Reducing the Immunogenicity of Pulchellin A-Chain, Ribosome-Inactivating Protein Type 2, by Computational Protein Engineering for Potential New Immunotoxins

Reza Maleki, Libing Fu, Ricardo Sobhie Diaz, Francisco Eduardo Gontijo Guimarães, Otávio Cabral-Marques, Gustavo Cabral-Miranda () and Mohammad Sadraeian ()
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Reza Maleki: Adelaide Medical School, University of Adelaide, Adelaide 5005, Australia
Libing Fu: Institute for Biomedical Materials and Devices (IBMD), Faculty of Science, University of Technology Sydney, Sydney 2007, Australia
Ricardo Sobhie Diaz: Laboratório de Retrovirologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04039-032, Brazil
Francisco Eduardo Gontijo Guimarães: Instituto de Física de São Carlos, Universidade de São Paulo, Caixa Postal 369, São Carlos 13560-970, Brazil
Otávio Cabral-Marques: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo (ICB/USP), São Paulo 05508-000, Brazil
Gustavo Cabral-Miranda: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo (ICB/USP), São Paulo 05508-000, Brazil
Mohammad Sadraeian: Institute for Biomedical Materials and Devices (IBMD), Faculty of Science, University of Technology Sydney, Sydney 2007, Australia

J, 2023, vol. 6, issue 1, 1-17

Abstract: Pulchellin is a plant biotoxin categorized as a type 2 ribosome-inactivating protein (RIPs) which potentially kills cells at very low concentrations. Biotoxins serve as targeting immunotoxins (IT), consisting of antibodies conjugated to toxins. ITs have two independent protein components, a human antibody and a toxin with a bacterial or plant source; therefore, they pose unique setbacks in immunogenicity. To overcome this issue, the engineering of epitopes is one of the beneficial methods to elicit an immunological response. Here, we predicted the tertiary structure of the pulchellin A-chain (PAC) using five common powerful servers and adopted the best model after refining. Then, predicted structure using four distinct computational approaches identified conformational B-cell epitopes. This approach identified some amino acids as a potential for lowering immunogenicity by point mutation. All mutations were then applied to generate a model of pulchellin containing all mutations (so-called PAM). Mutants’ immunogenicity was assessed and compared to the wild type as well as other mutant characteristics, including stability and compactness, were computationally examined in addition to immunogenicity. The findings revealed a reduction in immunogenicity in all mutants and significantly in N146V and R149A. Furthermore, all mutants demonstrated remarkable stability and validity in Molecular Dynamic (MD) simulations. During docking and simulations, the most homologous toxin to pulchellin, Abrin-A was applied as a control. In addition, the toxin candidate containing all mutations (PAM) disclosed a high level of stability, making it a potential model for experimental deployment. In conclusion, by eliminating B-cell epitopes, our computational approach provides a potential less immunogenic IT based on PAC.

Keywords: pulchellin A-chain (PAC); ribosome-inactivating protein (RIPs); immunotoxin (IT); immunogenicity; B-cell epitopes; molecular docking; molecular dynamic (MD) simulation (search for similar items in EconPapers)
JEL-codes: I1 I10 I12 I13 I14 I18 I19 (search for similar items in EconPapers)
Date: 2023
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