Synthetic Diastereomers of the Fungal Cycloheptapeptide Paraisariamide A Retain Ternatin-Like Biological Activity.

Authors

Sophia E Bonar, Daphne R Mattos, Takumi Arai, Yui Tagami, Dean A Buch, Richard M Tehan, Kerry L McPhail, Shinya Oishi, Jane E Ishmael

Published in

ACS medicinal chemistry letters. Volume 17. Issue 8. Pages 1787-1794. Aug 13, 2026. Epub Jul 01, 2026.

Abstract

Paraisariamides (Psds) are a family of fungal N-methylated cyclic heptapeptides with structural similarity to the translation eukaryotic elongation factor 1A inhibitor ternatin. Initial characterization of the eight known Psds A-H revealed a complex biological activity profile; Psd A and Psds E-H showed differential cytotoxicity to HCT116 colon cancer cells, whereas Psds B-D were inactive. Here, we report that Psd A is a weak inhibitor of total protein synthesis and that three synthetic diastereomers of Psd A retain comparable pharmacological activity. Psd A and all structural variants decreased the level of expression of extracellular Gaussia luciferase in a phenotypic assay that senses endoplasmic reticulum stress in living cells. Inhibition of cellular secretion was fully reversible; however, the three Psd A diastereomers were all eventually cytotoxic to HCT116 colon cancer cells. The stereochemistry of Psd A, a weak cytotoxin relative to Psds E-H, is anticipated to inform future structure-activity relationship studies of these ternatin-like molecules.

PMID:
42622016
Bibliographic data and abstract were imported from PubMed on 20 Aug 2026.

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