RESUMEN
Natural compounds that either increase or decrease polymerization of actin into filaments have become indispensable tools for cell biology. However, to date, it was not possible to use them as therapeutics due to their overall cytotoxicity and their unfavorable pharmacokinetics. Furthermore, their synthesis is in general quite complicated. In an attempt to find simplified analogues of miuraenamide, an actin nucleating compound, we identified derivatives with a paradoxical inversion of the mode of action: instead of increased nucleation, they caused an inhibition. Using an extensive computational approach, we propose a binding mode and a mode of action for one of these derivatives. Based on our findings, it becomes feasible to tune actin-binding compounds to one or the other direction and to generate new synthetic actin binders with increased functional selectivity.
RESUMEN
The miuraenamides, relatively simple representatives of a class of cyclodepsipeptides with high antitumor activity, can be easily and flexibly obtained by the concept of peptide modification. A reaction sequence consisting of an aldol reaction, oxidation, and methylation of the glycine subunit of the cyclodepsipeptides allows the incorporation of the unusual α,ß-unsaturated dehydroamino acid in one of the last steps of the synthesis.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Depsipéptidos/química , Depsipéptidos/farmacología , Actinas/metabolismo , Actinas/ultraestructura , Antineoplásicos/síntesis química , Línea Celular Tumoral , Depsipéptidos/síntesis química , Humanos , Metilación , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Oxidación-ReducciónRESUMEN
The Gram-positive bacterium Paenibacillus larvae is the causative agent of the fateful honey bee disease American Foulbrood (AFB). Sequence analysis of P. larvae genomic DNA showed the presence of numerous nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) encoding gene clusters, not correlating with secondary metabolite production. As NRPS and PKS derived metabolites are known to exhibit diverse biological activities, their identification is of particular interest for infection and drug research. Here an 11.6kb orphan NRPS gene cluster was directly cloned from the genomic DNA of P. larvae and expressed in Escherichia coli resulting in the production of sevadicin. Isolation of the metabolite was followed by structural characterization, synthesis and bioactivity studies.