Design, Synthesis, and Characterization of a High-Affinity Trivalent System Derived from Vancomycin and l-Lys-d-Ala-d-Ala

• DOI: 10.1021/ja992648l
• Publication Date: 2002-07-26T05:56:09Z
• Authors: Jianghong Rao; Joydeep Lahiri; Robert M. Weis; George M. Whitesides
• Keywords: Dissociation constant; Avidin; Dissociation rate

A trivalent derivative of vancomycin, tris(vancomycin carboxamide), [C6H3-1,3,5-(CONHC6H4-4-CH2NHCOV)3 (RtV3; V = vancomycin)], binds an analogous d-Ala-d-Ala, R'tL'3, (C6H3-1,3,5-[CONεH(Nα-Ac)-l-Lys-d-Ala-d-Ala]3) in water with a dissociation constant that is approximately 4 × 10-17 M, as estimated by HPLC using competitive assay against Nα,ε-diacetyl-l-Lys-d-Ala-d-Ala (L). This binding one the tightest known for low molecular weight organic species. The RtV3·R'tL'3 presence excess L could be followed HPLC. kinetics are quite different from those monovalent tight-binding systems such avidin and biotin. In particular, rate aggregate rapid at concentrations greater than value complex V; contrast, biotin·avidin independent concentration Two mechanisms which may occur postulated discussed. Calorimetric measurements system indicate enthalpy association ∼−40 kcal/mol, about three times + L, thus entropy ∼−18 4.5 L.