The alarmone nucleotide (p)ppGpp is a key regulator of bacterial metabolism, growth, stress tolerance and virulence, making (p)ppGpp-mediated signaling a promising target for development of antibacterials. Although ppGpp itself is an activator of the ribosome-associated ppGpp synthetase RelA, several ppGpp mimics have been developed as RelA inhibitors. However promising, the currently available ppGpp mimics are relatively inefficient, with IC50 in the sub-mM range. In an attempt to identify a potent and specific inhibitor of RelA capable of abrogating (p)ppGpp production in live bacterial cells, we have tested a targeted nucleotide library using a biochemical test system comprised of purified Escherichia coli components. While none of the compounds fulfilled this aim, the screen has yielded several potentially useful molecular tools for biochemical and structural work.

• MeSH
• Escherichia coli genetika   metabolismus   MeSH
• guanosintetrafosfát metabolismus   farmakologie   MeSH
• ligasy antagonisté a inhibitory   genetika   metabolismus   MeSH
• mutageneze * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• guanosine 3',5'-polyphosphate synthetases MeSH Prohlížeč
• guanosintetrafosfát MeSH
• ligasy MeSH

Conformational preferences of the pyrrolidine ring in nucleotide analogs 7-14 were investigated by means of NMR and molecular modeling. The effect of the relative configuration of hydroxy and nucleobase substituents as well as the effect of the alkylation or acylation of the pyrrolidine nitrogen atom on the conformation of the pyrrolidine ring were studied. The results of a conformational analysis show that the alkylation/acylation can be effectively used for tuning the pyrrolidine conformation over the whole pseudorotation cycle.

• Klíčová slova
• NMR, conformation, nucleic acids, nucleotide analog, phosphonic acid, pseudorotation, pyrrolidine,
• Publikační typ
• časopisecké články MeSH