Susceptibilities of Ugandan Plasmodium falciparum Isolates to Proteasome Inhibitors.

ABSTRACT: The proteasome is a promising target for antimalarial chemotherapy. We assessed ex vivo susceptibilities of fresh Plasmodium falciparum isolates from eastern Uganda to seven proteasome inhibitors: two asparagine ethylenediamines, two macrocyclic peptides, and three peptide boronates; five had median IC₅₀ values <100 nM. TDI8304, a macrocylic peptide lead compound with drug-like properties, had a median IC₅₀ of 16 nM. Sequencing genes encoding the β2 and β5 catalytic proteasome subunits, the predicted targets of the inhibitors, and five additional proteasome subunits, identified two mutations in β2 (I204T, S214F), three mutations in β5 (V2I, A142S, D150E), and three mutations in other subunits. The β2 S214F mutation was associated with decreased susceptibility t

SUBMITTER: Garg S 

PROVIDER: S-EPMC9578402 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature