We present a new family of peptide dendrimers based on polyproline helices and cis-4-amino-L-proline as a branching unit. Dendrimers were synthesized by a convergent solid-phase peptide synthesis approach. The conformational transition between polyproline type I helix and polyproline type II helix was observed by circular dichroism in branched polyproline building blocks with more than 14 proline residues and in the resulting dendrimers. Both linear and dendritic polyprolines were found to be actively internalized by rat kidney cells. Preliminary results show that the antibiotic ciprofloxacin form complexes with branched polyproline chains in 99.5% propanol.
Second-generation dendrimers have been prepared on solid phase by successive additions of branched polyproline building blocks starting from two different branching units anchored to the solid support. The preparation of Pro-rich building blocks was carried out by stepwise solid-phase synthesis and their iterative addition was performed by a convergent approach, also using solid-phase synthesis. cis-4-Amino-L-proline and imidazolidine-2-carboxylic acid were used as branching units due to their structural resemblance to proline. The optimized strategy allowed the target compounds to be obtained with high purities without the need for purification steps.
A synthetic method for the preparation of protein-like globular dendrimers derived from a combination of proline, glycine and imidazolidin ring as branching unit is described. The methodology allows the synthesis of novel peptide dendrimers up to fourth generation. Dendrimers were synthesized by a convergent solid-phase peptide synthesis approach. The conformational properties of branched polyproline peptides and proline dendrimers were studied by CD experiments. CD data suggest conformational plasticity of branched peptides for PPI and PPII, and a stable well-defined secondary structure of proline dendrimers for PPII.
The cover picture shows a branched poly(proline) peptide whose synthesis has successfully been achieved using a combination of step-wise and convergent solid-phase peptide methodology. Aminoproline was used as a branching unit in order to maintain structural coherence with the rest of the sequence, although other trifunctional amino acids were also tested. Assembly of different units of this peptide could lead to poly(proline) dendrimers. These new biocompatible architectures may have interesting applications in drug-delivery. Details are discussed in the article by F. Albericio et al. on p. 1756 ff.
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