TY - JOUR
T1 - New insight on the structural features of the cytotoxic auristatins MMAE and MMAF revealed by combined NMR spectroscopy and quantum chemical modelling
AU - Johansson, Mikael P.
AU - Maaheimo, Hannu
AU - Ekholm, Filip S.
N1 - Funding Information:
We acknowledge financial support from the Walter and Lisi Wahl foundation, the Ruth and Nils-Erik Stenbäck foundation, and the Academy of Finland (project 289179). CSC—The Finnish IT Centre for Science provided ample computing resources. The authors further thank Tero Satomaa (Glykos Finland Ltd.) and Dr. Jari Helin (Glykos Finland Ltd.) for fruitful discussions.
Publisher Copyright:
© 2017 The Author(s).
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2017/11/21
Y1 - 2017/11/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85034787744&partnerID=8YFLogxK
U2 - 10.1038/s41598-017-15674-1
DO - 10.1038/s41598-017-15674-1
M3 - Article
AN - SCOPUS:85034787744
SN - 2045-2322
VL - 7
SP - 15920
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 15920
ER -
