Combinatorial chemoenzymatic strategies for in vitro glycorandomization: Efforts toward antibiotic optimization.
Extract: The natural product pool, which includes many glycosylated secondary metabolites, is the source of over half of the world's drug leads. For example, the antibiotics vancomycin and erythromycin, the antitumor compounds bleomycin and doxorubicin, and the antifungal agents amphotericin and nystatin all contain essential sugar attachments. Carbohydrate groups of natural product-based drugs have long been known to generally influence pharmacokinetic properties and there is an increasing recognition that these carbohydrate appendages also play a key role in drug-target interactions. These findings suggest that the alteration of glycosylation patterns on secondary metabolites is a potential strategy for the generation of novel therapeutics. We postulate that combinatorial chemoenzymatic strategies toward glycorandomized natural products will be able to overcome the limitations associated with total synthesis (time, protecting group manipulations, regio- and stereo-selectivity problems) and with in vivo pathway engineering (structural complexity, pathway bias, toxicity) by combining the advantages of enzymatic catalysis (efficiency, possibility of fermentation-based scale-up) with the power of chemical synthesis (unlimited diversity). We have recently demonstrated the power of in vitro glycorandomization (IVG) using vancomycin as the model.
Fu
Xun
X
Laboratory for Biosynthetic Chemistry, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Ave., Madison WI 53705, USA.
Langenhan
Joseph M
JM
Thorson
Jon S
JS