An Optimized Route to the Syringolin Natural Products Enables Combinatorial Synthesis of Selective, Bioactive Inhibitors of the <i> <i>Plasmodium falciparum</i> </i> 20S Proteasome
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.
Authors
- Matthew S. Bogyo (ORCID: https://orcid.org/0000-0003-3753-4412)
- Aditi Saxena (ORCID: https://orcid.org/0000-0001-5736-5180)
- Euna Yoo (ORCID: https://orcid.org/0000-0001-5982-1979)
- Pavla Fajtová (ORCID: https://orcid.org/0000-0002-4029-0706)
- Nathan H. Buchwald
- Eric Tse (ORCID: https://orcid.org/0000-0002-2082-9006)
- Jiyun Zhu (ORCID: https://orcid.org/0000-0002-8861-5450)
- N. Yan (ORCID: https://orcid.org/0000-0003-4978-550X)
- Jason K. Sello (ORCID: https://orcid.org/0000-0001-6263-7902)
- Jason E. Gestwicki (ORCID: https://orcid.org/0000-0002-6125-3154)
- Daniel R. Southworth (ORCID: https://orcid.org/0000-0001-7108-9389)
- Xilin Gu (ORCID: https://orcid.org/0000-0002-5441-7958)
- Arthur Melo
- Joseph L. Derisi
- Fan Fei
- Anthony J. O’Donoghue
Institutions
- Harvard University (US)
- John Brown University (US)
- German Center for Neurodegenerative Diseases (DE)
- University of California System (US)
- University of California San Diego (US)
- Universidad Católica de Santa Fe (AR)
- Chan Zuckerberg Initiative (United States) (US)
- Stanford Medicine (US)
- Center for Cancer Research (US)
- Stanford University (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-04-01
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c03223
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Defense
- National Institutes of Health