A bifurcated proteoglycan binding small molecule carrier for siRNA delivery

Abstract

A wider application of siRNA- and miRNA- based therapeutics is restricted by the currently available delivery systems. We have designed a new type of small molecule carrier (SMoC) system for siRNA modeled to interact with cell surface proteoglycans. This bifurcated SMoC has similar affinity for the model proteoglycan heparin to an equivalent polyarginine peptide and exhibits significant mRNA knockdown of protein levels comparable to lipofectamine and the previously reported linear SMoC. A bifurcated guanidylated small molecule is modeled to access different clusters of sulfate esters in proteoglycans bound to the cell surface. Modular synthesis gives ready access to these molecules which have potential for the delivery of siRNA. © 2014 The Authors. Chemical Biology & Drug Design Published by John Wiley & Sons Ltd.