Optimization of Species-Selective Reversible Proteasome Inhibitors for the Treatment of Malaria

  • J Med Chem. 2025 Nov 13;68(21):23485-23520. doi: 10.1021/acs.jmedchem.5c02394.
Suraksha Gahalawat  1 ,  Sneha Ray  1 ,  Xiaoyu Zhang  1 ,  Xiaoyi Deng  1 ,  Yan Han  2 ,  Zhe Chen  2 ,  Aloysus Lawong  1 ,  David M Shackleford  3 ,  Kasiram Katneni  3 ,  Gong Chen  3 ,  Peng Li  3 ,  Alice Ng  3 ,  Longjin Zhong  3 ,  Meiyu Hu  3 ,  Mitchell McInerney  3 ,  Wen Wang  3 ,  Jessica Saunders  3 ,  Daniel Collins  3 ,  Jaya Jayaseelan  3 ,  Cassandra L Noack  3 ,  Bikash C Maity  4 ,  Nirupam De  4 ,  Benoît Laleu  5 ,  Simon F Campbell  5 ,  Margaret A Phillips  1 ,  Susan A Charman  3 ,  Joseph M Ready  1
Affiliations
  • 1. Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas 75390, United States.
  • 2. Department of Biophysics, UT Southwestern Medical Center, Dallas, Texas 75390, United States.
  • 3. Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
  • 4. TCG Lifesciences Pvt. Ltd., Kolkata 700091, West Bengal, India.
  • 5. MMV Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, 1215 Geneva, Switzerland.
PMID: 41148577 DOI: 10.1021/acs.jmedchem.5c02394
Abstract

Malaria remains a critical global health challenge, with increasing resistance to frontline therapies necessitating novel drug targets. The Proteasome has emerged as a promising target for antimalarial drug discovery. This study describes efforts to optimize a series of species-selective reversible inhibitors targeting the Plasmodium falciparum 20S Proteasome. Starting from the carboxypiperidine scaffold identified through a high-throughput viability screen, we conducted iterative structure-activity relationship studies, leading to the development of highly potent and selective inhibitors with good oral bioavailability. Lead compounds demonstrated nanomolar potency against P. falciparum blood-stage parasites and selective inhibition of the parasite Proteasome over the human counterpart. Cryo-EM structural studies confirmed binding at the β5 subunit, while in vivo pharmacokinetic studies identified promising candidates for further development. These findings support Proteasome inhibition as a viable strategy for novel antimalarial drug development.

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