bm9b01227_si_001.pdf (4.74 MB)
Effective Cellular Delivery of Antisense Peptide Nucleic Acid by Conjugation to Guanidinylated Diaminobutanoic Acid-Based Peptide Dendrons
journal contribution
posted on 2019-12-06, 19:45 authored by Isabel
Maicas Gabas, Peter E. NielsenA series of amino- and guanidino-terminating 3- and 4-generation
2,4-diaminobutanoic acid (Dab) dendrons have been robustly synthesized
on a solid phase and characterized as cellular delivery agents in
antisense peptide nucleic acid (PNA) conjugates in the pLuc705 HeLa
cell splice switching system. The dendron–PNA conjugates exhibited
splice correction activity at one digit micromolar concentrations,
and guanidino-terminating dendrons were significantly more effective
than analogous amine terminating ones. Furthermore, introduction of
lipophilic groups such as phenyl, alkyl, or fatty acids increased
efficacy, but also increased cellular toxicity. Fluorescence microscopy
analyses supported an endosomal uptake mechanism and furthermore predominantly
showed colocalization with late endosomes and lysosomes. The robust
solid phase synthesis should make such Dab–dendrons a useful
platform for further in vitro as well as in vivo optimization.
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endosomal uptake mechanismAntisense Peptide Nucleicguanidino-terminating 3-digit micromolar concentrationsconjugateacidDabantisense peptideguanidino-terminating dendronssplice correction activityEffective Cellular Deliverydelivery agentsvivo optimizationlipophilic groupsFluorescence microscopy analysespLuc 705 HeLa cell splicephase synthesisGuanidinylated Diaminobutanoic Acid-Based Peptide DendronsPNA
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