Covalent Macrocyclic Proteasome Inhibitors Mitigate Resistance in <i>Plasmodium falciparum</i>.

ABSTRACT: The Plasmodium proteasome is a promising antimalarial drug target due to its essential role in all parasite lifecycle stages. Furthermore, proteasome inhibitors have synergistic effects when combined with current first-line artemisinin and related analogues. Linear peptides that covalently inhibit the proteasome are effective at killing parasites and have a low propensity for inducing resistance. However, these scaffolds generally suffer from poor pharmacokinetics and bioavailability. Here we describe the development of covalent, irreversible, macrocyclic inhibitors of the Plasmodium falciparum proteasome. We identified compounds with excellent potency and low cytotoxicity; however, the first generation suffered from poor microsomal stability. Further optimization of an exist

SUBMITTER: Bennett JM 

PROVIDER: S-EPMC10591878 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature