PhD Theses (Biosciences and Bioengineering)

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Studies on recombinant protein and peptides derived from diphtheria toxin
(2017) Agarwal, Mahesh
Diphtheria toxin (DT) is a well characterized AB-toxin with three independent domains: C-domain for catalysis and toxicity, T-domain for translocation through the membrane and R-domain or receptor-binding domain. The toxicity of DT has been investigated extensively and is utilized to create therapeutic agents, like immunotoxins, which kill cells. However, the receptor-binding ability of DT is not extensively explored and used for therapeutic purposes. The receptor of DT is Heparin-binding EGF-like growth factor (HB-EGF). It is expressed as a membrane-bound molecule, which is eventually released by ectodomain shedding. HB-EGF is a growth factor. It is overexpressed in various cancer cells and activates different oncogenic signaling pathways. Therefore, HB-EGF on the cell surface can be targeted for cell-specific drug delivery. It can also be targeted to modulate its oncogenic signaling. In the current work, we have manipulated the receptor-binding domain of Diphtheria toxin (RDT) in two ways. First, we have used recombinant RDT to deliver drug-loaded nanoparticles to specific cells that express Human HB-EGF. In the second part, we have established that a short stretch of 26 amino acids in RDT is adequate for binding to HB-EGF with moderate affinity.