Bioinformatic Prediction and Experimental Validation of a PE38-Based Recombinant Immunotoxin Targeting the Fn14 Receptor in Cancer Cells

Keshtvarz, Maryam; Salimian, Jafar; Yaseri, Mehdi; Bathaie, S. Zahra; Rezaie, Ehsan; Aliramezani, Amir; Norouzbabaei, Zahra; Amani, Jafar; Douraghi, Masoumeh

doi:10.2217/imt-2017-0008

Cited by 21 publications

(8 citation statements)

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“…Tertiary structure of the fusion protein by C-score -3.36 contained the highest C-score. In this study, ASGGPE and (G4S)3 linkers were used to isolate different segments (37). In another study, we designed and analyzed TGFαL3-SEB fusion protein that were optimized by CAI index 0.85 and by GC content 44.06% the overall stability of mRNA increased.…”

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confidence: 99%

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

et al. 2019

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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 cytotoxic agents with these types of anticancer agents may 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 them with toxic molecules. Objectives: Pseudomonas exotoxin A (PE), ricin toxin (RT), and others in very minor quantities can be more potent and biologically active for this purpose. Methods: In this study, we used trastuzumab as a ligand for HER2 receptor along with 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 eradication was observed. An in silico method was used before the in vitro study to illustrate the properties and construction of the protein. Physicochemical properties, structure, stability, and ligand-receptor interaction of this chimeric protein were predicted by means 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 new antitumor candidate in cancer therapy. The results suggested that s1 and p2 were stable fusion proteins with accurate affinity to the overexpressed receptors making them potential candidates for inducing apoptosis in breast cancer cells.

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confidence: 99%

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

et al. 2019

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“…They declared that this recombinant mut 1 IT (with IC50 5.o3 and 0.2 pM for ch-hep-3 and ch-hep-1, respectively) specifically killed tumor cells in mice, with a weak induction of VLS. Moreover, using the KDEL motif instead of EDLK in this immunotoxin probably has been affective in its high cytotoxicity, as shown in our previous studies on PE38 with [92,93] or without [94] KDEL motif-based immunotoxin. The authors suggested that mut 1 could be presented as a novel and effective candidate of PE-based immunotoxin for use against SM5-1 binding positive cells such as HCC cells.…”

Section: Anti-hcc Immunotoxinsmentioning

confidence: 71%

Immunotoxins Immunotherapy against Hepatocellular Carcinoma: A Promising Prospect

Heiat

Yeganeh

Alavian

et al. 2021

Toxins

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Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. Therefore, fighting against such cancer is reasonable. Chemotherapy drugs are sometimes inefficient and often accompanied by undesirable side effects for patients. On the other hand, the emergence of chemoresistant HCC emphasizes the need for a new high-efficiency treatment strategy. Immunotoxins are armed and rigorous targeting agents that can purposefully kill cancer cells. Unlike traditional chemotherapeutics, immunotoxins because of targeted toxicity, insignificant cross-resistance, easy production, and other favorable properties can be ideal candidates against HCC. In this review, the characteristics of proper HCC-specific biomarkers for immunotoxin targeting were dissected. After that, the first to last immunotoxins developed for the treatment of liver cancer were discussed. So, by reviewing the strengths and weaknesses of these immunotoxins, we attempted to provide keynotes for designing an optimal immunotoxin against HCC.

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“…The highest C-score of -3.36 observed in tertiary structure of the fusion protein. For isolating two parts of the proteins, the ASGGPE and (G4S) 3 linkers were recruited (45).…”

Section: Discussionmentioning

confidence: 99%

Designing and Analyzing the Structure of DT-STXB Fusion Protein as an Anti-tumor Agent: An in Silico Approach

et al. 2019

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Background & Objective:A main contest in chemotherapy is to obtain regulator above the biodistribution of cytotoxic drugs. The utmost promising strategy comprises of drugs coupled with a tumor-targeting bearer that results in wide cytotoxic activity and particular delivery. The B-subunit of Shiga toxin (STxB) is nontoxic and possesses low immunogenicity that exactly binds to the globotriaosylceramide (Gb3/CD77). Gb3/CD77 extremely expresses on a number of human tumors such as pancreatic, colon, and breast cancer and acts as a functional receptor for Shiga toxin (STx). Then, this toxin can be applied to target Gb3-positive human tumors. In this study, we evaluated DT390-STXB chimeric protein as a new anti-tumor candidate via genetically fusing the DT390 fragment of DT538 (Native diphtheria toxin) to STxB.Methods:This study intended to investigate the DT390- STxB fusion protein structure in silico. Considering the Escherichia coli codon usage, the genomic construct was designed. The properties and the structure of the protein were determined by an in silico technique. The mRNA structure and the physicochemical characteristics, construction, and the stability of the designed chimeric protein were analyzed using computational and bioinformatics tools and servers. Hence, the GOR4 and I-TASSER online web servers were used to predict the secondary and tertiary structures of the designed protein.Results:The results demonstrated that codon adaptation index (CAI) of dt390-stxB chimeric gene raised from 0.6 in the wild type to 0.9 in the chimeric optimized gene. The mfold data revealed that the dt390-stxB mRNA was completely stable to be translated effectively in the novel host. The normal activity of the fusion protein determined by considering the secondary and tertiary structure of each construct. Energy calculation data indicated that the thermodynamic ensemble for mRNA structure was -427.40 kJ/mol. The stability index (SI) of DT390-STxB was 36.95, which is quite appropriate to preserve the stability of the construct. Ultimately, the DT390-STxB was classified as a steady fusion protein according to the Ramachandran plot. Conclusion:Our results showed that DT390-STXB was a stable chimeric protein and it can be recruited as a candidate of novel anti-tumor agents for the development of breast cancer treatment.

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Bioinformatic Prediction and Experimental Validation of a PE38-Based Recombinant Immunotoxin Targeting the Fn14 Receptor in Cancer Cells

Abstract: Coupled with bioinformatics, experimental approaches revealed that PE38-P4A8 could be used as a promising therapeutic agent for cancer cells expressing Fn14.

Cited by 21 publications

References 59 publications

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

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

Immunotoxins Immunotherapy against Hepatocellular Carcinoma: A Promising Prospect

Designing and Analyzing the Structure of DT-STXB Fusion Protein as an Anti-tumor Agent: An in Silico Approach

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