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Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Daniel Bobo, Kye J. Robinson, Jiaul Islam, Kristofer J. Thurecht, Simon R. Corrie
Ontak®, (Denileukin Diftitox) is an example of an approved engineered fusion protein combining cytotoxic molecules with targeting proteins. It was initially designed to treat the aggressive form of non-Hodgkin’s Peripheral T-cell Lymphomas (PTCL). Ontak®, approved in 2008, is an IL-2 receptor antagonist designed to direct the cytocidal action of diphtheria toxin to cells that overexpress the IL-2 receptor on T-cells. In this case diphtheria toxin may be considered the cytotoxic drug and the engineered IL-2 the delivery platform. IL-2R-targeted therapy appears to be an effective treatment option for PTCL patients. Combination therapy with Ontak® and CHOP (the traditional first-line chemotherapy for the disease) has an overall survival rate of 63.3% as opposed to 32–35% with CHOP alone [59, 60]. Ontak® is not myelosuppressive, nor is it associated with significant organ toxicity. Ontak® represented one of the first actively targeted proteinaceous nanoparticles, but is still a singular protein system. It could be used for a range of hematological tumors, many of which overexpress IL-2R [61].
Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
Bai et al. engineered a complex G-CSF-Tf containing the granulocyte colony-stimulating factor (G-CSF) in fusion with transferrin (Tf). Subcutaneous administration of this complex in mice resulted in an effective increase in absolute neutrophil counts as compared to the condition when the G-CSF was administered alone. The complex also resulted in myelopoietic effect that lastest for three days. This implies that fusion of recombinant proteins with transferrin is a promising technique for the future protein drugs (Bai et al., 2005). The researchers further improved the oral efficacy of the fusion protein by adding the linker peptide (helix linker H4-2) between the G-CSF and Tf domains. Addition of such a linker significantly improved their in vivo myelopoietic effect (Bai and Shen, 2006). A fusion conjugate of IL-2 and EDT (enzymatically active domain of diphtheria toxin) was approved as an engineered protein therapeutic as it is successful in treating cutaneous-T-cell lymphoma (Foss, 2006).
Mechanisms of Bacterial Heavy Metal Resistance and Homeostasis
Published in Edgardo R. Donati, Heavy Metals in the Environment, 2018
Pallavee Srivastava, Meenal Kowshik
The DtxR family is comprised of two subfamilies of metal sensing proteins viz., DtxR such as Fe2+ sensors and the MntR such as Mn2+ sensors (Merchant and Spatafora, 2014; Ma et al., 2009). The DtxR (diphtheria toxin repressor) were first studied in Corynebacterium diphtheriae as Fe2+ sensor proteins and since then several other members of this subfamily such as IdeR and SirR have also been studied (Gold et al., 2001; Hill et al., 1998). These proteins regulate genes involved in Fe2+ uptake and storage that are constitutively expressed under Fe2+ limiting conditions (Andrew et al., 2003). DtxR/IdeR/SirR mediated repression of these genes is observed in the presence of elevated levels of Fe2+ in the cytosol. The founding member of the MntR like subfamily is the B. subtilis MntR, that represses the expression of genes involved in Mn2+ uptake and is highly specific for Mn2+ and Cd2+ (Que and Helmann, 2000). ScaR and TroR are the other regulators belonging to this subfamily (Jakubovics et al., 2000; Posey et al., 1999), whereas SloR and MtsR are regulators that sense both, Fe2+ and Mn2+ (Merchant and Spatafora, 2014). DtxR like and MntR like regulators contain an N-terminal winged helix DNA binding domain followed by a helical dimerization domain and a C-terminal SH3-like domain. The C-terminal SH3-like domain enhances the DNA binding affinity by stabilizing intra- and/or inter-subunit protein-protein interactions (Liu et al., 2008).
Molecularly imprinted nanoparticles with recognition properties towards diphtheria toxin for ELISA applications
Published in Journal of Biomaterials Science, Polymer Edition, 2023
Süleyman Serdar Alkanlı, Fulya Dal Yöntem, Merve Yaşar, Celal Güven, M. Vezir Kahraman, Nilhan Kayaman Apohan, Zerrin Aktaş, Mustafa Oral Öncül, Ayhan Ünlü, Handan Akçakaya
Although small template molecules can be imprinted, there are some technical difficulties in the imprinting of macromolecules. Macromolecules are incompatible with organic solvents therefore the polymerization process must be carried out in an aqueous solution [5–8]. Epitope imprinting approach, which is a molecular imprinting method, can produce MIPs with high affinity for the target macromolecule by using fragments of macromolecules [9–12]. Diphtheria toxin (DT), a macromolecule with A-B fragments, is secreted by Corynebacterium diphtheria bacterium and enters the cell by endocytosis and then causes diphtheria, a respiratory tract and skin disease. DT consists of receptor-binding (R-), transmembrane (T-), and catalytic (C-) domains. The C-domain, which is an independent folding domain, forms fragment A (FA), and the T- and R-domains form fragment B (FB) [13,14]. The R-domain binds to the cell surface receptors such as epidermal growth factor receptor (EGFR), allowing DT to enter the cell by endocytosis. T-domain inserts into the membrane after decrease of pH in the endosome interior. T-domain has a monomeric globular form comprised of ten α-helices at neutral pH (pH: 7.0). In the presence of anionic bilayers and acidity, the protein undergoes conformational changes. T-domain assists membrane insertion and translocation of C-domain across the endosome membrane into the cytosol [15]. The C-domain is then proteolyzed from the R- and T-domains. The C-domain reaching the cytosol inhibits the eukaryotic elongation factor 2 (eEF2) translation factor, ending protein synthesis and causing cell death [13–16]. FA inhibits globular G-actin polymerization and initiates depolymerization of filamentous F-actin [17–19].