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. 2023 Nov;76(11):642-649.
doi: 10.1038/s41429-023-00655-6. Epub 2023 Sep 20.

Sheptide A: an antimalarial cyclic pentapeptide from a fungal strain in the Herpotrichiellaceae

Robert A Shepherd  1 , Cody E Earp  1 , Kristof B Cank  1 , Huzefa A Raja  1 , Joanna Burdette  2 , Steven P Maher  3 , Adriana A Marin  3 , Anthony A Ruberto  3 , Sarah Lee Mai  3 , Blaise A Darveaux  4 , Dennis E Kyle  3 , Cedric J Pearce  4 , Nicholas H Oberlies  5
Affiliations

Sheptide A: an antimalarial cyclic pentapeptide from a fungal strain in the Herpotrichiellaceae

Robert A Shepherd et al. J Antibiot (Tokyo). 2023 Nov.

Abstract

As part of ongoing efforts to isolate biologically active fungal metabolites, a cyclic pentapeptide, sheptide A (1), was discovered from strain MSX53339 (Herpotrichiellaceae). The structure and sequence of 1 were determined primarily by analysis of 2D NMR and HRMS/MS data, while the absolute configuration was assigned using a modified version of Marfey's method. In an in vitro assay for antimalarial potency, 1 displayed a pEC50 value of 5.75 ± 0.49 against malaria-causing Plasmodium falciparum. Compound 1 was also tested in a counter screen for general cytotoxicity against human hepatocellular carcinoma (HepG2), yielding a pCC50 value of 5.01 ± 0.45 and indicating a selectivity factor of ~6. This makes 1 the third known cyclic pentapeptide biosynthesized by fungi with antimalarial activity.

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Conflict of interest statement

The authors declare the following competing financial interest(s): NHO, CJP and HAR are members of the Scientific Advisory Board of Clue Genetics, Inc. NHO is also a member of the Scientific Advisory Boards of Mycosynthetix, Inc and Ionic Pharmaceuticals, LLC.

Figures

Fig. 1
Fig. 1
Structure and amino acid sequence of the cyclic pentapeptide, sheptide A (1)
Fig. 2
Fig. 2
Key 2D NMR correlations for sheptide A (1)
See this image and copyright information in PMC

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