Branched Poly(proline) Peptides: An Efficient New Approach to the Synthesis of Repetitive Branched Peptides

Crespo, Laia; Sanclimens, Glòria; Royo, Míriam; Giralt, Ernest; Alberício, Fernando

doi:10.1002/1099-0690(200206)2002:11<1756::aid-ejoc1756>3.0.co;2-a

Cited by 15 publications

(3 citation statements)

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“…We proposed that this property would be stressed in our system due to the plasticity conferred by the polyproline sequence. The dendrimer was prepared using cis -4 amino- l -proline as the scaffold (Figure C). , The second amino group was used as a branch point. Extensive conformational analysis proved the transition from a compacted PPI structure to a more extended PPII conformation as well as the contrary.…”

Section: Proline Rich Cell-penetrating Peptidesmentioning

confidence: 99%

Jumping Hurdles: Peptides Able To Overcome Biological Barriers

2017

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The cell membrane, the gastrointestinal tract, and the blood-brain barrier (BBB) are good examples of biological barriers that define and protect cells and organs. They impose different levels of restriction, but they also share common features. For instance, they all display a high lipophilic character. For this reason, hydrophilic compounds, like peptides, proteins, or nucleic acids have long been considered as unable to bypass them. However, the discovery of cell-penetrating peptides (CPPs) opened a vast field of research. Nowadays, CPPs, homing peptides, and blood-brain barrier peptide shuttles (BBB-shuttles) are good examples of peptides able to target and to cross various biological barriers. CPPs are a group of peptides able to interact with the plasma membrane and enter the cell. They display some common characteristics like positively charged residues, mainly arginines, and amphipathicity. In this field, our group has been focused on the development of proline rich CPPs and in the analysis of the importance of secondary amphipathicity in the internalization process. Proline has a privileged structure being the only amino acid with a secondary amine and a cyclic side chain. These features constrain its structure and hamper the formation of H-bonds. Taking advantage of this privileged structure, three different families of proline-rich peptides have been developed, namely, a proline-rich dendrimer, the sweet arrow peptide (SAP), and a group of foldamers based on γ-peptides. The structure and the mechanism of internalization of all of them has been evaluated and analyzed. BBB-shuttles are peptides able to cross the BBB and to carry with them compounds that cannot reach the brain parenchyma unaided. These peptides take advantage of the natural transport mechanisms present at the BBB, which are divided in active and passive transport mechanisms. On the one hand, we have developed BBB-shuttles that cross the BBB by a passive transport mechanism, like diketoperazines (DKPs), (N-MePhe), or (PhPro). On the other hand, we have investigated BBB-shuttles that utilize active transport mechanisms such as SGV, THRre, or MiniAp-4. For the development of both groups, we have explored several approaches, such as the use of peptide libraries, both chemical and phage display, or hit-to-lead optimization processes. In this Account, we describe, in chronologic order, our contribution to the development of peptides able to overcome various biological barriers and our efforts to understand the mechanisms that they display. In addition, the potential use of both CPPs and BBB-shuttles to improve the transport of promising therapeutic compounds is described.

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Section: Proline Rich Cell-penetrating Peptidesmentioning

confidence: 99%

Jumping Hurdles: Peptides Able To Overcome Biological Barriers

2017

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“…Based on previous observations of Narita et al that protected peptide segments in a random coil conformation are more soluble in organic solvent suitable DAEFRHDSGYEVHHQKLVFFAEDVGSNKG AIIGLMVGGVVIA [90] amyloidogenic neurotoxin prion peptide (106-126) KTNMKHMAGAAAAGAVVGGLG [91] acanthoscurrin (101-132) GGGLGGGRGGGYGGGGGYGGGYGGGYG GGKYK-NH 2 [35] Resin for aminoacylation conditions [82,83], Milton et al proposed a method that uses the Chou-Fasman conformational parameter P c (coil parameter for each amino acid) as follows: the average, <P c >, of a peptide segment reveals its tendency to assume a random coil conformation instead of a a-helix or b-sheet structure; consequently, <P c Ã > (P c Ã can be obtained from the linear regression of the function 1/P c ¼ 0.739P a þ 0.345P b ) values greater than 1.0 indicated easy coupling of the subsequent residue in an acceptable time; values in the range of 0.9-1.0 indicated a longer reaction time and need for recoupling; values lower than 0.9 indicated persistent difficult coupling [79]. The use of P a allowed for the preparation of aggregation profiles, such as those of acyl carrier protein (63-74), (Ala) 10 , cytochrome c (66-104), HIV-1 aspartyl protease (86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99), and growth hormone releasing factor , and for predicting potentially difficult couplings [93]. In 1993, Krchnak et al followed the volume changes of swollen peptide-resins during SPPS and derived a P a for each amino acid coupled (P a : aggregation potential, which reflects the propensity of the amino acid to contribute to peptide aggregation).…”

Section: Difficult Peptide Sequencesmentioning

confidence: 99%

Difficult Peptides

Miranda

and

Remuzgo

2010

Amino Acids, Peptides and Proteins in Organic Chemistry

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As thousands of biologically active peptides have been discovered in the last 50 years, to date no one contests that all living organismsfrom bacteria to mammals and complex plant formsproduce such compounds for vital purposes. A few examples are given in Table 16.1.In association with the first discoveries of biologically active peptides, it was noted that natural sources could provide quite restricted amounts of them. At that time, the composition and structure of proteins were not sufficiently understood and the ribosomal machinery remained unknown. Hence, many first-rate chemists started searching for methods, procedures, and protocols that could allow for the preparation of peptides in a variable range of scales and purities. Such circumstances turned peptide synthesis into an important research topic [1,2].In the following decades, peptide synthesis reached a high level of efficacy, and also became a fundamental tool for research in the chemistry and biology of these macromolecules [1,3]. Indeed, most of the current knowledge on peptide hormones, antibiotics, cytotoxins, opioids, and hormone-releasing factors has been generated with the help of synthetics.Peptide synthesis has also been critical for providing a wide range of information in biochemistry, medicine, biology, and chemistry as its applications include: (i) therapeutic purposes [4,5]; (ii) development of techniques for peptide detection, separation, identification, quantification, and analysis [6, 7]; (iii) characterization of proteinase-substrate or inhibitor interactions [8,9]; (iv) study of protein-protein interactions and the basis of protein folding [10,11]; (v) mapping of protein epitopes [12, 13]; (vi) mimicking of enzyme activity [14, 15]; (vii) engineering of new peptide-based drugs with therapeutic potential [16, 17]; (viii) design of new biomaterials [18, 19]; (ix) synthesis of prodrugs [20, 21]; and (x) chemical synthesis of proteins [22, 23].Despite these advances, peptide synthesis remains a research topic that attracts an impressive number of scientists worldwide. Most current studies focus

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“…So far, several examples for the solid phase-assisted synthesis of dendrimers are available [4], including the syntheses of polyamidoamine (PAMAM) dendrimers [5,6,7], polylysine dendrimers [8,9,10], poly-amino acid dendrimers [11,12,13,14,15], aromatic polyethers [16,17,18,19] and polyurea-based dendrimers [20,21,22]. However, the vast majority of these syntheses apply definite building blocks, defining the structure of the resulting dendrimers and thus do not enable a modular dendritic molecular design.…”

Section: Introductionmentioning

confidence: 99%

Optimized Solid Phase-Assisted Synthesis of Dendrons Applicable as Scaffolds for Radiolabeled Bioactive Multivalent Compounds Intended for Molecular Imaging

Fischer

Wängler

2014

Molecules

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Dendritic structures, being highly homogeneous and symmetric, represent ideal scaffolds for the multimerization of bioactive molecules and thus enable the synthesis of compounds of high valency which are e.g., applicable in radiolabeled form as multivalent radiotracers for in vivo imaging. As the commonly applied solution phase synthesis of dendritic scaffolds is cumbersome and time-consuming, a synthesis strategy was developed that allows for the efficient assembly of acid amide bond-based highly modular dendrons on solid support via standard Fmoc solid phase peptide synthesis protocols. The obtained dendritic structures comprised up to 16 maleimide functionalities and were derivatized on solid support with the chelating agent DOTA. The functionalized dendrons furthermore could be efficiently reacted with structurally variable model thiol-bearing bioactive molecules via click chemistry and finally radiolabeled with 68 Ga. Thus, this solid phase-assisted dendron synthesis approach enables the fast and straightforward assembly of bioactive multivalent constructs for example applicable as radiotracers for in vivo imaging with Positron Emission Tomography (PET).

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Branched Poly(proline) Peptides: An Efficient New Approach to the Synthesis of Repetitive Branched Peptides

Cited by 15 publications

References 10 publications

Jumping Hurdles: Peptides Able To Overcome Biological Barriers

Jumping Hurdles: Peptides Able To Overcome Biological Barriers

Difficult Peptides

Optimized Solid Phase-Assisted Synthesis of Dendrons Applicable as Scaffolds for Radiolabeled Bioactive Multivalent Compounds Intended for Molecular Imaging

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