Applying Bioinformatic Tools for Modeling and Modifying Type II E. coli l-Asparginase to Present a Better Therapeutic Agent/Drug for Acute Lymphoblastic Leukemia

Mahboobi, Mahdieh; Sedighian, Hamid; Hedayati, Mojtaba; Bambai, Bijan; Soofian, Saeed Esmaeil; Amani, Jafar

doi:10.5812/ijcm.5785

Cited by 22 publications

(19 citation statements)

References 35 publications

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“…Therefore, from the QbD perspective, a reduction in immunogenicity would result in an improved quality profile. Studies involving bioinformatics analysis, antigenic peptide prediction, prediction of B-cell epitopes and site-directed mutagenesis were carried out and revealed numerous B-cell epitopes on the surface of E. coli ASNase II which are accountable for immunogenicity (Jianhua et al, 2006; Mehta et al, 2014; Mahboobi et al, 2017). To overcome this limitation, several ASNase variants have been created.…”

Section: Protein Engineering For Improvement Of L-asparaginase Therapmentioning

confidence: 99%

Development of L-Asparaginase Biobetters: Current Research Status and Review of the Desirable Quality Profiles

Brumano

Silva

Costa-Silva

et al. 2019

Front. Bioeng. Biotechnol.

144

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L-Asparaginase (ASNase) is a vital component of the first line treatment of acute lymphoblastic leukemia (ALL), an aggressive type of blood cancer expected to afflict over 53,000 people worldwide by 2020. More recently, ASNase has also been shown to have potential for preventing metastasis from solid tumors. The ASNase treatment is, however, characterized by a plethora of potential side effects, ranging from immune reactions to severe toxicity. Consequently, in accordance with Quality-by-Design (QbD) principles, ingenious new products tailored to minimize adverse reactions while increasing patient survival have been devised. In the following pages, the reader is invited for a brief discussion on the most recent developments in this field. Firstly, the review presents an outline of the recent improvements on the manufacturing and formulation processes, which can severely influence important aspects of the product quality profile, such as contamination, aggregation and enzymatic activity. Following, the most recent advances in protein engineering applied to the development of biobetter ASNases (i.e., with reduced glutaminase activity, proteolysis resistant and less immunogenic) using techniques such as site-directed mutagenesis, molecular dynamics, PEGylation, PASylation and bioconjugation are discussed. Afterwards, the attention is shifted toward nanomedicine including technologies such as encapsulation and immobilization, which aim at improving ASNase pharmacokinetics. Besides discussing the results of the most innovative and representative academic research, the review provides an overview of the products already available on the market or in the latest stages of development. With this, the review is intended to provide a solid background for the current product development and underpin the discussions on the target quality profile of future ASNase-based pharmaceuticals.

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Section: Protein Engineering For Improvement Of L-asparaginase Therapmentioning

confidence: 99%

Development of L-Asparaginase Biobetters: Current Research Status and Review of the Desirable Quality Profiles

Brumano

Silva

Costa-Silva

et al. 2019

Front. Bioeng. Biotechnol.

144

View full text Add to dashboard Cite

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“…3D models of chimeric protein have been created by i-Tasser, uploaded to the Swiss-PdbViewer server to describe the tertiary structural illustrations (32).…”

Section: Tertiary Structural Prediction For the Chimeric Proteinmentioning

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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“…The identification of immunogenic epitopes in the protein structure by computational tools has been a strategy used to achieve a reduction in the immunogenicity of several proteins [78][79][80]. It is also the case of ASNase from E. coli, where the use of bioinformatics techniques has allowed engineering the enzyme with the aim of obtaining an improved therapeutic agent [58,81,82].…”

Section: Resultsmentioning

confidence: 99%

Immunogenicity assessment of fungal l-asparaginases: an in silico approach

et al. 2020

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Acute lymphoblastic leukemia is the most common cancer among children worldwide, characterized by an overproduction of undifferentiated lymphoblasts in the bone marrow. The enzyme l-asparaginase isolated from Escherichia coli and Dickeya chrysanthemi is a key factor in multiple therapies against this disease. Regardless of their effectiveness, these formulations present well-known adverse effects, highlighting the immunogenicity and allergenicity they cause. Some strategies have been adopted in this regard, such as PEGylation and modification by bioengineering as well as the search for new non-bacterial microorganisms producing the enzyme. Fungi have been shown to be asparaginase producers with high antitumor activity; however, little is known about the immunological features of fungal asparaginase. In this work, we developed the first immunoinformatics study focused on revealing the antigenic determinants that contribute to the immunogenicity of nine asparaginases of filamentous fungi experimentally tested, and compared them with the enzyme from E. coli. We were able to predict that the fungal asparaginases evaluated have a high degree of immunogenicity, which is an important result to consider if the aim is to produce clinical l-asparaginase from a fungal source. Likewise, for the first time, a bioinformatics-based approach was used to predict the immunogenic and allergenic epitopes present in fungal asparaginases.

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Applying Bioinformatic Tools for Modeling and Modifying Type II E. coli l-Asparginase to Present a Better Therapeutic Agent/Drug for Acute Lymphoblastic Leukemia

Cited by 22 publications

References 35 publications

Development of L-Asparaginase Biobetters: Current Research Status and Review of the Desirable Quality Profiles

Development of L-Asparaginase Biobetters: Current Research Status and Review of the Desirable Quality Profiles

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

Immunogenicity assessment of fungal l-asparaginases: an in silico approach

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