Hahm, H. S. ; Hurevich, M. ; Seeberger, P. H. .
Automated Assembly Of Oligosaccharides Containing Multiple Cis-Glycosidic Linkages.
NATURE COMMUNICATIONS 2016,
7.
Abstract
Automated glycan assembly (AGA) has advanced from a concept to a commercial technology that rapidly provides access to diverse oligosaccharide chains as long as 30-mers. To date, AGA was mainly employed to incorporate trans-glycosidic linkages, where C2 participating protecting groups ensure stereoselective couplings. Stereocontrol during the installation of cis-glycosidic linkages cannot rely on C2-participation and anomeric mixtures are typically formed. Here, we demonstrate that oligosaccharides containing multiple cis-glycosidic linkages can be prepared efficiently by AGA using monosaccharide building blocks equipped with remote participating protecting groups. The concept is illustrated by the automated syntheses of biologically relevant oligosaccharides bearing various cis-galactosidic and cis-glucosidic linkages. This work provides further proof that AGA facilitates the synthesis of complex oligosaccharides with multiple cis-linkages and other biologically important oligosaccharides.

Weishaupt, M. W. ; Matthies, S. ; Hurevich, M. ; Pereira, C. L. ; Hahm, H. S. ; Seeberger, P. H. .
Automated Glycan Assembly Of A S-Pneumoniae Serotype 3 Cps Antigen.
BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY 2016,
12, 1440-1446.
Publisher's VersionAbstractVaccines against S. pneumoniae, one of the most prevalent bacterial infections causing severe disease, rely on isolated capsular polysaccharide (CPS) that are conjugated to proteins. Such isolates contain a heterogeneous oligosaccharide mixture of different chain lengths and frame shifts. Access to defined synthetic S. pneumoniae CPS structures is desirable. Known syntheses of S. pneumoniae serotype 3 CPS rely on a time-consuming and low-yielding late-stage oxidation step, or use disaccharide building blocks which limits variability. Herein, we report the first iterative automated glycan assembly (AGA) of a conjugation-ready S. pneumoniae serotype 3 CPS trisaccharide. This oligosaccharide was assembled using a novel glucuronic acid building block to circumvent the need for a late-stage oxidation. The introduction of a washing step with the activator prior to each glycosylation cycle greatly increased the yields by neutralizing any residual base from deprotection steps in the synthetic cycle. This process improvement is applicable to AGA of many other oligosaccharides.
Chandra, K. ; Das, P. ; Mamidi, S. ; Hurevich, M. ; Iosub-Amir, A. ; Metanis, N. ; Reches, M. ; Friedler, A. .
Covalent Inhibition Of Hiv-1 Integrase By N-Succinimidyl Peptides.
CHEMMEDCHEM 2016,
11, 1987-1994.
Abstract
We present a new approach for the covalent inhibition of HIV-1 integrase (IN) by an LEDGF/p75-derived peptide modified with an N-terminal succinimide group. The covalent inhibition is mediated by direct binding of the succinimide to the amine group of a lysine residue in IN. The peptide serves as a specific recognition sequence for the target protein, while the succinimide serves as the binding moiety. The combination of a readily synthesizable peptide precursor with easy and efficient binding to the target protein makes this approach a promising new strategy for designing lead compounds.