Function-oriented biosynthesis of beta-lactone proteasome inhibitors in Salinispora tropica.
The natural proteasome inhibitor salinosporamide A from the marine bacterium Salinispora tropica is a promising drug candidate for the treatment of multiple myeloma and mantle cell lymphoma. Using a comprehensive approach that combined chemical synthesis with metabolic engineering, we generated a series of salinosporamide analogues with altered proteasome binding affinity. One of the engineered compounds is equipotent to salinosporamide A in inhibition of the chymotrypsin-like activity of the proteasome yet exhibits superior activity in the cell-based HCT-116 assay.
Nett
Markus
M
Scripps Institution of Oceanography, University of California at San Diego, La Jolla, California 92093, USA.
Gulder
Tobias A M
TA
Kale
Andrew J
AJ
Hughes
Chambers C
CC
Moore
Bradley S
BS
D039903:Actinobacteria / Q000235:genetics*; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000138:chemical synthesis*; D011480:Protease Inhibitors / Q000138:chemical synthesis*; D061988:Proteasome Inhibitors; D015202:Protein Engineering; D011758:Pyrroles / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship
D007783:Lactones; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011758:Pyrroles; C475865:marizomib