Nobutaka Kato

Abstract Malaria, caused by the parasite Plasmodium falciparum, remains a significant global health threat, with multidrug resistance posing a major challenge to treatment. The P-glycoprotein homolog P. falciparum Multidrug Resistance Protein 1 (PfMDR1) is a key determinant of resistance to first-line antimalarials like mefloquine (MFQ) and chloroquine.

Highlights • Crystal structure of glucose-bound PfHT1 was determined at 2.6-Å resolution • Crystal structure of PfHT1 bound to a selective inhibitor, C3361, was elucidated • C3361 binding induces a pocket that can be employed for inhibitor optimization • Rational design yielded more potent selective inhibitors with low cytotoxicity Summary Plasmodium species, the causative agent of malaria, rely on glucose for energy supply during blood stage.

Abstract Antimalarial drugs have thus far been chiefly derived from two sources—natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections.