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. 2023 Aug 1;62(31):e202303202.
doi: 10.1002/anie.202303202. Epub 2023 Jun 22.

Combining Solid-State NMR with Structural and Biophysical Techniques to Design Challenging Protein-Drug Conjugates

Linda Cerofolini  1   2   3 , Kristian Vasa  3 , Elisa Bianconi  4 , Maria Salobehaj  1   2   3 , Giulia Cappelli  3 , Alice Bonciani  3 , Giulia Licciardi  1   2   3 , Anna Pérez-Ràfols  1   5 , Luis Padilla-Cortés  1   2   3 , Sabrina Antonacci  1   3 , Domenico Rizzo  1   2   3 , Enrico Ravera  1   2   3 , Caterina Viglianisi  3 , Vito Calderone  1   2   3 , Giacomo Parigi  1   2   3 , Claudio Luchinat  1   2   3   5 , Antonio Macchiarulo  4 , Stefano Menichetti  3 , Marco Fragai  1   2   3
Affiliations

Combining Solid-State NMR with Structural and Biophysical Techniques to Design Challenging Protein-Drug Conjugates

Linda Cerofolini et al. Angew Chem Int Ed Engl. .

Abstract

Several protein-drug conjugates are currently being used in cancer therapy. These conjugates rely on cytotoxic organic compounds that are covalently attached to the carrier proteins or that interact with them via non-covalent interactions. Human transthyretin (TTR), a physiological protein, has already been identified as a possible carrier protein for the delivery of cytotoxic drugs. Here we show the structure-guided development of a new stable cytotoxic molecule based on a known strong binder of TTR and a well-established anticancer drug. This example is used to demonstrate the importance of the integration of multiple biophysical and structural techniques, encompassing microscale thermophoresis, X-ray crystallography and NMR. In particular, we show that solid-state NMR has the ability to reveal effects caused by ligand binding which are more easily relatable to structural and dynamical alterations that impact the stability of macromolecular complexes.

Keywords: Drug Delivery; Drug Design; NMR Spectroscopy; Protein-Drug Conjugates; Structural Biology.

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References

    1. P. Akkapeddi, S.-A. Azizi, A. M. Freedy, P. M. S. D. Cal, P. M. P. Gois, G. J. L. Bernardes, Chem. Sci. 2016, 7, 2954-2963.
    1. R. V. J. Chari, M. L. Miller, W. C. Widdison, Angew. Chem. Int. Ed. 2014, 53, 3796-3827.
    1. J. M. Harris, R. B. Chess, Nat. Rev. Drug Discovery 2003, 2, 214-221.
    1. P. Caravan, N. J. Cloutier, M. T. Greenfield, S. A. McDermid, S. U. Dunham, J. W. M. Bulte, J. C. Amedio, R. J. Looby, R. M. Supkowski, W. D. Horrocks, T. J. McMurry, R. B. Lauffer, J. Am. Chem. Soc. 2002, 124, 3152-3162.
    1. J. Huang, B. Wu, Z. Zhou, S. Hu, H. Xu, Y. Piao, H. Zheng, J. Tang, X. Liu, Y. Shen, Nanomedicine: Nanotechnol. Biol. Med. 2019, 21, 102058.

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