Enzyme-Instructed Assembly and Disassembly Processes for Targeting Downregulation in Cancer Cells

Presenter: 

Zhaoqianqi Feng

Authors: 

Zhaoqianqi Feng and Bing Xu*

Author Affiliation: 

Brandeis University

Abstract: 

Cancer cells differ from normal cells in both gain-of-functions (i.e., upregulation) and loss-of-functions (i.e., downregulation). While it is common to suppress gain-of-function for chemotherapy, it remains challenging to develop drugs for downregulated targets in cancer cells. Here we show the combination of enzyme-instructed assembly and disassembly to target downregulation in cancer cells by designing peptidic precursors as the substrates of both carboxylesterases (CES) and alkaline phosphatases (ALP). The precursors turn into self-assembling molecules to form nanofibers upon dephosphorylation by ALP, but CES-catalyzed cleavage of ester bond on the molecules results in the disassembly of nanofibers. The precursors selectively inhibit the cancer cells (e.g., OVSAHO) that downregulates CES, but are innocuous to a hepatocyte (HepG2) that overexpresses CES, while both the cell lines exhibit comparable ALP activities. This work illustrates a potential approach for the development of chemotherapy via targeting down-regulation (or loss-of-functions) in cancer cells.