Quantum biochemistry in cancer immunotherapy: New insights about CTLA-4/ipilimumab and design of ipilimumab-derived peptides with high potential in cancer treatment

Quantum biochemistry in cancer immunotherapy: New insights about CTLA-4/ipilimumab and design of ipilimumab-derived peptides with high potential in cancer treatment

•Quantum Biochemistry revealed new aspects of CTLA-4:Ipilimumab interaction in detail.•The CTLA-4:Ipilimumab complex is stabilized by Ionic, aromatic-aromatic, aromatic-sulfur, and cation-pi interactions.•Ipilimumab-derived cyclic peptides are more resistant to proteolysis than both Ipilimumab heavy...

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Bibliographic Details
Published in:Molecular immunology Vol. 127; pp. 203 - 211
Main Authors: Amaral, Jackson L., Santos, Samuel J.M., Souza, Pedro F.N., de Morais, Pablo A., Maia, F.F., Carvalho, Hernandes F., Freire, Valder N.
Format: Journal Article
Language:English
Published: Elsevier Ltd 01-11-2020
Subjects:
Cancer
Checkpoint proteins
Immunotherapy
Immunotherapy
Checkpoint proteins
Cancer
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Summary:•Quantum Biochemistry revealed new aspects of CTLA-4:Ipilimumab interaction in detail.•The CTLA-4:Ipilimumab complex is stabilized by Ionic, aromatic-aromatic, aromatic-sulfur, and cation-pi interactions.•Ipilimumab-derived cyclic peptides are more resistant to proteolysis than both Ipilimumab heavy and light chains. Cancer is a group of diseases involving disordered growth of abnormal cells with the potential to invade and spread to other parts of the body. Today, immunotherapy is the most efficient treatment, with fewer side effects. Notably, the employment of monoclonal antibodies to inhibit checkpoint proteins, such as CTLA-4, has caused much excitement among cancer immunotherapy researchers. Thus, in-depth analysis through quantum biochemistry and molecular dynamics simulations was performed to understand the complex formed by ipilimumab and its target CTLA-4. Our computational results provide a better understanding of the binding mechanisms and new insights about the CTLA-4: ipilimumab interaction, identifying essential amino acid residues to support the complex. Additionally, we report new interactions such as aromatic-aromatic, aromatic-sulfur, and cation-pi interactions to stabilize the CTLA-4:ipilimumab complex. Finally, quantum biochemistry analyses reveal the most important amino acid residues involved in the CTLA-4:ipilimumab interface, which were used to design synthetic peptides to inhibit CTLA-4. The computational results presented here provide a better understanding of the CTLA-4:ipilimumab binding mechanisms, and can support the development of alternative antibody-based drugs with high relevance in cancer immunotherapy.
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ISSN:0161-5890
1872-9142
DOI:10.1016/j.molimm.2020.09.013