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TitleOptimization of Species-Selective Reversible Proteasome Inhibitors for the Treatment of Malaria.
Journal, issue, pagesJ Med Chem, Vol. 68, Issue 21, Page 23485-23520, Year 2025
Publish dateNov 13, 2025
AuthorsSuraksha Gahalawat / Sneha Ray / Xiaoyu Zhang / Xiaoyi Deng / Yan Han / Zhe Chen / Aloysus Lawong / David M Shackleford / Kasiram Katneni / Gong Chen / Peng Li / Alice Ng / Longjin Zhong / Meiyu Hu / Mitchell McInerney / Wen Wang / Jessica Saunders / Daniel Collins / Jaya Jayaseelan / Cassandra L Noack / Bikash C Maity / Nirupam De / Benoît Laleu / Simon F Campbell / Margaret A Phillips / Susan A Charman / Joseph M Ready /
PubMed AbstractMalaria 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 ...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 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 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.
External linksJ Med Chem / PubMed:41148577 / PubMed Central
MethodsEM (single particle)
Resolution2.28 - 2.79 Å
Structure data

70077

9o3e

EMDB-70077, PDB-9o3e:
Plasmodium falciparum 20S proteasome bound to inhibitor 159
Method: EM (single particle) / Resolution: 2.79 Å

70078

9o3f

EMDB-70078, PDB-9o3f:
Plasmodium falciparum 20S proteasome bound to inhibitor 296
Method: EM (single particle) / Resolution: 2.28 Å

Chemicals

PDB-1b74:
GLUTAMATE RACEMASE FROM AQUIFEX PYROPHILUS

PDB-1b73:
GLUTAMATE RACEMASE FROM AQUIFEX PYROPHILUS

Source
  • plasmodium falciparum 3d7 (eukaryote)
KeywordsCYTOSOLIC PROTEIN / Malaria / Plasmodium falciparum / proteasome / drug discovery / CYTOSOLIC PROTEIN-INHIBITOR complex

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