Enzyme-Instructed Activation of Pro-protein Therapeutics In Vivo.

Abstract

The selective and temporal control of protein activity in living cells provides a powerful tool to manipulate cellular function and to develop pro-protein therapeutics (PPT) for targeted therapy. In this work, we reported a facile but general chemical approach to design PPT by modulating protein activity in response to endogenous enzyme of disease cells, and its potential for targeted cancer therapy. We demonstrated that the chemical modification of a protein with quinone propionic acid (QPN), a ligand that could be reduced by tumor-cell-specific NAD(P)H dehydrogenase [quinone] 1 (NQO1), was reversible in the presence of NQO1. Importantly, the QPN-modified cytochrome c (Cyt c-QPN) and ribonuclease A (RNase A-QPN) showed NQO1-regulated protein activity in a highly selective manner. Furthermore, the intracellular delivery of RNase A-QPN using a novel type of lipid-based nanoparticles, and subsequent protein activation by cellular NQO1, selectively inhibit cancer cell growth in vitro and effectively suppress tumor growth in vivo. We believe that our approach increases the number of potentially useful chemical tools for reversibly controlling the structure and function of protein using a disease-cell-specific enzyme, opening opportunities in the study of dynamic biological processes and developing precise protein therapeutics.

• Authors: Jin Chang, Weiqi Cai, Chunjing Liang, Qiao Tang, Xianghan Chen, Ying Jiang, Lanqun Mao, Ming Wang
• Journal: Journal of the American Chemical Society (J Am Chem Soc) Vol. 141 Issue 45 Pg. 18136-18141 (11 13 2019) ISSN: 1520-5126 [Electronic] United States
• PMID: 31589435 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Drug Carriers
• Prodrugs
• Propionates
• Quinones
• Green Fluorescent Proteins
• Cytochromes c
• NAD(P)H Dehydrogenase (Quinone)
• NQO1 protein, human
• Ribonuclease, Pancreatic
• Lysine

Topics

• Antineoplastic Agents (chemistry, metabolism, pharmacology)
• Cell Proliferation (drug effects)
• Cytochromes c (chemistry, metabolism)
• Drug Carriers (chemistry)
• Drug Screening Assays, Antitumor
• Gene Knockdown Techniques
• Green Fluorescent Proteins (chemistry, metabolism)
• HEK293 Cells
• HeLa Cells
• Humans
• Lysine (chemistry)
• NAD(P)H Dehydrogenase (Quinone) (genetics, metabolism)
• Oxidation-Reduction
• Prodrugs (chemistry, metabolism, pharmacology)
• Propionates (chemistry, metabolism)
• Quinones (chemistry, metabolism)
• Ribonuclease, Pancreatic (chemistry, metabolism, pharmacology)