RESUMO
Startling reports described the paradoxical triggering of the human mitogen-activated protein kinase pathway when a small-molecule inhibitor specifically inactivates the BRAF V600E protein kinase but not wt-BRAF. We performed a conceptual analysis of the general phenomenon "activation by inhibition" using bacterial and human HtrA proteases as models. Our data suggest a clear explanation that is based on the classic biochemical principles of allostery and cooperativity. Although substoichiometric occupancy of inhibitor binding sites results in partial inhibition, this effect is overrun by a concomitant activation of unliganded binding sites. Therefore, when an inhibitor of a cooperative enzyme does not reach saturating levels, a common scenario during drug administration, it may cause the contrary of the desired effect. The implications for drug development are discussed.
Assuntos
Sítio Alostérico , Antineoplásicos/farmacologia , Proteínas de Choque Térmico/antagonistas & inibidores , Serina Peptidase 1 de Requerimento de Alta Temperatura A/antagonistas & inibidores , Proteínas Periplásmicas/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Regulação Alostérica , Antineoplásicos/química , Escherichia coli , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/metabolismo , Serina Peptidase 1 de Requerimento de Alta Temperatura A/química , Serina Peptidase 1 de Requerimento de Alta Temperatura A/metabolismo , Humanos , Proteínas Periplásmicas/química , Proteínas Periplásmicas/metabolismo , Inibidores de Proteases/química , Ligação Proteica , Serina Endopeptidases/química , Serina Endopeptidases/metabolismoRESUMO
Covering: 1989 up to 2019 Ahp-cyclodepsipeptides (also known as Ahp-containing cyclodepsipeptides, cyanopeptolins, micropeptins, microginines, and lyngbyastatins, and by many other names) are a family of non-ribosomal peptide synthesis (NRPS)-derived natural products with potent serine protease inhibitory properties. Here, we review their isolation and structural elucidation from natural sources as well as studies of their biosynthesis, molecular mode of action, and use in drug discovery efforts. Accordingly, this summary aims to provide a comprehensive overview of the current state-of-the-art Ahp-cyclodepsipeptide research.
Assuntos
Depsipeptídeos/química , Depsipeptídeos/farmacologia , Oligopeptídeos/química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Depsipeptídeos/biossíntese , Depsipeptídeos/síntese química , Estrutura Molecular , Oligopeptídeos/metabolismo , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologiaRESUMO
The S1 serine protease family is one of the largest and most biologically important protease families. Despite their biomedical significance, generic approaches to generate potent, class-specific, bioactive non-covalent inhibitors for these enzymes are still limited. In this work, we demonstrate that Ahp-cyclodepsipeptides represent a suitable scaffold for generating target-tailored inhibitors of serine proteases. For efficient synthetic access, we developed a practical mixed solid- and solution-phase synthesis that we validated through performing the first chemical synthesis of the two natural products Tasipeptinâ A and B. The suitability of the Ahp-cyclodepsipeptide scaffold for tailored inhibitor synthesis is showcased by the generation of the most potent human HTRA protease inhibitors to date. We anticipate that our approach may also be applied to other serine proteases, thus opening new avenues for a systematic discovery of serine protease inhibitors.
