2019
DOI: 10.1021/jacs.9b08669
|View full text |Cite
|
Sign up to set email alerts
|

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 co… Show more

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...
4
1

Citation Types

0
58
0

Year Published

2020
2020
2024
2024

Publication Types

Select...
6
1

Relationship

0
7

Authors

Journals

citations
Cited by 60 publications
(58 citation statements)
references
References 35 publications
0
58
0
Order By: Relevance
“…To overcome the cell membrane limit, many strategies including functionalization of cell‐penetrating peptides, ligands, pore‐forming proteins, and targeting agents have been developed for the enhancement of the intracellular drug delivery. [ 128–130 ] However, on the one hand, the cell‐penetrating peptides, pore‐forming proteins usually have no cellular selectivity, which may also increase the phagocytosis of drug and drug carriers by the normal cells. In this case, not only did the therapeutic effect improved, but the toxicity also increased.…”
Section: Overcoming Biological Barriersmentioning
confidence: 99%
“…To overcome the cell membrane limit, many strategies including functionalization of cell‐penetrating peptides, ligands, pore‐forming proteins, and targeting agents have been developed for the enhancement of the intracellular drug delivery. [ 128–130 ] However, on the one hand, the cell‐penetrating peptides, pore‐forming proteins usually have no cellular selectivity, which may also increase the phagocytosis of drug and drug carriers by the normal cells. In this case, not only did the therapeutic effect improved, but the toxicity also increased.…”
Section: Overcoming Biological Barriersmentioning
confidence: 99%
“…Because many drug targets identified by molecular cell biology are inside cells, considerable efforts have focused on engineering molecules for intracellular delivery of various cargo. [1][2][3] Besides the use of cationic molecules for enhancing cellular uptake of therapeutics, [4][5][6] one of the most explored approaches for intracellular delivery is to engineer molecules to be responsive to chemical or physical stimuli, such as redox, [7][8][9][10] pH, [11][12][13] enzymes, [14][15][16][17][18][19][20][21][22][23] or light. 24,25 Among enzymatic approach, alkaline phosphatases (ALP) instructed self-assembly of peptides is particularly effective to facilitate the cellular uptake of the peptide assemblies.…”
Section: Introductionmentioning
confidence: 99%
“…[14] While the use of stimuli-responsive carriers can enable selective protein release in target cells,t he inevitable pre-leakage or non-specific protein release would increase the risk of side toxicity. [15] Recently,t he strategy of reversible caging of proteins with trigger-cleavable motifs has been explored to enable spatiotemporal control of protein function in response to chemical, biological, or physical signals,s uch as acid, [16] reactive oxygen species (ROS), [17] enzyme, [18] or light. [19] However,the potential of these protein prodrugs in mediating selective protein therapy may still remain doubtful, mainly because of the insufficient sensitivity to exogeneous/endogenous triggers or the low specificity to discriminate between diseased and normal cells.…”
Section: Introductionmentioning
confidence: 99%
“…To fulfill the demands for the intracellular pro-protein therapy toward cancer treatment, we herein designed ahypoxia-activatable pro-protein, assisted with the construction of self-catalyzed cascaded nanozymogen to realize hypoxiastrengthened intracellular pro-protein delivery as well as sensitive and selective control over the hypoxia-instructed pro-protein activation in cancer cells.W hile various protein prodrugs capable of trigger-responsive activation have been reported, [16][17][18][19] hypoxia-instructed pro-protein engineering is still lacking,w hich makes it the first example of hypoxiaresponsive protein prodrug.P articularly,R Nase was reversibly caged with hypoxia-cleavable azobenzene domains on its lysine residues,g enerating the pro-protein (RPAB) deprived of the enzymatic activity along with elevated net anionic charge density (Scheme 1). Thus,RPA Bwas deprived of the non-specific toxicity to normal cells.T he azobenzene group could be reduced under hypoxic condition by the various reductases that are over-expressed and mainly localized inside tumor cells,t hus restoring the hydrolytic activity of RNase intracellularly upon hypoxia-triggered uncaging of the azobenzene protection group.W hile the tumoral microenvironment is often hypoxic due to fast metabolism and proliferation of cancer cells,t he hypoxia level in many solid tumors is heterogeneous and insufficient, which hurdles the effective re-activation of RPAB.A ssuch, RPAB was co-delivered with glucose oxidase (GOx), an enzyme that catalyzes the decomposition of glucose accompanied with concurrent exhaustion of O 2 and generation of H 2 O 2 .…”
Section: Introductionmentioning
confidence: 99%