A rapid oxime linker-based library approach to identification of bivalent inhibitors of the Yersinia pestis protein-tyrosine phosphatase, YopH.
A bivalent tethered approach toward YopH inhibitor development is presented that joins aldehydes with mixtures of bis-aminooxy-containing linkers using oxime coupling. The methodology is characterized by its facility and ease of use and its ability to rapidly identify low micromolar affinity inhibitors. The generality of the approach may potentially make it amenable to the development of bivalent inhibitors directed against other phosphatases.
Liu
Fa
F
Chemical Biology Laboratory, Molecular Discovery Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, NCI-Frederick, Frederick, MD 21702, USA.
Hakami
Ramin Mollaaghababa
RM
Dyas
Beverly
B
Bahta
Medhanit
M
Lountos
George T
GT
Waugh
David S
DS
Ulrich
Robert G
RG
Burke
Terrence R
TR
D000447:Aldehydes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010091:Oximes / Q000737:chemistry*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries; D015010:Yersinia pestis / Q000201:enzymology*
D000447:Aldehydes; D001425:Bacterial Outer Membrane Proteins; D004791:Enzyme Inhibitors; D010091:Oximes; D054852:Small Molecule Libraries; D017027:Protein Tyrosine Phosphatases; C067571:yopH protein, Yersinia