RESUMEN
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-tuned agonism. The developed synthetic partial agonist can regulate therapeutically relevant cellular activities by eliciting fine-tuned receptor signaling.
Asunto(s)
Aptámeros de Nucleótidos/metabolismo , Péptidos y Proteínas de Señalización Intercelular/agonistas , Receptores de Citocinas/agonistas , Células A549 , Aptámeros de Nucleótidos/química , Aptámeros de Nucleótidos/farmacología , Movimiento Celular/efectos de los fármacos , Dimerización , Factor de Crecimiento de Hepatocito/agonistas , Factor de Crecimiento de Hepatocito/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Ligandos , Microscopía Fluorescente , Unión Proteica , Proteínas Proto-Oncogénicas c-met/agonistas , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/metabolismo , Receptores de Citocinas/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
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 living cells.
Asunto(s)
ADN/metabolismo , Proteínas/metabolismo , Animales , ADN/química , Fenómenos Ópticos , Células PC12 , Proteínas/química , Ratas , Transducción de Señal , Rayos UltravioletaRESUMEN
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.