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.