BioCentury
ARTICLE | Distillery Therapeutics

Infectious disease

August 29, 2018 5:50 PM UTC

In vitro, cell culture and mouse studies identified asparagine ethylenediamine-based inhibitors of Plasmodium falciparum proteasome subunit β type 5 that could help treat malarial infection. Screening of a library of tool compound proteasome inhibitors and in vitro enzymatic activity assays identified seven asparagine ethylenediamine-based compounds that inhibited P. falciparum proteasome subunit β type 5 with IC50 values of 2-115 nM. In P. falciparum cultures, one of the compounds decreased viability compared with the generic antimalarial atovaquone, with potency comparable to Daraprim pyrimethamine. In a mouse model of P. yoelii infection, a second proteasome subunit β type 5 inhibitor plus a tool compound that inhibits P. falciparum proteasome subunit β type 2 decreased parasitemia compared with either agent alone. Next steps could include optimizing and testing the compounds in additional animal models of malaria infection...