2. Academic Validation
  3. Design, Synthesis, and Biochemical Evaluation of Alpha-Amanitin Derivatives Containing Analogs of the trans-Hydroxyproline Residue for Potential Use in Antibody-Drug Conjugates

Design, Synthesis, and Biochemical Evaluation of Alpha-Amanitin Derivatives Containing Analogs of the trans-Hydroxyproline Residue for Potential Use in Antibody-Drug Conjugates

  • Chemistry. 2021 Jul 16;27(40):10282-10292. doi: 10.1002/chem.202101373.
Kaveh Matinkhoo 1,  Antonio A W L Wong 1,  Chido M Hambira 1,  Brandon Kato 1,  Charlie Wei 1,  Christoph Müller 2,  Torsten Hechler 2,  Alexandra Braun 2,  Francesca Gallo 2,  Andreas Pahl 2,  David M Perrin 1
Affiliations

Affiliations

  • 1 Chemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, V6T-1Z1, Canada.
  • 2 Heidelberg Pharma, Gregor-Mendel-Straße 22, 68526, Ladenburg, Germany.
PMID: 34058032 DOI: 10.1002/chem.202101373
Abstract

Alpha-amanitin, an extremely toxic bicyclic octapeptide extracted from the death-cap mushroom, Amanita phalloides, is a highly selective allosteric inhibitor of RNA polymerase II. Following on growing interest in using this toxin as a payload in antibody-drug conjugates, herein we report the synthesis and biochemical evaluation of several new derivatives of this toxin to probe the role of the trans-hydroxyproline (Hyp), which is known to be critical for toxicity. This structure activity relationship (SAR) study represents the first of its kind to use various Hyp-analogs to alter the conformational and H-bonding properties of Hyp in amanitin.

Keywords

Amanitin; amatoxin; antibody-drug conjugates; hydroxyproline; peptides.

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