Abstract：
:Smart nanocarriers for the transport of drugs to tumor cells are nowadays of great interest for treating cancer. The use of enzymatic stimuli to cleave peptide-based drug nanocapsules for the selective release of nanocapsule cargo in close proximity to tumor cells opens new possibilities in cancer research. In the present work, we demonstrate a methodology for finding and optimizing cleavable substrate sequences by the type II transmembrane serine protease hepsin, which is highly overexpressed in prostate cancer. The design and screening of combinatorial libraries in silico against the binding cavity of hepsin allow the identification of a panel of promising substrates with high-calculated docking scores. In vitro screening verifies the predictions and showed that all substrates are cleaved by hepsin with higher efficiency than the literature known hepsin substrate RQLR↓VVGG. The introduction of d-amino acids on a selected peptide with the highest catalytic efficiency (kcat/Km) renders it resistant to cleavage by plasma or serum while maintaining their susceptibility to hepsin.
journal_name
Biomacromoleculesjournal_title
Biomacromoleculesauthors
Knaff PM,Kersten C,Willbold R,Champanhac C,Crespy D,Wittig R,Landfester K,Mailänder Vdoi
10.1021/acs.biomac.0c00240subject
Has Abstractpub_date
2020-04-13 00:00:00pages
1636-1643issue
4eissn
1525-7797issn
1526-4602journal_volume
21pub_type
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