Title: Design, Synthesis, and Biochemical Evaluation of Alpha‐Amanitin Derivatives Containing Analogs of the trans‐Hydroxyproline Residue for Potential Use in Antibody‐Drug Conjugates.
Authors: Matinkhoo, Kaveh; Wong, Antonio A. W. L.; Hambira, Chido M.; Kato, Brandon; Wei, Charlie; Müller, Christoph; Hechler, Torsten; Braun, Alexandra; Gallo, Francesca; Pahl, Andreas; Perrin, David M.
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.
Subjects: ANTIBODY-drug conjugates; STRUCTURE-activity relationships; TOXINS
Publication: Chemistry - A European Journal, 2021, Vol 27, Issue 40, p10282
ISSN: 0947-6539
Publication type: Academic Journal
DOI: 10.1002/chem.202101373

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

Matinkhoo, Kaveh; Wong, Antonio A. W. L.; Hambira, Chido M.; Kato, Brandon; Wei, Charlie; Müller, Christoph; Hechler, Torsten; Braun, Alexandra; Gallo, Francesca; Pahl, Andreas; Perrin, David M.