Abstract
A novel convergent synthetic strategy for the construction of multicomponent self-adjuvanting lipopeptide vaccines was developed. A tetraalkyne-functionalized glucose derivative and lipidated Fmoc-lysine were prepared by novel efficient and convenient syntheses. The carbohydrate building block was coupled to the self-adjuvanting lipidic moiety (three lipidated Fmoc-lysines) on solid support. Four copies of a group A streptococcal B cell epitope (J8) were then conjugated to the glyco-lipopeptide using a copper-catalyzed cycloaddition reaction. The approach was elaborated by the preparation of a second vaccine candidate which incorporated an additional promiscuous T-helper epitope.
Highlights
Vaccination is often the most effective and economic long-term way to prevent disease [1]
The previously reported carbohydrate-based vaccine constructs [11] were prepared by a divergent approach, where the carbohydrate core was coupled to the resin-bound LCP adjuvanting moiety, followed by stepwise synthesis of the B cell epitopes using solid-phase peptide synthesis (SPPS)
As part of the new convergent approach, here, we report an efficient and convenient synthesis of a versatile alkyne-functionalized carbohydrate building block 1, which can be conveniently incorporated into peptide sequences using SPPS (Scheme 1)
Summary
Vaccination is often the most effective and economic long-term way to prevent disease [1]. We developed methodologies for the synthesis of carbohydrate building blocks as scaffold carriers of multiple B cell epitopes derived from GAS. The vaccine constructs consisted of the LCP adjuvanting moiety, and a carbohydrate core bearing four copies of a GAS B cell epitope [11,15,16,17,18].
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