Peptide dendrimers: applications and synthesis

Sadler, Kristen; Tam, James P.

doi:10.1016/s1389-0352(01)00061-7

Cited by 326 publications

(249 citation statements)

References 261 publications

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“…Although the possible higher stability of dendrimeric peptides has been speculated previously (6), to our knowledge this is the first demonstration of MAPs resistance to blood and brain proteases. A higher stability of MAP activity following trypsin treatment, with respect to the corresponding linear peptide, was already reported for an antimicrobial peptide (21), although no chemical characterization of peptide proteolysis was reported.…”

Section: Discussionmentioning

confidence: 64%

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Synthetic Peptides in the Form of Dendrimers Become Resistant to Protease Activity

Bracci

Falciani

Lelli

et al. 2003

Journal of Biological Chemistry

156

162

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In previous papers, we observed that dendrimers of peptide mimotopes of the nicotinic receptor ligand site are strong antidotes against the lethality of the nicotinic receptor ligand ␣-bungarotoxin. Although their in vitro activity is identical to that of dendrimers, the corresponding monomeric peptide mimotopes are not effective in vivo. Because the higher in vivo efficiency of dendrimers could not in this case be related to polyvalent interaction, the stability to blood protease activity of monomeric versus tetrabranched dendrimeric mimotope peptides was compared here by incubating three different mimotopes with human plasma and serum. Unmodified peptides and cleaved sequences were followed by high pressure liquid chromatography and mass spectrometry. Tetrabranched peptides were shown to be much more stable in plasma and also in serum. To assess the notable stability of multimeric peptides, different bioactive neuropeptides, including enkephalins, neurotensin and nociceptin, were synthesized in monomeric and tetrabranched forms and incubated with human plasma and serum and with rat brain membrane extracts. All the tetrabranched neuropeptides fully retained biological activity and generally showed much greater stability to blood and brain protease activity. Some tetrabranched peptides were also resistant to trypsin and chymotrypsin. Our findings provide new insights into the possible therapeutic use of bioactive peptides.Hundreds of peptides with potential therapeutic activities have been identified. These include naturally occurring peptide hormones and neurotransmitters, which influence and control series of vital functions, such as cell proliferation, tissue development, metabolism, immune defense, perception of pain, reproduction, behavior, and blood pressure. Selective agonists or antagonists of these natural peptides are extremely useful for the investigation of peptidergic systems and are also potential therapeutic agents (1). Moreover, several peptide fragments or mimotopes derived from potential therapeutic proteins show promising biological activity (2).However, the use of peptides as therapeutic drugs has largely been limited by their short half-life in vivo. Because peptides are mainly broken down by proteases and peptidases, peptide delivery is the bottleneck in the development of new peptide drugs. To increase peptide half-life, many strategies involving different levels of chemical modification are possible (3, 4). The introduction of D-amino acids, or pseudo amino acids, and peptide cyclization are the most common strategies to increase peptide stability. However, these modifications may profoundly alter peptide activity. Alternatively, peptidomimetic molecules can be developed by the synthesis of conformationally restricted compounds, in which the peptide is locally or globally constrained in order to reproduce the active conformation. The resulting structures are mostly non-peptide molecules, more resistant to degrading enzymes.In general, peptide molecules have the advantage of good specifici...

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Section: Discussionmentioning

confidence: 64%

“…MAPs can be more efficient than monomeric peptides in diagnostic applications. Moreover, they also proved to be good immunogens against a number of pathogens (6). The in vitro and in vivo efficiency of dendrimeric peptides like MAPs is generally ascribed to their multimeric nature, which enables polyvalent interactions.…”

mentioning

confidence: 99%

Synthetic Peptides in the Form of Dendrimers Become Resistant to Protease Activity

Bracci

Falciani

Lelli

et al. 2003

Journal of Biological Chemistry

156

162

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“…The unique architecture and monodispersity of dendrimers allow their principle use as molecular cages for a direct transport of different guest molecules like drugs and DNA [1][2][3][4]. Complexes of dendrimers with these compounds in water solutions at neutral or low pH are stabilized mainly due to the electrostatic forces.…”

Section: Introductionmentioning

confidence: 99%

Dynamics of Complexation of a Charged Dendrimer by Linear Polyelectrolyte: Computer Modelling

Lyulin

Darinskii

2007

E-Polymers

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Brownian-dynamics simulations have been performed for complexes formed by a charged dendrimer and a long oppositely charged linear polyelectrolyte when overcharging phenomenon is always observed. After complex formation the orientational mobility of the individual dendrimer bonds, the fluctuations of the dendrimer size, and the dendrimer rotational diffusion have been simulated. Corresponding relaxation times do not depend on the linear-chain length in a complex and are close to those for a single neutral dendrimer. At the same time fluctuations of the size of a complex are completely defined by the corresponding fluctuations of a linear polyelectrolyte size. Adsorbed polyelectrolyte practically does not feel the rotation of a dendrimer; simulated complexes may be considered as nuts with light core (dendrimer) and heavy shell (adsorbed linear polymer); the electrostatic contacts between dendrimer and oppositely charged linear polymer are easily broken due to the very fast dendrimer-size fluctuations.

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“…Syntheses of dendrimers include the use of Tomalia's divergent growth approach, convergent growth approach, and orthogonal coupling strategy 26,66,67 , while solid lipid nanoparticles are prepared by high shear homogenization, ultrasound dispersion technique, high pressure homogenization, solvent emulsification/evaporation, microemulsion and solvent diffusion 33,68,69 .…”

Section: Methods Of Fabricationmentioning

confidence: 99%