Lipopeptides for the Fragment-Based Pharmaceutics Design

Abstract

This paper describes the synthesis of peptide fragments for use in a new type of combinatorial discovery technology, in which the building blocks are brought together by non-covalent interactions, rather than direct chemical bonding. The building blocks of interest-in this case different amino acids-are converted to amphiphiles by attachment to lipid tails. The amphiphiles, when mixed together in aqueous phase, are designed so that they aggregate spontaneously to form micelles. The building blocks form the headgroups of each of the amphiphiles, and these headgroups cover the surface of the micelle in a dynamic close-packed fluid mosaic array. These building blocks come together so closely that twoor three-dimensional structures are created on the surface of the micelles, and these can be screened in biological assays to find out which combination of building blocks is able to elicit a biological response. Lipopeptides consisting of two residues of lipoamino acid and other amino acids moieties have been designed, synthesized, characterized and the ability of these constructs to form supra-molecular assemblies is demonstrated.

Use of Mixed Micelles for Presentation of Building Blocks in a New Combinatorial Discovery Methodology: Proof-of-Concept Studies

“…Micelles: Amphiphiles were synthesised as described in reference [2]. Laurel sarcosine, octadecyl rhodamine, hexadecyl fluorescein, octyl glucoside and phosphate buffer tablets were purchased from Sigma UK Ltd. (Dorset, UK).…”

“…In one of the studies described here, the pool of amino acids has been supplemented by sugars; when these constitute the head groups of the amphiphile, they are bound to the rest of the peptide chain via an ester linkage, usually through the side chain of a terminal glutamic acid residue. A description of the synthesis of these amphiphiles, and some properties of the resultant micelles are given in papers published by the authors [2,3].…”