RESUMEN
Mycobacterium tuberculosis is a global pathogen of huge importance which can adapt to several host niche environments in which carbon source availability is likely to vary. We developed and ran a phenotypic screen using butyrate as the sole carbon source to be more reflective of the host lung environment. We screened a library of â¼87,000 small compounds and identified compounds which demonstrated good antitubercular activity against M. tuberculosis grown with butyrate but not with glucose as the carbon source. Among the hits, we identified an oxadiazole series (six compounds) which had specific activity against M. tuberculosis but which lacked cytotoxicity against mammalian cells.
Asunto(s)
Antituberculosos/farmacología , Ácido Butírico/metabolismo , Medios de Cultivo/metabolismo , Mycobacterium tuberculosis/efectos de los fármacos , Oxadiazoles/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Antituberculosos/química , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Medios de Cultivo/química , Glucosa/metabolismo , Ensayos Analíticos de Alto Rendimiento , Isoniazida/farmacología , Kanamicina/farmacología , Levofloxacino/farmacología , Redes y Vías Metabólicas/fisiología , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/crecimiento & desarrollo , Mycobacterium tuberculosis/metabolismo , Oxadiazoles/química , Bibliotecas de Moléculas Pequeñas/química , Especificidad de la Especie , Relación Estructura-Actividad , Células VeroRESUMEN
Molecular characterization of the binding epitope of IL-23R and its cognate cytokine IL-23 is paramount to understand the role in autoimmune diseases and to support the discovery of new inhibitors of this protein-protein interaction. Our results revealed that HDX-MS was able to identify the binding epitope of IL-23R:IL-23, which opened the way to evaluate a peptide macrocycle described in the literature as disrupter of this autoimmune target. Thus, the characterization of the interactions of this chemotype by HDX-MS in combination with computational approaches was achieved. To our knowledge, this is the first reported structural evidence regarding the site where a small compound binds to IL-23R.
RESUMEN
GPR142, a putative amino acid receptor, is expressed in pancreatic islets and the gastrointestinal tract, but the ligand affinity and physiological role of this receptor remain obscure. In this study, we show that in addition to L-Tryptophan, GPR142 signaling is also activated by L-Phenylalanine but not by other naturally occurring amino acids. Furthermore, we show that Tryptophan and a synthetic GPR142 agonist increase insulin and incretin hormones and improve glucose disposal in mice in a GPR142-dependent manner. In contrast, Phenylalanine improves in vivo glucose disposal independently of GPR142. Noteworthy, refeeding-induced elevations in insulin and glucose-dependent insulinotropic polypeptide are blunted in Gpr142 null mice. In conclusion, these findings demonstrate GPR142 is a Tryptophan receptor critically required for insulin and incretin hormone regulation and suggest GPR142 agonists may be effective therapies that leverage amino acid sensing pathways for the treatment of type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Glucosa/metabolismo , Fenilalanina/metabolismo , Receptores Acoplados a Proteínas G/genética , Triptófano/metabolismo , Animales , Glucemia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Glucosa/genética , Humanos , Incretinas/genética , Incretinas/metabolismo , Insulina/genética , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina , Islotes Pancreáticos/metabolismo , Ratones , Ratones Noqueados , Fenilalanina/administración & dosificación , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/efectos de los fármacos , Triptófano/administración & dosificaciónRESUMEN
Cyclic peptide (CP) natural products provide useful model systems for mapping "beyond-Rule-of-5" (bRo5) space. We identified the phepropeptins as natural product CPs with potential cell permeability. Synthesis of the phepropeptins and epimeric analogues revealed much more rapid cellular permeability for the natural stereochemical pattern. Despite being more cell permeable, the natural compounds exhibited similar aqueous solubility as the corresponding epimers, a phenomenon explained by solvent-dependent conformational flexibility among the natural compounds. When analyzing the polarity of the solution structures we found that neither the number of hydrogen bonds nor the total polar surface area accurately represents the solvation energies of the high and low dielectric conformations. This work adds to a growing number of natural CPs whose solvent-dependent conformational behavior allows for a balance between aqueous solubility and cell permeability, highlighting structural flexibility as an important consideration in the design of molecules in bRo5 chemical space.
RESUMEN
To develop novel treatments for type 2 diabetes and dyslipidemia, we pursued inhibitors of serine palmitoyl transferase (SPT). To this end compounds 1 and 2 were developed as potent SPT inhibitors in vitro. 1 and 2 reduce plasma ceramides in rodents, have a slight trend toward enhanced insulin sensitization in DIO mice, and reduce triglycerides and raise HDL in cholesterol/cholic acid fed rats. Unfortunately these molecules cause a gastric enteropathy after chronic dosing in rats.