In pursuit of carbohydrate-based HIV vaccines, Part 2: The total synthesis of high-mannose-type gp120 fragments-evaluation of strategies directed to maximal convergence
In pursuit of carbohydrate-based HIV vaccines, Part 2: The total synthesis of high-mannose-type gp120 fragments-evaluation of strategies directed to maximal convergence
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DOI：
10.1002/anie.200353626
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发表时间：
2004-01-01
影响因子：
16.6
通讯作者：
Danishefsky, SJ
中科院分区：
文献类型：
--
作者：
Geng, XD;Dudkin, VY;Danishefsky, SJ
There are strong grounds to suppose that some selected glycosylation patterns of the HIV viral protein gp120 can themselves serve as epitopes for potent, broadly neutralizing antibodies (eg 2g12).[1, 2] The epitopes in question may comprise several hybrid or high-mannose-type glycans at particular asparagine loci (Asn295, 332, 339, 386, and 392). The 2g12 antibody has been shown to recognize a cluster of α1! 2 linked mannose residues on the HIV surface. Another argument in favor of the high-mannose-type glycan cluster epitope was reported by Burton, Wilson, and co-workers.[3] These workers described a structure of 2g12 cocrystallized with the high-mannose-type reducing oligosaccharide Man9-GlcNAc2. The crystal structure demonstrated that the antibody may bind up to four individual high-mannose glycans simultaneously, thus favoring a very high affinity recognition. Accordingly, a synthetic construct that is able to elicit a strong immune response to a conserved cluster of gp120 highmannose glycans could potentially emerge as a valuable candidate for incorporation into an HIV vaccine. In the preceding paper,[4] we related a strategy for the construction of a hybrid type gp120 glycopeptide construct. Herein we describe the synthesis of gp120 fragments comprising one of key asparagine sites (332) modified with a fully synthetic high-mannose glycan. Although the nonamannose section of the molecule was previously prepared and tested in binding with cyanovirin-N,[5–7] no total chemical synthesis of any Man9GlcNAc2 containing glycopeptides has been reported.[8]In our route to the glycan portion of the glycopeptide, we utilized, as proposed earlier, trisaccharide 2,[9] which already encompasses the synthetically difficult β-mannosidic linkage, as well as differentiated C3 and C6 access points (see asterisks) for the subsequent introduction of the nonsymmetrical mannose branching pattern. From this point onward, two strategies for progression to the octamannose motif presented themselves. One strategy would start with two consecutive mannosylations of the 3-OH and 6-OH groups of 2, employing mannoside donors 3 and 4, respectively, to complete the first “mannose layer”. In turn, the second “layer” of three mannose units would be introduced by triple mannosylation of the pentasaccharide triol acceptor with mannoside donor 3, providing the Man-6 octasaccharide. Saponification of the esters followed by the introduction of another trimannose layer should provide the desired Man-9 undecamer glycan (Scheme 1;“layered approach”).
