RESUMO
The circadian clock controls daily rhythms of physiological processes. The presence of the clock mechanism throughout the body is hampering its local regulation by small molecules. A photoresponsive clock modulator would enable precise and reversible regulation of circadian rhythms using light as a bio-orthogonal external stimulus. Here we show, through judicious molecular design and state-of-the-art photopharmacological tools, the development of a visible light-responsive inhibitor of casein kinase I (CKI) that controls the period and phase of cellular and tissue circadian rhythms in a reversible manner. The dark isomer of photoswitchable inhibitor 9 exhibits almost identical affinity towards the CKIα and CKIδ isoforms, while upon irradiation it becomes more selective towards CKIδ, revealing the higher importance of CKIδ in the period regulation. Our studies enable long-term regulation of CKI activity in cells for multiple days and show the reversible modulation of circadian rhythms with a several hour period and phase change through chronophotopharmacology.
Assuntos
Caseína Quinase Ialfa/antagonistas & inibidores , Caseína Quinase Idelta/antagonistas & inibidores , Ritmo Circadiano/efeitos dos fármacos , Cronofarmacoterapia , Inibidores de Proteínas Quinases/farmacologia , Animais , Caseína Quinase Ialfa/metabolismo , Caseína Quinase Ialfa/ultraestrutura , Caseína Quinase Idelta/metabolismo , Linhagem Celular Tumoral , Transtornos Cronobiológicos/tratamento farmacológico , Relógios Circadianos/efeitos da radiação , Avaliação Pré-Clínica de Medicamentos , Ensaios Enzimáticos , Humanos , Luz , Camundongos , Camundongos Transgênicos , Simulação de Acoplamento Molecular , Fotoperíodo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/efeitos da radiação , Núcleo Supraquiasmático/efeitos dos fármacos , Núcleo Supraquiasmático/metabolismo , Técnicas de Cultura de TecidosRESUMO
Control of biological function by the use of photoremovable protecting groups (PPGs) is a gateway towards many new medical developments. Herein, we report the synthesis and application of efficient and biocompatible BODIPY-based photoprotecting groups for amines, which are cleavable with red light in the phototherapeutic window region (λ > 650 nm). We use the most promising PPG for the protection of dopamine and apply it to control the beating frequency of human cardiomyocytes.
Assuntos
Aminas/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Compostos de Boro/química , Luz , Fototerapia , Aminas/química , Humanos , Estrutura Molecular , Miócitos Cardíacos/efeitos dos fármacos , Processos FotoquímicosRESUMO
The field of photopharmacology uses molecular photoswitches to establish control over the action of bioactive molecules. It aims to reduce systemic drug toxicity and the emergence of resistance, while achieving unprecedented precision in treatment. By using small molecules, photopharmacology provides a viable alternative to optogenetics. We present here a critical overview of the different pharmacological targets in various organs and a survey of organ systems in the human body that can be addressed in a non-invasive manner. We discuss the prospects for the selective delivery of light to these organs and the specific requirements for light-activatable drugs. We also aim to illustrate the druggability of medicinal targets with recent findings and emphasize where conceptually new approaches have to be explored to provide photopharmacology with future opportunities to bring "smart" molecular design ultimately to the realm of clinical use.
Assuntos
Optogenética , Preparações Farmacêuticas/química , Processos Fotoquímicos/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Humanos , Estrutura Molecular , Preparações Farmacêuticas/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/químicaRESUMO
Selection of a single bacterial strain out of a mixture of microorganisms is of crucial importance in healthcare and microbiology research. Novel approaches that can externally control bacterial selection are a valuable addition to the microbiology toolbox. In this proof-of-concept, two complementary antibiotics are protected with photocleavable groups that can be orthogonally addressed with different wavelengths of light. This allows for the light-triggered selection of a single bacterial strain out of a mixture of multiple strains, by choosing the right wavelength. Further improvement toward additional orthogonally addressable antibiotics might ultimately lead to a novel methodology for bacterial selection in complex populations.