orders of magnitude more potent than blasticidin S against Plasmodium falciparum drug-sensitive and -resistant lines while displaying low cytotoxicity toward mammalian cells. These analogs exhibited improved kinetics of inhibition of protein synthesis in cultured parasites and arrested asexual development after the onset of plasmodial surface anion channel expression, a transporter required for nutrient acquisition and blasticidin S uptake. They also exhibited a dramatically improved speed of killing over blasticidin S. Molecular docking analysis revealed that these analogs are able to form more interactions with the P. falciparum ribosomal peptidyl transferase center than is blasticidin S, which is consistent with their increased potency. Together, these studies demonstrate the feasibility of generating blasticidin S analogs with potent antimalarial activity and provide a roadmap for further development.