Rationally Designed Amanitins Achieve Enhanced Cytotoxicity

For 70 years, α-amanitin, the most cytotoxic peptide in its class, has been without a synthetic rival; through synthesis, we address the structure–activity relationships to inform the design of new amatoxins and disclose analogues that are more cytotoxic than the natural product when evaluated on CH...

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Bibliographic Details
Published inJournal of medicinal chemistry Vol. 65; no. 15; pp. 10357 - 10376
Main Authors Todorovic, Mihajlo, Rivollier, Paul, Wong, Antonio A. W. L., Wang, Zhou, Pryyma, Alla, Nguyen, Tuan Trung, Newell, Kayla C., Froelich, Juliette, Perrin, David M.
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 11.08.2022
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
RNA-POLYMERASE-II
TRANSLOCATION
INHIBITION
PEPTIDES
STRUCTURAL BASIS
ANALOGS
ALPHA-AMANITIN
TRANSCRIPTION
TRYPTATHIONINE
AMATOXINS
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Summary:For 70 years, α-amanitin, the most cytotoxic peptide in its class, has been without a synthetic rival; through synthesis, we address the structure–activity relationships to inform the design of new amatoxins and disclose analogues that are more cytotoxic than the natural product when evaluated on CHO, HEK293, and HeLa cells, whereas on liver-derived HepG2 cells, the same toxins show diminished cytotoxicity.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.1c02226