Incorporating small
modifications to peptidic macrocycles can have
a major influence on their properties. For instance, N-methylation
has been shown to impact permeability. A better understanding of the
relationship between permeability and structure is of key importance
as peptidic drugs are often associated with unfavorable pharmacokinetic
profiles. Starting from a semipeptidic macrocycle backbone composed
of a tripeptide tethered head-to-tail with an alkyl linker, we investigated
two small changes: peptide-to-peptoid substitution and various methyl
placements on the nonpeptidic linker. Implementing these changes in
parallel, we created a collection of 36 compounds. Their permeability
was then assessed in parallel artificial membrane permeability assay
(PAMPA) and Caco-2 assays. Our results show a systematic improvement
in permeability associated with one peptoid position in the cycle,
while the influence of methyl substitution varies on a case-by-case
basis. Using a combination of molecular dynamics simulations and NMR
measurements, we offer hypotheses to explain such behavior.
The discovery of new original scaffolds for selective RNA targeting is one of the main challenges of current medicinal chemistry since therapeutically relevant RNAs represent potential targets for a number...
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