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

Autor: Amaral JL; Department of Biochemistry and Molecular Biology, Federal University of Ceará, Fortaleza, Ceará, CEP 60.440-554, Brazil; Department of Physics, Federal University of Ceará, Fortaleza, Ceará, CEP 60.440-970, Brazil. Electronic address: jacksoncesarc@gmail.com., Santos SJM; Federal Institute of Education, Science and Technology of Rio Grande Do Sul, Feliz, Rio Grande Do Sul, CEP 95770-000, Brazil., Souza PFN; Department of Biochemistry and Molecular Biology, Federal University of Ceará, Fortaleza, Ceará, CEP 60.440-554, Brazil., de Morais PA; Federal Institute of Education, Science and Technology of Ceará, Horizonte, Ceará, CEP 62.884-105, Brazil., Maia FF Jr; Department of Nature Sciences, Mathematics and Statistics, Federal Rural University of Semi-arid, Mossoró, Rio Grande Do Norte, CEP 59.625-900, Brazil., Carvalho HF; Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas, SP, CEP 13.083-862, Brazil., Freire VN; Department of Physics, Federal University of Ceará, Fortaleza, Ceará, CEP 60.440-970, Brazil.
Jazyk: angličtina
Zdroj: Molecular immunology [Mol Immunol] 2020 Nov; Vol. 127, pp. 203-211. Date of Electronic Publication: 2020 Oct 01.
DOI: 10.1016/j.molimm.2020.09.013
Abstrakt: 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.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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