Design of an Oligosaccharide Scaffold That Binds in the Minor Groove of DNA

Abstract

Many biological recognition events involve extensive interactions between macromolecules. Strategies to design compounds that mimic large peptides or other elements of secondary structure could be useful for blocking interactions between large surfaces. In this paper, the use of oligosaccharides as scaffolds for the design of peptidomimetics is addressed. A functionalized oligosaccharide modeled after a basic region peptide helix has been designed and synthesized. This oligosaccharide binds to duplex DNA with micromolar affinity. The mode of binding has been established by 2D NMR, and shows that the oligosaccharide binds DNA in the minor groove with one surface of the oligosaccharide contacting the floor of the DNA.

Tailoring Peptidomimetics for Targeting Protein–Protein Interactions

“…The first versions of synthetic non-peptidic scaffolds were oligosaccharide structures, which mimicked projections of the a-helical structure found on the transcription factor GCN4. However, limited to no success was seen with these compounds with respect to GCN4-DNA binding inhibition (82).…”

Alpha‐Helix Mimetics in Drug Discovery

“…The work of Xuereb et al (2000) represents the first example of a synthetic scaffold to mimic an extended surface area of an a-helix, in which a pentasaccharide scaffold (9, Fig. 11.5) was used to mimic the basic region of the transcription factor GCN4.…”

Design and synthesis of functionalized trisaccharides as p53-peptide mimics

“…Oligosaccharides offer attractive scaffolds for the development of peptdomimetics 1–5. Monosaccharides possess polyhydroxyl groups which can be readily functionalized and their well-defined conformation allows the presentation of the functionalities to be designed in a predictable fashion.…”

“…However, oligosaccharides had not been extensively exploited to mimic relatively large protein secondary structures. We previously demonstrated the use of a pentasaccharide as a scaffold for an α-helical peptide mimic 5. A functionalized pentasaccharide was designed based on an α-helical DNA-binding peptide region of a bZIP protein and was shown to indeed bind DNA.…”

“…To test this notion, we designed a p53-peptide mimic based on a trisaccharide scaffold as shown in Figure 1c. Based on the design strategy developed in our prior studies,5 an α-1,4 linked tri-2-deoxygalactose was employed as a suitable scaffold to match the molecular dimension of the MDM2-binding region of the p53 peptide 10. It has been proposed earlier that overall conformation of oligosaccharides could be predicted qualitatively through conformational analysis of glycosidic bonds, which are primarily governed by an exo-anomeric effect and non-bonded steric effects between the adjacent sugars 4,8.…”