Gearing antimalarial lactate transport inhibitors for the clinical phase

• Applicant: Professor Dr. Eric Beitz
• Subject Area: Pharmacy
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 387280051

Malaria parasites draw vital energy from anaerobic glycolysis in the erythrocytes of the host. Per glucose, two lactate anions and two protons are generated as waste that need to be rapidly released from the parasite to prevent lethal acidification. We discovered the missing Plasmodium lactate/H+ transporter as a member of the exclusively microbial format-nitrite transporter family, FNT, and validated it as a novel antimalarial drug target. Screening of an antimalarial compound library with unknown targets, yielded specific and potent FNT-inhibitors, i.e. pentafluoro-3-hydroxy-pent-2-en-1-ones. The recent Plasmodium falciparum FNT cryo-electron microscopy structure confirmed our proposed binding mode. In the previous funding period, we developed this novel class of antimalarials and established sub-micromolar in vitro activity at low toxicity for human cells. We also showed in vivo potency in mouse malaria models. Our compound cleared 99.9% of the parasites and led to longer survival times of the mice after four consecutive oral doses than the current commercial drug artesunate. We just achieved another breakthrough in terms of potency by adding a para-substituent to the common pyridine ring of our compounds via a secondary amine moiety. This increased the in vitro activity by a factor of 20 reaching 15 nM EC50 against cultured parasites, yet at the cost of metabolic stability. In the proposed project, we will address the introduced weak spot in the secondary amine line of FNT inhibitors to render them metabolically stable by generating bioisosteres such as anilides, ketons or secondary alcohols. We will also evaluate if the vinylogous acid moiety can be replaced by alternatives such as sulfonacylamides or phosphinates to increase the acid strength of the compounds and, thus, affinity. In order to work towards the current aim in antimalaria therapy shifting to a single-shot long-acting injectable to overcome compliance issues, we will test if the FNT inhibitors can be turned into prodrugs via esterification of the vinylogous acid by long-chain alcohols. Several other protozoa besides malaria parasites express FNTs, such as human pathogenic Toxoplasma gondii, Entamoeba histolytica, and Naegleria fowleri parasites. We have cloned the FNT-encoding DNAs, and will assay our inhibitor compounds to evaluate their putative use against other parasitic infections. We envision the new compounds to conclude the pre-clinical development of FNT-inhibitors as a novel regime to treat malaria and other protozoan infections.

• DFG Programme: Research Grants