Optimization of Species-Selective Reversible Proteasome Inhibitors for the Treatment of Malaria
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 <i>Plasmodium falciparum</i> 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 <i>P. falciparum</i> 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.
Authors
- Benoı̂t Laleu (ORCID: https://orcid.org/0000-0002-7530-2113)
- Margaret A. Phillips (ORCID: https://orcid.org/0000-0001-5250-5578)
- Aloysus K. Lawong (ORCID: https://orcid.org/0000-0002-3367-4883)
- Cassandra L. Noack
- Kasiram Katneni
- David M. Shackleford (ORCID: https://orcid.org/0000-0002-8229-6591)
- Jessica Saunders
- Suraksha Gahalawat (ORCID: https://orcid.org/0000-0002-8004-0322)
- Mitchell P. McInerney (ORCID: https://orcid.org/0009-0001-1411-3650)
- Daniel Collins (ORCID: https://orcid.org/0000-0002-4826-1889)
- Jaya Jayaseelan
- Peng Li (ORCID: https://orcid.org/0000-0002-3939-1585)
- Yan Han (ORCID: https://orcid.org/0000-0002-1207-7756)
- Susan A. Charman (ORCID: https://orcid.org/0000-0003-1753-8213)
- Nirupam De (ORCID: https://orcid.org/0000-0002-6328-2610)
- S. Ray (ORCID: https://orcid.org/0000-0001-6649-956X)
- Long‐Jin Zhong (ORCID: https://orcid.org/0000-0003-4682-1157)
- Joseph M. Ready (ORCID: https://orcid.org/0000-0003-1305-9581)
- Gong Chen (ORCID: https://orcid.org/0000-0002-1857-3670)
- Xiaoyu Zhang (ORCID: https://orcid.org/0000-0002-0637-5669)
- Zhe Chen (ORCID: https://orcid.org/0000-0002-1668-4051)
- Wen Wang (ORCID: https://orcid.org/0000-0002-5812-6744)
- Xiaoyi Deng (ORCID: https://orcid.org/0000-0001-8827-4812)
- Bikash C. Maity
- Simon F. Campbell
- Alice Ng
- Meiyu Hu
Institutions
- Australian Regenerative Medicine Institute (AU)
- Southwestern Medical Center (US)
- TCG Lifesciences (India) (IN)
- Southwestern Medical Center (US)
- Medicines for Malaria Venture (CH)
- Monash University (AU)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-10-28
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02394
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00