8g6f

Publication Abstract from PubMed

The proteasome of the malaria parasite Plasmodium falciparum (Pf20S) is an advantageous drug target because its inhibition kills P. falciparum in multiple stages of its life cycle and synergizes with artemisinins. We recently developed a macrocyclic peptide, TDI-8304, that is highly selective for Pf20S over human proteasomes and is potent in vitro and in vivo against P. falciparum. A mutation in the Pf20S beta6 subunit, A117D, confers resistance to TDI-8304, yet enhances both enzyme inhibition and anti-parasite activity of a tripeptide vinyl sulfone beta2 inhibitor, WLW-vs. Here we present the high-resolution cryo-EM structures of Pf20S with TDI-8304, of human constitutive proteasome with TDI-8304, and of Pf20Sbeta6(A117D) with WLW-vs that give insights into the species selectivity of TDI-8304, resistance to it, and the collateral sensitivity associated with resistance, including that TDI-8304 binds beta2 and beta5 in wild type Pf20S as well as WLW-vs binds beta2 and beta5 in Pf20Sbeta6(A117D). We further show that TDI-8304 kills P. falciparum as quickly as chloroquine and artemisinin and is active against P. cynomolgi at the liver stage. This increases interest in using these structures to facilitate the development of Pf20S inhibitors that target multiple proteasome subunits and limit the emergence of resistance.

Structures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors.,Hsu HC, Li D, Zhan W, Ye J, Liu YJ, Leung A, Qin J, Crespo B, Gamo FJ, Zhang H, Cui L, Roth A, Kirkman LA, Li H, Lin G Nat Commun. 2023 Dec 14;14(1):8302. doi: 10.1038/s41467-023-44077-2. PMID:38097652^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.