Rational design of urea-based glutamate carboxypeptidase II (GCPII) inhibitors as versatile tools for specific drug targeting and delivery
Language English Country Great Britain, England Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
24954515
DOI
10.1016/j.bmc.2014.05.061
PII: S0968-0896(14)00420-9
Knihovny.cz E-resources
- Keywords
- GCPII, PSMA, Specific drug targeting, Structure-aided drug design,
- MeSH
- Glutamate Carboxypeptidase II antagonists & inhibitors genetics metabolism MeSH
- Protease Inhibitors chemical synthesis chemistry toxicity MeSH
- Catalytic Domain MeSH
- Kinetics MeSH
- Humans MeSH
- Urea analogs & derivatives chemical synthesis toxicity MeSH
- Cell Line, Tumor MeSH
- Nanoparticles chemistry MeSH
- Drug Carriers chemistry MeSH
- Surface Plasmon Resonance MeSH
- Drug Design MeSH
- Gene Expression Regulation drug effects MeSH
- Recombinant Proteins biosynthesis chemistry genetics MeSH
- Molecular Dynamics Simulation MeSH
- Protein Binding MeSH
- Binding Sites MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Glutamate Carboxypeptidase II MeSH
- Protease Inhibitors MeSH
- Urea MeSH
- Drug Carriers MeSH
- Recombinant Proteins 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.
References provided by Crossref.org
Characterization of glutamate carboxypeptidase 2 orthologs in trematodes
