Structures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors

Hao-Chi Hsu, Daqiang Li, Wenhu Zhan, Jianxiang Ye, Yi Jing Liu, Annie Leung, Junling Qin, Benigno Crespo, Francisco-Javier Gamo, Hao Zhang, Liwang Cui, Alison Roth, Laura A. Kirkman, Huilin Li () and Gang Lin ()
Additional contact information
Hao-Chi Hsu: Van Andel Institute
Daqiang Li: Weill Cornell Medicine
Wenhu Zhan: Weill Cornell Medicine
Jianxiang Ye: Weill Cornell Medicine
Yi Jing Liu: Weill Cornell Medicine
Annie Leung: Weill Cornell Medicine
Junling Qin: University of South Florida
Benigno Crespo: GlaxoSmithKline
Francisco-Javier Gamo: GlaxoSmithKline
Hao Zhang: Weill Cornell Medicine
Liwang Cui: University of South Florida
Alison Roth: Experimental Therapeutics Branch, The Walter Reed Army Institute of Research
Laura A. Kirkman: Weill Cornell Medicine
Huilin Li: Van Andel Institute
Gang Lin: Weill Cornell Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract 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 β6 subunit, A117D, confers resistance to TDI-8304, yet enhances both enzyme inhibition and anti-parasite activity of a tripeptide vinyl sulfone β2 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 Pf20Sβ6A117D 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 β2 and β5 in wild type Pf20S as well as WLW-vs binds β2 and β5 in Pf20Sβ6A117D. 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.

Date: 2023
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DOI: 10.1038/s41467-023-44077-2

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