Peptide‐Decorated Dendrimers and Their Bioapplications

Abstract

Peptide-decorated dendrimers (PDDs) are a class of spherical, regular, branched polymers that are modified by peptides covalently attached to their surface. PDDs have been used as protein mimetics, novel biomaterials, and in a wide range of biomedical applications. Since their design and development in the late eighties, poly-l-lysine has been a preferred core structure for PDDs. However, numerous recent innovations in polymer synthesis and ligation chemistry have re-energized the field and led to the emergence of well-defined peptide dendrimers with more diverse core structures and functions. This Minireview highlights the development of PDDs driven by significantly improved ligation chemistry incorporating structurally well-defined peptides and the emerging use of PDDs in imaging and drug development.

Neue Modalitäten für schwierige Zielstrukturen in der Wirkstoffentwicklung

“…So wurde ein dimeres cyclisches Peptid entwickelt, um effektiv die Dimerisierung des Hepatozytenwachstumsfaktor(HGF)-Rezeptors (auch Met genannt) auszulçsen. B. gegen Peptide gerichtete Motive,w urden kovalent an Dendrimere gebunden, um peptiddekorierte Dendrimere (PDDs) zu erhalten, [230] besonders fürdie Ausrichtung auf Tumoren. [229] Ein Vorteil von Dendrimeren ist die Mçglichkeit, sie mit verschiedenen chemischen Einheiten zu dekorieren.…”

Inhibition of the norepinephrine transporter by χ‐conotoxin dendrimers

“…CuSO 4 and sodium ascorbate were dissolved in water at a concentration of 0.1 M. Alkyne dendrons 2 or 3 (dendron concentration 5 μM) were dissolved in DMF. Azido-PEG(n)-[Pro] 11 MrIA[2-13] (4 or 5; 2 equiv/branch) was weighed, and the solution of CuSO 4 (0.2 equiv/branch) and TBTA ligand (0.2 equiv/branch) was added. The mixture was degassed with nitrogen for 15 min, and the solution of sodium ascorbate (0.5 equiv/branch) was added to the sealed reaction vessel to initiate the click reaction.…”

“…Moreover, a truncated analogue χ-MrIA with residue asparagine-1 deleted maintained its 3D structure and binding affinity comparable with amidated χ-MrIA [22,33]. To avoid the formation of aspartimide [32], the truncated χ-MrIA analogue 1 ([Pro] 11 MrIA [2][3][4][5][6][7][8][9][10][11][12][13], GVCCGYKLCHPC-NH 2 , 1-4, 2-3 connectivity) was used to build the azido-modified χ-MrIA moieties 4 and 5. The azido group was introduced to the N-terminus of 1 by coupling of azido-PEG(9)-COOH or azido-PEG(24)-COOH with chain lengths of approximately 35 and 90 Å, respectively.…”

“…To ensure correct folding of 4 and 5, pairs of Fmoccysteine(Acm)-OH and Fmoc-cysteine(Trt)-OH were utilized in the synthesis to direct regioselective disulfide bond formation (Scheme 2) [46]. The crude peptides were oxidized stepwise, purified after each oxidation step, and then subjected to the RP-HPLC for purification to give >90% pure peptides 4 and 5 (denoted as azido-PEG(9)-[Pro] 11 MrIA [2][3][4][5][6][7][8][9][10][11][12][13] and azido-PEG(24)-[Pro] 11 MrIA [2][3][4][5][6][7][8][9][10][11][12][13], respectively) with native (1-4, 2-3) disulfide connectivity ( Figure S2, see Supporting Information).…”

“…In this study, we undertook the synthesis of χ-MrIA dendrimers of differing-size PEG spacers with molecular weights ranging from 8 to 22 kDa and further investigated their structural and functional features. Initially, χ-MrIA dendrimers carrying four and eight copies of the χ-MrIA analogues ([Pro] 11 MrIA [2][3][4][5][6][7][8][9][10][11][12][13], 1) were successfully synthesized through the CuAAc reaction, based on the alkynemodified polylysine dendrons (2 and 3, Scheme 1) and azido-PEG chain-modified χ-MrIA analogues [N 3 -PEG(9 or 24)-[Pro] 11 MrIA[2-13]-NH 2 ] (4 and 5, Scheme 2). The CuAAc reaction is a widely used strategy in peptide conjugation promising high efficiency and high selectivity [35,36].…”