Systematic Solid Phase Synthesis of Linear Pseudooligolysines Containing Multiple Adjacent CH₂NH Amide Bond Surrogates: Potential Agents for Gene Delivery

Abstract

Positively charged peptides have been extensively used as vehicles to deliver functional DNA molecules into cultured cells [1,2]. Indeed polypeptides such as polylysine and polyarginine have been shown to efficiently complex negatively charged DNA molecules and to introduce the complexed DNA into the nuclei of recipient cultured cells. However being composed of amino acids, peptidic carriers should be digested by proteolytic enzymes present within the circulation and within cells and hence their action in vivo is limited. It is well known that chemical reduction of peptide bonds render them unsusceptible to proteolytic digestion. Indeed it has been shown that replacement of a CO-NH peptide bond by the CH₂NH isostere, i.e. a reduced peptide bond, results in increased resistance of the peptide towards enzymatic degradation [3]. In addition, such modification increases the number of the positively charged moieties within the peptide and enlarges the flexibility of the backbone [3].