A bifurcated proteoglycan binding small molecule carrier for siRNA delivery.
Bottom Line: 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.
Affiliation: The Wolfson Institute for Biomedical Research, UCL, Gower Street, London, WC1E 6BT, UK.Show MeSH
Mentions: To gauge the interaction between our molecules and heparin and chondroitin sulfate, the pairwise distances between the carbon atoms of the guanidine group from different phenyl rings for each conformation observed during molecular dynamics simulation of structure 3 were measured; that is, four distances were measured: between C2-C2′, C2-C3′, C3-C2′, and C3-C3′ as labeled in Figure 3. The results are plotted as a histogram showing the frequency of the C-C distances. More than 75% of the time, the C-C distances are above 11 Å. The most frequently occurring distances between two carbons (35%) are between 11 and 12 Å, mainly between groups C3-C2′ and C2-C3′. The longest distance is averaged around 16.48 Å, contributed mainly from groups C3-C3′. This distance is sufficient for binding to heparin sulfates in the same cluster, as well as binding to chondroitin sulfates on opposite sides of the sugar chain. However, to optimize binding to these GAGs, the distance between guanidine residues should be slightly increased in order that it is possible to bridge the gap between heparin sulfate clusters, as heparan sulfate is less sulfated than heparin, and the sulfate groups may be more sparsely arranged. Furthermore, macropinocytosis is initiated by clustering of GAG chains attached to different proteoglycan molecules 26. Therefore, increased spacing between SMoC guanidine groups may allow for binding of sulfates on different GAG chains.
Affiliation: The Wolfson Institute for Biomedical Research, UCL, Gower Street, London, WC1E 6BT, UK.