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

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 alre...

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Published in:Angewandte Chemie International Edition 2023-08, Vol.62 (31), p.e202303202-n/a
Main Authors: Cerofolini, Linda, Vasa, Kristian, Bianconi, Elisa, Salobehaj, Maria, Cappelli, Giulia, Bonciani, Alice, Licciardi, Giulia, Pérez‐Ràfols, Anna, Padilla‐Cortés, Luis, Antonacci, Sabrina, Rizzo, Domenico, Ravera, Enrico, Viglianisi, Caterina, Calderone, Vito, Parigi, Giacomo, Luchinat, Claudio, Macchiarulo, Antonio, Menichetti, Stefano, Fragai, Marco
Format: Article
Language:English
Subjects:
Antitumor agents
Cancer therapies
Conjugates
Crystallography
Cytotoxicity
Drug Delivery
Drug Design
Drug development
Dynamic stability
Macromolecules
NMR
NMR Spectroscopy
Nuclear magnetic resonance
Organic compounds
Protein-Drug Conjugates
Proteins
Structural Biology
Thermophoresis
Transthyretin
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Summary: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. A new molecule that results from the conjugation of the cytotoxic Paclitaxel and Tafamidis, and maintains a high affinity for human transthyretin, demonstrates the potential contribution of solid‐state NMR to the structure‐based design of novel protein‐drug conjugates.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202303202