The University of Tokyo · Biochemistry, Genetics and Molecular Biology
Professor Ryosuke Ueki's research lab specializes in the development of oligonucleotide-based synthetic biology tools, particularly DNA aptamers, to mimic and reprogram growth factor signaling pathways. The lab focuses on designing functional mimetics of growth factors—such as HGF and bFGF—that can regulate cell behavior including proliferation, migration, and pluripotency—offering stable, cost-effective, and genetically non-invasive alternatives to natural proteins. A central theme is the engineering of aptamer assemblies that act as synthetic agonists or switches, enabling precise control over receptor activation with tunable signaling outputs, and demonstrating therapeutic potential in regenerative medicine and cancer therapy.
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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
The HGF/c-Met pathway is known to play a key role in cancer metastasis. CLN0003_SL1, a 50-mer DNA aptamer that binds to the c-Met protein, was found to inhibit HGF-induced c-Met activation. This aptamer could suppress cancer cell motility in vitro.
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
Replacing expensive and thermally unstable growth factors with synthetic alternatives has been an important issue in stem cell-based regenerative medicines. Here we developed DNA aptamer-assemblies that act as functional mimics of basic fibroblast growth factor (bFGF), one of the essential factors for stem cell culture. The most potent aptamer assembly named TD0, composed solely of 76-mer single-stranded DNA, could support the self-renewal and pluripotency of induced pluripotent stem cells (iPSC
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
Designing synthetic surrogates of functional proteins is an important, albeit challenging, task in the field of chemistry. A strategy toward the design of synthetic agonists for growth factor or cytokine receptors that elicit a desired signal activity has been in high demand, as such ligands hold great promise as safer and more effective therapeutics. In the present study, we used a DNA aptamer as a building block and described the strategy-guided design of a synthetic receptor agonist with fine
Abstract 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 d
Optochemical tools that can modulate the activity of the target protein provide an opportunity for studying and regulating the related biological processes. Here we present a DNA-based nongenetic optochemical tool that can control the dynamics of growth factor signaling. This photo-caged mimicry of growth factor can be a promising tool for elucidating a linkage between the dynamics of signaling and the resulting biological outcomes, as well as for manipulating cellular functions and the fate of
Dopamine (DA) is a monoamine neurotransmitter that plays important roles in the brain, and whose levels in the brain are associated with several neurological and psychiatric disorders. Therefore, DA metabolism inhibitors have been used as therapeutic agents. Here, we report a (1)H NMR probe for the in situ analysis of DA metabolism, and its application to DA inhibitor screening. We designed doubly (13)C-labeled DA ((13)C(2)-DA) as the probe. The combination of the (13)C(2)-DA and (1)H-{(13)C-(13
Growth factor receptors are activated through dimerization by the binding of their ligands and play pivotal roles in normal cell function. However, the aberrant activity of the receptors has been associated with cancer malignancy. One of the main causes of the aberrant receptor activation is the overexpression of receptors and the resultant formation of unliganded receptor dimers, which can be activated in the absence of external ligand molecules. Thus, the unliganded receptor dimer is a promisi
Cell membrane receptors regulate cellular responses through sensing extracellular environmental signals and subsequently transducing them. Receptor engineering provides a means of directing cells to react to a designated external cue and exert programmed functions. However, rational design and precise modulation of receptor signaling activity remain challenging. Here, we report an aptamer-based signal transduction system and its applications in controlling and customizing the functions of engine
Artificial ligands that recognize membrane receptors with high affinity and specificity provide a means for the precise control of receptor activity and the resulting biological functions. In the present work, we focused on a previously reported DNA aptamer that is a functional mimic of fibroblast growth factor (FGF) and evaluated its receptor specificity. It was revealed that the aptamer works as a selective agonist for FGF receptor (FGFR) 1 owing to its high specificity toward the receptor, de
Abstract Designing synthetic surrogates of functional proteins is an important, albeit challenging, task in the field of chemistry. A strategy toward the design of synthetic agonists for growth factor or cytokine receptors that elicit a desired signal activity has been in high demand, as such ligands hold great promise as safer and more effective therapeutics. In the present study, we used a DNA aptamer as a building block and described the strategy‐guided design of a synthetic receptor agonist
Recently, targeted protein degradation (TPD) has attracted much attention as a powerful strategy for effective inhibition of disease-related proteins. However, development of ligands with high affinity and specificity for a target protein is still a demanding task and poses a particular challenge for designing TPD therapeutics. In this work, we report a novel TPD strategy called aptamer-mediated cleavage of extracellular antigen (Apt-clean), where oligonucleotide-based affinity agents are used f
Optochemical tools that can modulate activity of the target protein provide an opportunity for studying and regulating the related biological processes. Here we present a DNA-based nongenetic optochemical tool that can control dynamics of growth factor signaling. A photo-caged DNA aptamer for a growth factor receptor was designed to assemble into an active dimer form, depending on UV irradiation, thereby enabling optical control of the dimerization and subsequent activation of the receptor. This
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