RESUMEN
Protein N-glycosylation is a widespread post-translational modification. The first committed step in this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. 2.7.8.15). Missense DPAGT1 variants cause congenital myasthenic syndrome and disorders of glycosylation. In addition, naturally-occurring bactericidal nucleoside analogues such as tunicamycin are toxic to eukaryotes due to DPAGT1 inhibition, preventing their clinical use. Our structures of DPAGT1 with the substrate UDP-GlcNAc and tunicamycin reveal substrate binding modes, suggest a mechanism of catalysis, provide an understanding of how mutations modulate activity (thus causing disease) and allow design of non-toxic "lipid-altered" tunicamycins. The structure-tuned activity of these analogues against several bacterial targets allowed the design of potent antibiotics for Mycobacterium tuberculosis, enabling treatment in vitro, in cellulo and in vivo, providing a promising new class of antimicrobial drug.
Asunto(s)
Antibióticos Antituberculosos/farmacología , Trastornos Congénitos de Glicosilación/metabolismo , Inhibidores Enzimáticos/farmacología , N-Acetilglucosaminiltransferasas/química , Animales , Antibióticos Antituberculosos/química , Sitios de Unión , Trastornos Congénitos de Glicosilación/genética , Inhibidores Enzimáticos/química , Femenino , Células HEK293 , Células Hep G2 , Humanos , Metabolismo de los Lípidos , Ratones , Simulación del Acoplamiento Molecular , Mutación , N-Acetilglucosaminiltransferasas/antagonistas & inhibidores , N-Acetilglucosaminiltransferasas/genética , N-Acetilglucosaminiltransferasas/metabolismo , Unión Proteica , Células Sf9 , Spodoptera , Tunicamicina/química , Tunicamicina/farmacología , Uridina Difosfato Ácido Glucurónico/química , Uridina Difosfato Ácido Glucurónico/metabolismoRESUMEN
A procedure for the cyclization of dipeptidoyl benzotriazolides containing proline derivatives promoted by triethylamine under MW activation is introduced. The reaction is general for a variety of dipeptidoyl benzotriazolides and represents a very practical and convenient method for the preparation of Pro- or Hyp-derived 2,5-diketopiperazines (2,5-DKPs) and bis-DKPs with a disulfide linker. This method can be used for the construction of 2,5-DKP compound libraries and for the synthesis of natural products with diketopiperazine cores.
Asunto(s)
Productos Biológicos/síntesis química , Dicetopiperazinas/síntesis química , Poríferos/química , Prolina/análogos & derivados , Triazoles/química , Animales , Productos Biológicos/química , Ciclización , Dicetopiperazinas/química , Dipéptidos/química , Etilaminas/química , Prolina/síntesis química , EstereoisomerismoRESUMEN
Dimerization-macrocyclization has been a long-standing problem in the cyclization of peptides since, together with the desired cyclic product, many cyclic oligomers and linear polymers may also be formed during the reaction. Therefore, the development of a process that affords the cyclic dimer predominantly is difficult. A novel and versatile strategy for the synthesis of symmetric cyclo-tetrapeptides by palladium-promoted tandem deprotection/cyclo-dimerization from readily available Cbz-dipeptidoyl benzotriazolides is reported (Cbz=carboxybenzyl).