dc.contributor.author
Sallandt, Laura L.
dc.contributor.author
Wolf, Clemens A.
dc.contributor.author
Schuster, Sabine
dc.contributor.author
Enke, Heike
dc.contributor.author
Enke, Dan
dc.contributor.author
Wolber, Gerhard
dc.contributor.author
Niedermeyer, Timo H. J.
dc.date.accessioned
2025-01-29T12:48:09Z
dc.date.available
2025-01-29T12:48:09Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/45329
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-45041
dc.description.abstract
Microcystins, a large family of nonribosomal cyclic heptapeptides known for their hepatotoxicity, are among the best-studied cyanobacterial toxins. Recently, they have been discussed as leads for the development of anticancer drug substances. Their main mode-of-action is inhibition of the eukaryotic serine/threonine protein phosphatases 1 and 2A. Unlike many cytotoxins that can cross cell membranes by passive diffusion, microcystins depend on active uptake via organic anion transporting polypeptides 1B1 or 1B3. Both phosphatase inhibition and transportability strongly depend on the structure of the individual microcystin. Here, we present how chemical modification of positions 2 and 4 of the microcystin core structure can alter these two properties. Aiming to reduce transportability and increase phosphatase inhibition, we used pharmacophore modeling to investigate the phosphatase inhibition potential of microcystins derivatized with small molecules containing a variety of functional groups. The respective derivatives were synthesized using click chemistry. We discovered that some derivatized microcystins can address a yet undescribed subpocket of the protein phosphatase 1. The derivatized microcystins were tested for phosphatase 1 inhibition and cytotoxicity on transporter-expressing cell lines, revealing that target inhibition and transportability of microcystins can independently be influenced by the physicochemical properties, especially of the residue located in position 2 of the microcystin. Derivatization with small acids or amino acids resulted in microcystins with a favorable ratio of inhibition to transportability, making these derivatives potentially suitable for drug development.
en
dc.format.extent
12 Seiten
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
Noncovalent interactions
en
dc.subject
Peptides and proteins
en
dc.subject
Reaction products
en
dc.subject
Surface analysis
en
dc.subject.ddc
500 Naturwissenschaften und Mathematik::570 Biowissenschaften; Biologie::570 Biowissenschaften; Biologie
dc.title
Derivatization of Microcystins Can Increase Target Inhibition while Reducing Cellular Uptake
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.doi
10.1021/acs.jnatprod.4c00688
dcterms.bibliographicCitation.journaltitle
Journal of Natural Products
dcterms.bibliographicCitation.number
1
dcterms.bibliographicCitation.pagestart
3
dcterms.bibliographicCitation.pageend
14
dcterms.bibliographicCitation.volume
88
dcterms.bibliographicCitation.url
https://doi.org/10.1021/acs.jnatprod.4c00688
refubium.affiliation
Biologie, Chemie, Pharmazie
refubium.affiliation.other
Institut für Pharmazie

refubium.funding
ACS Publications
refubium.note.author
Die Publikation wurde aus Open Access Publikationsgeldern der Freien Universität Berlin gefördert.
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.isPartOf.eissn
1520-6025