New insight on the structural features of the cytotoxic auristatins MMAE and MMAF revealed by combined NMR spectroscopy and quantum chemical modelling

Mikael P. Johansson, Hannu Maaheimo, Filip S. Ekholm

    Research output: Contribution to journalArticleScientificpeer-review

    7 Citations (Scopus)

    Abstract

    Antibody-drug conjugates (ADCs) are emerging as a promising class of selective drug delivery systems in the battle against cancer and other diseases. The auristatins monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) appear as the cytotoxic drug in almost half of the state-of-the-art ADCs on the market or in late stage clinical trials. Here, we present the first complete NMR spectroscopic characterisation of these challenging molecules, and investigate their structural properties by a combined NMR and quantum chemical modelling approach. We find that in solution, half of the drug molecules are locked in an inactive conformation, severely decreasing their efficiency, and potentially increasing the risk of side-effects. Furthermore, we identify sites susceptible to future modification, in order to potentially improve the performance of these drugs.

    Original languageEnglish
    Article number15920
    Pages (from-to)15920
    JournalScientific Reports
    Volume7
    Issue number1
    DOIs
    Publication statusPublished - 21 Nov 2017
    MoE publication typeA1 Journal article-refereed

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