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<p>L-asparaginase (L-ASNase) is an amidohydrolase with high therapeutic value for the treatment of acute lymphoblastic leukemia (ALL). However, its clinical application is limited by immunogenicity, allergenicity, and adverse effects from glutaminase activity. In this study, we engineered and characterized in silico chimeric variants of L-ASNase derived from <i>Penicillium cerradense</i>, aiming to reduce epitopes by replacing predicted T-cell epitopes with structurally and sequence-related fragments from human blood proteins while preserving catalytic activity. A multi-step computational workflow integrated sequence analysis, structural modeling, immunogenicity and allergenicity prediction, and molecular docking. More than 11,000 chimeric variants were generated and screened. Selected variants showed up to a 33% reduction in predicted allergenic potential compared to native <i>P. cerradense</i> L-ASNase, particularly for the HLA-DRB1*07:01 allele, which has been associated with hypersensitivity reactions. Molecular docking analyses indicated that three variants met ChemPLP criteria. The fitness scores were more than 25% higher than those observed for <i>Escherichia coli</i> L-ASNase, while preserving interactions with key catalytic residues. Overall, these results demonstrate that rational in silico engineering of chimeric L-ASNase variants using human blood protein fragments may reduce predicted immunogenicity and allergenicity while preserving catalytic features. As the first effort to humanize this enzyme using fragments from human blood proteins unrelated to L-ASNase, these variants represent promising candidates for validation.</p>

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A large-scale in silico chimera-based strategy for engineering low-immunogenic L-asparaginase from Penicillium cerradense

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月4日

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  • Joel A. Cordeiro de Abreu,
  • Jorge F. Beltrán,
  • Mauricio Homem-de-Mello,
  • Gabriel Mendonça de Souza,
  • Juliana Betini Fachini-Gomes,
  • Pérola de Oliveira Magalhães,
  • Jorge Farías Avendaño

摘要

L-asparaginase (L-ASNase) is an amidohydrolase with high therapeutic value for the treatment of acute lymphoblastic leukemia (ALL). However, its clinical application is limited by immunogenicity, allergenicity, and adverse effects from glutaminase activity. In this study, we engineered and characterized in silico chimeric variants of L-ASNase derived from Penicillium cerradense, aiming to reduce epitopes by replacing predicted T-cell epitopes with structurally and sequence-related fragments from human blood proteins while preserving catalytic activity. A multi-step computational workflow integrated sequence analysis, structural modeling, immunogenicity and allergenicity prediction, and molecular docking. More than 11,000 chimeric variants were generated and screened. Selected variants showed up to a 33% reduction in predicted allergenic potential compared to native P. cerradense L-ASNase, particularly for the HLA-DRB1*07:01 allele, which has been associated with hypersensitivity reactions. Molecular docking analyses indicated that three variants met ChemPLP criteria. The fitness scores were more than 25% higher than those observed for Escherichia coli L-ASNase, while preserving interactions with key catalytic residues. Overall, these results demonstrate that rational in silico engineering of chimeric L-ASNase variants using human blood protein fragments may reduce predicted immunogenicity and allergenicity while preserving catalytic features. As the first effort to humanize this enzyme using fragments from human blood proteins unrelated to L-ASNase, these variants represent promising candidates for validation.