Glycorandomization

Glycorandomization, is a drug discovery and drug development technology platform to enable the rapid diversification of bioactive small molecules, drug leads and/or approved drugs through the attachment of sugars. Initially developed as a facile method to manipulate carbohydrate substitutions of naturally occurring glycosides to afford the corresponding differentially glycosylated natural product libraries, glycorandomization applications have expanded to include both small molecules (drug leads and approved drugs) and even macromolecules (proteins). Also referred to as 'glycodiversification', glycorandomization has led to the discovery of new glycoside analogs which display improvements in potency, selectivity and/or ADMET as compared to the parent molecule.

The traditional method for attaching sugars to natural products, drugs or drug leads is by chemical glycosylation. This classical approach typically requires multiple protection/deprotection steps in addition to the key anomeric activation/coupling reaction which, depending upon the glycosyl donor/acceptor pair, can lead to a mixture of anomers. Unlike classical chemical glycosylation, glycorandomization methods are divergent (i.e., diverge from a common starting material, see divergent synthesis) and are not dependent upon sugar/aglycon protection/deprotection or sugar anomeric activation. Two complementary strategies to achieve glycorandomization/diversification have been developed: an enzyme-based strategy referred to as 'chemoenzymatic glycorandomization' and a chemoselective method known as 'neoglycorandomization'. Both methods start with free reducing sugars and a target aglycon to afford a library of compounds which differ solely by the sugars appended to the target natural product, drug or drug lead.

Chemoenzymatic glycorandomization was inspired by the early pathway engineering work of Hutchinson and coworkers that suggested natural product glycosyltransferases were capable of utilizing non-native sugar nucleotide donors. The initial platform for chemoenzymatic glycorandomization was based upon a set of two highly permissive sugar activation enzymes (a sugar anomeric kinase and sugar-1-phosphate nucleotidyltransferase) to afford sugar nucleotide libraries as donors for these promiscuous glycosyltransferases where the permissivity of the corresponding sugar kinase and nucleotidyltransferase was expanded by enzyme engineering and directed evolution. The first application of this three enzyme (kinase, nucleotidyltransferase and glycosyltransferase) strategy enabled the product of a set of >30 differentially glycosylated vancomycins, some members of which were further diversified chemoselectively by virtue of the installation of sugars bearing chemoselective handles. This enzymatic platform has been further advanced through glycosyltransferase evolution and capitalizing upon the discovery of the reversibility of glycosyltransferase-catalyzed reactions first discovered in the context of calicheamicin biosynthesis.

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