In Silico Design of a Chimeric Humanized L-asparaginase.

Abstract

Acute lymphoblastic leukemia (ALL) is the most common cancer among children worldwide, characterized by an overproduction of undifferentiated lymphoblasts in the bone marrow. The treatment of choice for this disease is the enzyme L-asparaginase (ASNase) from bacterial sources. ASNase hydrolyzes circulating L-asparagine in plasma, leading to starvation of leukemic cells. The ASNase formulations of E. coli and E. chrysanthemi present notorious adverse effects, especially the immunogenicity they generate, which undermine both their effectiveness as drugs and patient safety. In this study, we developed a humanized chimeric enzyme from E. coli L-asparaginase which would reduce the immunological problems associated with current L-asparaginase therapy. For these, the immunogenic epitopes of E. coli L-asparaginase (PDB: 3ECA) were determined and replaced with those of the less immunogenic Homo sapiens asparaginase (PDB:4O0H). The structures were modeled using the Pymol software and the chimeric enzyme was modeled using the SWISS-MODEL service. A humanized chimeric enzyme with four subunits similar to the template structure was obtained, and the presence of asparaginase enzymatic activity was predicted by protein-ligand docking.

• Authors: Alejandro Pedroso, Lisandra Herrera Belén, Jorge F Beltrán, Rodrigo L Castillo, Adalberto Pessoa, Enrique Pedroso, Jorge G Farías
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 24 Issue 8 (Apr 20 2023) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 37108713 (Publication Type: Journal Article)

Chemical References

• Asparaginase
• Asparagine
• Recombinant Fusion Proteins
• Antineoplastic Agents

Topics

• Child
• Humans
• Asparaginase (genetics, therapeutic use)
• Escherichia coli (genetics)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy)
• Asparagine
• Recombinant Fusion Proteins (therapeutic use)
• Antineoplastic Agents (therapeutic use)