Glycorandomization: Difference between revisions
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'''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,<ref>Yang, J.; Hoffmeister, D.; Liu, L.; Thorson, J. S. “Natural product glycorandomization”. ''Bioorg. Med. Chem.'' '''2004''', ''12'', 1577-1584.</ref><ref name=a>Langenhan, J. M.; Griffith, B. R., Thorson, J. S. “Neoglycorandomization and chemoenzymatic glycorandomization: two complementary tools for natural product diversification”. ''J. Nat. Prod.'' '''2005''', ''68'', 1696-1711.</ref><ref>Griffith, B. R.; Langenhan, J. M.; Thorson, J. S. “’Sweetening’ natural products via glycorandomization”. ''Curr. Opin. Biotechnol.'' '''2005''', ''16'', 622-630.</ref> glycorandomization applications have expanded to include both small molecules (drug leads and approved drugs) and even macromolecules ([[proteins]]).<ref>Gantt, R.W.; Peltier-Pain, P.; Thorson, J. S. “Enzymatic methods for glyco(diversification/randomization) of drugs and small molecules”. ''Nat. Prod. Rep.'' '''2011''', ''28'', 1811-1853.</ref> Also referred to as 'glycodiversification',<ref>Thibodeaux, C.J.; Melançon, C.E.; Liu, H.-w. “Unusual sugar biosynthesis and natural product glycodiversification”. ''Nature'' '''2007''', ''446'', 1008-1016.</ref> 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. |
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== Classification == |
== Classification == |
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Revision as of 18:11, 27 January 2014
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,[1][2][3] glycorandomization applications have expanded to include both small molecules (drug leads and approved drugs) and even macromolecules (proteins).[4] Also referred to as 'glycodiversification',[5] 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.
Classification
The traditional method for obtaining natural product analogues is by total synthesis via laborious and time consuming protection and deprotection steps. To generate analogues more efficiently, chemists have recently developed two complementary strategies to achieve glycorandomization: chemoenzymatic glycorandomization and neoglycorandomization. These two methods do not require protection of the sugar or aglycone. Both methods start with unprotected and unactivated reducing sugars, and end with a library of sugars attached to the same aglycone.
Chemoenzymatic glycorandomization
This is a biocatalytic approach, based on enzymatic glycosylation, that relies on the promiscuous enzymes to catalyze the coupling between sugars and aglycons. The three enzymes involved in this strategy possess anomeric kinase, nucleotidyltransferase and glycosyltransferase activities. Altering the substrate specificities of these enzymes will enhance their promiscuity to catalyze additional reactions, which leads to diverse randomized sugar libraries, like sugar phosphate libraries, NDP sugar libraries and glycosylated sugar libraries.[2] Modifying any one of these three enzymes will eventually lead to final glycorandomization of the natural products. (Figure adapted from reference[2])
Currently available strategies to alter the substrate specificities include directed evolution and structure-based engineering. Directed evolution[6] takes advantage of natural selection to produce the desired promiscuous enzyme mutant via mutation, recombination, screening and selection. While structure-based engineering[7] modifies the active site pocket of the wild type enzyme to allow it accommodate unnatural substrates, thus, enhance the substrate flexibility of the enzyme.
Neoglycorandomization
This is a chemical approach using a one step ligation between a reducing sugar and a secondary alkoxylamine containing aglycon to form glycosides that are termed as “neoglycosides”.[2][8] In this chemoselective ligation, the two reactive functional groups selectively form a covalent bond to produce an oxy-iminium intermediate, which then undergoes ring closure immediately under physiological conditions. In this strategy, the only requirement is the installation of the alkoxylamine into the aglycon before glycosylation. (Figure adapted from reference[2])
Comparison
Both chemoenzymatic glycorandomization and neoglycorandomization do not require any protected sugars and aglycons. However, the biocatalytic approach is limited by the availability of either the promiscuous enzymes or the engineering techniques to alter the substrate specificities of enzymes. In contrast, the chemical approach is only limited by the efficiency of installing the alkoxylamine into the aglycon. However, the anomeric selectivity of the chemical approach might be scrambled in some cases, depending on the structure of the involved reducing sugars.
Uses
Glycorandomization is used in the pharmaceutical industry and academic community to alter glycosylation patterns of sugar-containing natural products. It provides a fast way to investigate the effect of subtle sugar modification on the pharmacological properties of the natural products analogues, thus, affording a new approach to drug discovery.
See also
References
- ^ Yang, J.; Hoffmeister, D.; Liu, L.; Thorson, J. S. “Natural product glycorandomization”. Bioorg. Med. Chem. 2004, 12, 1577-1584.
- ^ a b c d e Langenhan, J. M.; Griffith, B. R., Thorson, J. S. “Neoglycorandomization and chemoenzymatic glycorandomization: two complementary tools for natural product diversification”. J. Nat. Prod. 2005, 68, 1696-1711.
- ^ Griffith, B. R.; Langenhan, J. M.; Thorson, J. S. “’Sweetening’ natural products via glycorandomization”. Curr. Opin. Biotechnol. 2005, 16, 622-630.
- ^ Gantt, R.W.; Peltier-Pain, P.; Thorson, J. S. “Enzymatic methods for glyco(diversification/randomization) of drugs and small molecules”. Nat. Prod. Rep. 2011, 28, 1811-1853.
- ^ Thibodeaux, C.J.; Melançon, C.E.; Liu, H.-w. “Unusual sugar biosynthesis and natural product glycodiversification”. Nature 2007, 446, 1008-1016.
- ^ Williams, G. J.; Zhang, C. ; Thorson, J. S. “Expanding the promiscuity of a natural-product glycosyltransferase by directed evolution”. Nat. Chem. Biol. 2007, 3, 657-662.
- ^ Thorson, J. S.; Barton, W. A.; Hoffmeister, D.; Albermann, C.; Nikolov, D. B. “Structure-based enzyme engineering and its impact on in vivo glycorandomization”. Chembiochem. 2004, 5, 16-25.
- ^ Langenhan, J. M.; Peters, N. R.; Guzei, I. A.; Hoffmann, F. M.; Thorson, J. S. “Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization”. Proc. Natl. Acad. Sci. 2005, 102, 12305-12310.