Multi-Mannosides Based on a Carbohydrate Scaffold: Synthesis, Force Field Development, Molecular Dynamics Studies, and Binding Affinities for Lectin Con A
文摘
BLE> |
A short and efficient strategy for the synthesis of multi-valent mannosides based on a selectively functionalizedcarbohydrate scaffold was reported involving (i) direct regioselective azidation of unprotected commercialsaccharides, (ii) acetylation, (iii) grafting of the mannosyl ligands by click chemistry, and (iv) deacetylation.New glycoclusters with a valency ranging from 1 to 4 and different spatial arrangements of the epitopes wereobtained. Binding affinities of the new glycoclusters toward concanavalin A (Con A) lectin were investigatedby an enzyme-linked lectin essay (ELLA). The synthetic multi-valent compounds exhibited a remarkable clustereffect with a relative potency per mannoside residue ranging from 8.1 to 9.1 depending on the structures.ELLA experiments were in agreement with the establishment of favorable interactions between triazole ringand Con A, increasing the binding affinity. A new force field topology database was developed in agreementwith the GLYCAM 2004 force field. Molecular dynamics performed on representative glyco-conjugates revealedinteresting structural features such as rigidity of the scaffold for a well-defined presentation of the ligands andhighly flexible mannose counterparts. The new glycoconjugates reported may be promising tools as probes oreffectors of biological processes involving lectins.
