In Silico Evaluation of Two Targeted Chimeric Proteins Based on Bacterial Toxins for Breast Cancer Therapy.

Background: Despite major advances in cancer research, breast cancer still remains the most common cancer in women. Breast cancer is a heterogeneous disease, including at least 5 subtypes. Overexpression of human epidermal growth factor receptor 2 (HER2) in the patients denotes poor prognosis leading to a reduced survival rate compared to other subtypes of breast cancer. Therefore, HER2 can be a potential therapeutic target. To enhance the potency of HER2 blockers, the conjugation of specific cyto- toxic agentswith these types of anticancer agentsmay be successful. Application of antibody-based agents are important emerging anticancer therapies. One novel approach to increase the potency of monoclonal antibodies (mAbs) is combining themwith toxic molecules. Objectives: Pseudomonas exotoxin A (PE), ricin toxin (RT), and others in veryminor quantities can bemore potent and biologically active for this purpose. Methods: In this study,we used trastuzumab as a ligand forHER2 receptor alongwith Pseudomonas exotoxin A (PE38) and A subunit of Shiga toxin 2a (Stx2a). This fusion protein selectively bound to the HER2 receptor. Upon uptake by the target cells, apoptosis and cell eradicationwas observed. An in silicomethodwas used before the in vitro study to illustrate the properties and construction of theprotein. Physicochemicalproperties, structure, stability, andligand-receptor interactionof this chimericproteinwerepredicted bymeans of computational and bioinformatics tools and servers. Results: The results of this study showed that codon adaptation index of s1 and p2 fusion gene has improved to 0.98 and .99, respectively. The mfold result has revealed that s1 and p2 mRNA were stable sufficient for efficient translation in the new host. Based on Ramachandran plot, s1 and p2 were categorized as constant fusion protein. Conclusions: Finally, based on docking software analysis, the binding ability of Herceptin was robust enough to its receptor, so these constructs could be assigned as a newantitumor candidate in cancer therapy. The results suggested that s1 and p2were stable fusion proteins with accurate affinity to the overexpressed receptorsmaking thempotential candidates for inducing apoptosis in breast cancer cells. [ABSTRACT FROM AUTHOR]