Oligonucleotide-based hepatocyte growth factor (HGF) mimetics are described. A DNA aptamer to Met, a cognate receptor for HGF, was shown to induce Met activation when used in dimer form. The most potent aptamer dimer, ss-0, which was composed solely of 100-mer single-stranded DNA, exhibited nanomolar potency. Aptamer ss-0 reproduced HGF-induced cellular behaviors, including migration and proliferation. The present work sheds light on oligonucleotides as a novel chemical entity for the design of growth factor mimetics.

The reprogramming of receptor-ligand interactions affords an opportunity to direct cells to respond to user-defined external cues. Although this has often been achieved via the genetic engineering of receptors, an alternative, nongenetic approach is highly demanded. In this article, we propose the design of oligonucleotide-based synthetic switches that feature the ability to reprogram the ligand specificity of the growth factor receptor. We demonstrated that our synthetic switches induced growth factor signaling via the formation of the dynamic complex with specific external cues that would otherwise not induce the signaling. This chemical approach may be applied to designing a new class of chemical tools that can control the activities of native cells and represent smart and safer regenerative drugs.

A 76-mer single-stranded DNA acts as functional mimic of basic fibroblast growth factor (bFGF), one of the essential factors for stem cell culture.

Although growth factors have great therapeutic potential because of their regenerative functions, they often have intrinsic drawbacks, such as low thermal stability and high production cost. Oligonucleotides have recently emerged as promising chemical entities for designing synthetic alternatives to growth factors. However, their applications in vivo have been recognized as a challenge because of their susceptibility to nucleases and limited distribution to a target tissue. Here, we present the first example of oligonucleotide-based growth factor mimetics that exerts therapeutic effects at a target tissue after systemic injection. The aptamer was designed to dimerize a growth factor receptor for its activation and mitigated the progression of Fas-induced fulminant hepatitis in a mouse model. This unprecedented functionality of the aptamer can be reasonably explained by its high nuclease stability and migration to the liver parenchyma. These mechanistic analyses provided insights for the successful application of aptamer-based receptor agonists.

Oligonucleotide-based hepatocyte growth factor (HGF) mimetics are described. AD NA aptamer to Met, ac ognate receptor for HGF,w as shown to induce Met activation when used in dimer form. The most potent aptamer dimer,s s-0, which was composed solely of 100-mer singlestranded DNA, exhibited nanomolar potency.A ptamer ss-0 reproduced HGF-induced cellular behaviors,including migration and proliferation. The present work sheds light on oligonucleotides as an ovel chemical entity for the design of growth factor mimetics.