Peptide-based scaffolds for in vivo immobilization and enzyme attachment in therapeutic applications

David L. Lee; Hsiao-Ling M. Chin; Christopher G. Knudsen; George L. Mayers; David S. Rose; Roy K. Skogstrom; Timothy Palzkill; Hikaru Fujita; Yunlong Zhang; Zhiyuan Wu; Jonathan S. Lindsey

doi:10.1117/12.2566895

21 August 2020 Peptide-based scaffolds for in vivo immobilization and enzyme attachment in therapeutic applications

David L. Lee, Hsiao-Ling M. Chin, Christopher G. Knudsen, George L. Mayers, David S. Rose, Roy K. Skogstrom, Timothy Palzkill, Hikaru Fujita, Yunlong Zhang, Zhiyuan Wu, Jonathan S. Lindsey

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Proceedings Volume 11477, Molecular and Nano Machines III; 1147708 (2020) https://doi.org/10.1117/12.2566895
Event: SPIE Organic Photonics + Electronics, 2020, Online Only

Abstract

Advances in molecular design and synthetic chemistry enable the development of novel molecular therapeutic treatments of diverse diseases. A strategy proposed nearly 25 years ago for the treatment of metastatic cancer, but never realized, entails the following general processes: (i) Accumulation of an insoluble scaffold in the tumor extracellular space upon native enzyme (E_nat) cleavage of a soluble precursor, and (ii) covalent attachment to the scaffold of a non-native (heterologous) enzyme (E_het), which catalytically converts an abundance of aqueous-soluble radionuclide-bearing prodrug to an aqueous-insoluble drug; the latter precipitates in the tumor extracellular space. Here, the design and chemical synthesis of a molecular entity (1) for formation of the scaffold are described. Compound 1 is an “A₂BC”-type lysine-based architecture that contains two chromogenic indoxyl-glucoside units (A), which upon cleavage by a glucosidase (E_nat) undergo oxidative dimerization to provide a water-insoluble indigoid polymer; a maleimide (B) for attachment to a cancer-targeting agent; and the binding motif Loracarbef (C), a carbacephem antibiotic that forms a covalent adduct with a mutant β-lactamase (a proposed tether to, and/or possible fusion protein with, E_het). Studies here also include maleimide–thiol conjugation of I to transferrin (a cell uptake carrier) and the covalent attachment of a mutant b-lactamase to Loracarbef. Together, the work supports an approach for molecular brachytherapy (or endoradiotherapy), where radionuclide seeds are self-assembled directly in the region of therapeutic need.

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David L. Lee, Hsiao-Ling M. Chin, Christopher G. Knudsen, George L. Mayers, David S. Rose, Roy K. Skogstrom, Timothy Palzkill, Hikaru Fujita, Yunlong Zhang, Zhiyuan Wu, and Jonathan S. Lindsey "Peptide-based scaffolds for in vivo immobilization and enzyme attachment in therapeutic applications", Proc. SPIE 11477, Molecular and Nano Machines III, 1147708 (21 August 2020); https://doi.org/10.1117/12.2566895

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