Rational design of urea-based glutamate carboxypeptidase II (GCPII) inhibitors as versatile tools for specific drug targeting and delivery
Jazyk angličtina Země Velká Británie, Anglie Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
24954515
DOI
10.1016/j.bmc.2014.05.061
PII: S0968-0896(14)00420-9
Knihovny.cz E-zdroje
- Klíčová slova
- GCPII, PSMA, Specific drug targeting, Structure-aided drug design,
- MeSH
- glutamátkarboxypeptidasa II antagonisté a inhibitory genetika metabolismus MeSH
- inhibitory proteas chemická syntéza chemie toxicita MeSH
- katalytická doména MeSH
- kinetika MeSH
- lidé MeSH
- močovina analogy a deriváty chemická syntéza toxicita MeSH
- nádorové buněčné linie MeSH
- nanočástice chemie MeSH
- nosiče léků chemie MeSH
- povrchová plasmonová rezonance MeSH
- racionální návrh léčiv MeSH
- regulace genové exprese účinky léků MeSH
- rekombinantní proteiny biosyntéza chemie genetika MeSH
- simulace molekulární dynamiky MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- glutamátkarboxypeptidasa II MeSH
- inhibitory proteas MeSH
- močovina MeSH
- nosiče léků MeSH
- rekombinantní proteiny MeSH
Glutamate carboxypeptidase II (GCPII), also known as prostate specific membrane antigen (PSMA), is an established prostate cancer marker and is considered a promising target for specific anticancer drug delivery. Low-molecular-weight inhibitors of GCPII are advantageous specific ligands for this purpose. However, they must be modified with a linker to enable connection of the ligand with an imaging molecule, anticancer drug, and/or nanocarrier. Here, we describe a structure-activity relationship (SAR) study of GCPII inhibitors with linkers suitable for imaging and drug delivery. Structure-assisted inhibitor design and targeting of a specific GCPII exosite resulted in a 7-fold improvement in Ki value compared to the parent structure. X-ray structural analysis of the inhibitor series led to the identification of several inhibitor binding modes. We also optimized the length of the inhibitor linker for effective attachment to a biotin-binding molecule and showed that the optimized inhibitor could be used to target nanoparticles to cells expressing GCPII.
Citace poskytuje Crossref.org
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