Structure-Activity Relationship Study of Antimalarial Asparagine-Derived Proteasome Inhibitors.

Authors

Hao Zhang, Daqiang Li, Hao-Chi Hsu, Akshay Vishwanatha, Wenhu Zhan, Takafumi Yukawa, Joseph Visone, Toshihiro Imaeda, Rei Okamoto, Pavla Fajtova, Ryoma Hara, Masanori Kawasaki, Kenjiro Sato, Mayako Michino, Shreeya Garg, Oriana Kreutzfeld, Patrick K Tumwebaze, Stephen Orena, Martin Okitwi, Kazuyoshi Aso, Roland A Cooper, Philip J Rosenthal, Peter T Meinke, Michael Foley, Anthony J O'Donoghue, Huilin Li, Laura A Kirkman, Gang Lin

Published in

ACS omega. Volume 11. Issue 30. Pages 45549-45559. Aug 04, 2026. Epub Jul 21, 2026.

Abstract

Malaria remains a significant global health threat, affecting millions of lives each year. The causative agents, Plasmodium parasites, are highly resilient and have developed resistance to nearly all existing antimalarial drugs. The Plasmodium 20S proteasome core (Pf20S), a central component of the parasite's proteostasis pathway, has emerged as a promising therapeutic target. Inhibiting Pf20S effectively suppresses parasite growth at multiple stages of the parasite life cycle, synergizes with artemisinin-based therapies, and shows no cross-resistance with other antimalarial drug classes. Previously, we identified a novel class of proteasome inhibitors with potent activity against Pf20S, which we subsequently optimized for improved potency and selectivity over human proteasomes. However, these inhibitors exhibited suboptimal pharmacokinetic properties, potentially attributable to a high number of rotatable bonds and hydrogen bond donors. Here, we describe further optimization of this inhibitor class and provide structural insights into Pf20S-inhibitor interactions. Cryo-EM structural studies reveal a novel binding pose of the inhibitor at the Pf20S β5 active site, explaining the enhanced activity of an N-cap sulfonamide modification compared to an N-cap amide. These findings offer insights into the development of next-generation antimalarial Pf20S-targeting compounds with improved drug-like properties.

PMID:
42569042
Bibliographic data and abstract were imported from PubMed on 08 Aug 2026.

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