Computational Study of Interspecies TOP2A Similarities for Further Development of New Double Targeted Therapeutic Immunoconjugates

摘要

Targeted therapies are a growing research area with important implications inveterinary and human health. DNA topoisomerase 2-alpha (TOP2A) is over-expressed inhighly proliferative cells and represents the molecular target of the anticancer quinones(anthracycline antibiotics and naphthoquinones). The purpose of this study is to identifyinterspecies TOP2A similarities as possible epitopes for further development of therapeuticimmunoconjugates with multiple species reactivity: Mus musculus (Ms), Rattus norvegicus(R) and Homo sapiens (H). The main idea is to make possible testing the same therapeuticimmunoconjugates (with various quinones as active substance) on main species used aslaboratory animals before clinical trials. Moreover, in this case, TOP2A acts as double target:first as epitope for a specific antibody and second as molecular target for quinones. This paperused NCBI Reference Sequences and NCBI Blastp Suite to finds regions of similaritybetween protein sequences of H-TOP2A (NP_001058.2) as query sequence, and Ms-TOP2A(NP_035753.2) and R-TOP2A (NP_071519.2) as blasts hits. An overview of the two blastsequences aligned to the query sequence is shown in Fig. 1.Results and colour-codes indicate that both blast hits are in the range of bestalignments with query sequence. Reliabilities of alignments are high predicting goodsimilarities between structures of the three isomerases. It is highly probable that quinoneshave inhibitor activities on all three species and antibody to have interspecies reactivity.Acknowledgments. This study has been financed by Romanian Ministry of Educationand Research, National Authority for Scientific Research, National Centre for ProgrammesManagement on Grant Agreement no. 61-002/2007 (Project no. 1885/2007): Obtaining andcharacterization of new targeted-nanodrugs with naphthoquinonic active substance.