RESUMEN
Nucleic acid therapeutics (NATs) hold promise in treating undruggable diseases and are recognized as the third major category of therapeutics in addition to small molecules and antibodies. Despite the milestones that NATs have made in clinical translation over the past decade, one important challenge pertains to increasing the specificity of this class of drugs. Activating NATs exclusively in disease-causing cells is highly desirable because it will safely broaden the application of NATs to a wider range of clinical indications. Smart NATs are triggered through a photo-uncaging reaction or a specific molecular input such as a transcript, protein, or small molecule, thus complementing the current strategy of targeting cells and tissues with receptor-specific ligands to enhance specificity. This review summarizes the programmable modalities that have been incorporated into NATs to build in responsive behaviors. We discuss the various inputs, transduction mechanisms, and output response functions that have been demonstrated to date.
Asunto(s)
Ácidos Nucleicos , Ácidos Nucleicos/genética , Ácidos Nucleicos/uso terapéuticoRESUMEN
Back and forth motions of the acid-base-operated molecular switch 1 are photo-controlled by irradiation of a solution, which also contains the photolabile pre-fuel 4. The photo-stimulated deprotection of the pre-fuel produces controlled amounts of acid 2, the base-promoted decarboxylation of which fuels the back and forth motions of the Sauvage-type [2]-catenane-based molecular switch. Because switch 1 and pre-fuel 4 do not interact in the absence of irradiation, an excess of the latter with respect to 1 can be added to the solution from the beginning. In principle, photocontrol of the back and forth motions of any molecular machine, the operation of which is guided by protonation/deprotonation, could be attained by use of pre-fuel 4, or of any other protected acid that undergoes deprotection by irradiation with light at a proper wavelength, followed by decarboxylation under conveniently mild conditions.
RESUMEN
It is now possible to functionally impair mitochondria through light illumination with high specificity. These optogenetic tools permit precise control on the timing, location, and extent of mitochondrial damage within a cell population with subcellular resolution, allowing quantitative probing of the various types of mitochondrial damage responses within cells. This approach can generally be extended toward the probing of other organelle damage responses.
Asunto(s)
Autofagia , Mitocondrias/efectos de la radiación , Enfermedades Mitocondriales/etiología , Mitofagia , Modelos Biológicos , Neuronas/efectos de la radiación , Enfermedad de Parkinson/fisiopatología , Técnicas de Ablación , Animales , Humanos , Mitocondrias/metabolismo , Neuronas/metabolismo , Optogenética/efectos adversos , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismoRESUMEN
Photolysis of an aryl sulfide-containing 5,6-dihydropyrimidine (1) at 350 nm produces high yields of thymidine and products resulting from trapping of a 5,6-dihydrothymidin-5-yl radical by O2 or thiols. Thymidine is believed to result from disproportionation of the radical pair originally generated from C--S bond homolysis of 1 on the microsecond timescale, which is significantly shorter than other photochemical transformations of modified nucleotides into their native forms. Duplex DNA containing 1 is destabilized, presumably due to disruption of π-stacking. Incorporation of 1 within the binding site of the restriction endonuclease EcoRV provides a photochemical switch for turning on the enzyme's activity. In contrast, 1 is a substrate for endonuclease VIII and serves as a photochemical off switch for this base excision repair enzyme. Modification 1 also modulates the activity of the 10-23 DNAzyme, despite its incorporation into a nonduplex region. Overall, dihydropyrimidine 1 shows promise as a tool to provide spatiotemporal control over DNA structure on the miscrosecond timescale.