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TitleAn Optimized Route to the Syringolin Natural Products Enables Combinatorial Synthesis of Selective, Bioactive Inhibitors of the 20S Proteasome.
Journal, issue, pagesJ Med Chem, Year 2026
Publish dateApr 1, 2026
AuthorsXilin Gu / Pavla Fajtova / Nicholas L Yan / Aditi Saxena / Fan Fei / Jiyun Zhu / Eric Tse / Arthur Melo / Euna Yoo / Nathan H Buchwald / Daniel R Southworth / Matthew Bogyo / Joseph L Derisi / Jason E Gestwicki / Anthony J O'Donoghue / Jason K Sello /
PubMed AbstractThe syringolin natural products are covalent inhibitors of the 20S proteasome that inspire therapeutic development. Here, we report a new route to the syringolins amenable to solution and solid-phase ...The syringolin natural products are covalent inhibitors of the 20S proteasome that inspire therapeutic development. Here, we report a new route to the syringolins amenable to solution and solid-phase synthesis that overcomes a problematic macrocyclization. Exploiting our synthetic approach and substrate mimicry models for proteasome inhibition by the syringolins, we generated a collection of hypothetically selective inhibitors of the proteasome, which is an emerging target for antimalarial drugs. We identified compounds from the library having high second-order rate constants for proteasome inhibition and nanomolar antiparasitic activity. They exhibited selectivity for the proteasome over the human proteasome. We solved cryo-EM structures of an inhibitor bound to both 20S proteasomes, revealing key contacts favoring species-selective inhibition. Together, this work provides an improved route to syringolin analogs, sheds new light on substrate mimicry by the syringolins, and provides a structural basis for the pursuit of new antimalarial drugs.
External linksJ Med Chem / PubMed:41921688
MethodsEM (single particle)
Resolution2.6 - 2.7 Å
Structure data

73509

9yuy

EMDB-73509, PDB-9yuy:
Structure of the Plasmodium falciparum 20S proteasome in complex with a beta5-selective covalent syringolin analogue inhibitor.
Method: EM (single particle) / Resolution: 2.7 Å

73510

9yuz

EMDB-73510, PDB-9yuz:
Structure of the human 20S proteasome in complex with a beta5-selective covalent syringolin analogue inhibitor.
Method: EM (single particle) / Resolution: 2.6 Å

Chemicals

PDB-1cy6:
COMPLEX OF E.COLI DNA TOPOISOMERASE I WITH 3' THYMIDINE MONOPHOSPHATE

PDB-1cy5:
CRYSTAL STRUCTURE OF THE APAF-1 CARD

Source
  • plasmodium falciparum 3d7 (eukaryote)
  • homo sapiens (human)
KeywordsHYDROLASE / Proteasome / 20S / Inhibitor / Plasmodium / Covalent

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