Impact of fluorination on proteolytic stability of peptides: a case study with α-chymotrypsin and pepsin

Asante, Vivian; Mortier, Jérémie; Wolber, Gerhard; Koksch, Beate

doi:10.1007/s00726-014-1819-7

Cited by 39 publications

(49 citation statements)

References 76 publications

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“…Trypsin exclusively cleaves Arg or Lys residues on the C terminal, and α-chymotrypsin preferentially cleaves peptide amide bonds and prefers hydrophobic residues, such as Tyr, Trp, or Phe (Kim et al, 2013;Asante et al, 2014). These AA are sensitive to free radicals and transformed into carbonyl groups (Kim et al, 2013).…”

Section: In Vitro Digestibility Of Oxidized Wpimentioning

confidence: 99%

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Susceptibility of whey protein isolate to oxidation and changes in physicochemical, structural, and digestibility characteristics

Feng

Ullah

et al. 2015

Journal of Dairy Science

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Oxidation is an important factor for denaturing of whey protein isolate (WPI) during food processing. We studied the effects of chemical oxidation on physicochemical and structural changes along with in vitro digestibility of WPI in this work. Evaluation of physicochemical changes showed that carbonyl level and dityrosine content increased, whereas total and free thiol group levels decreased for oxidized WPI samples. For the structural changes, protein aggregation was measured by surface hydrophobicity, turbidity, and particle diameter, which was increased for oxidized WPI samples. The increase of the secondary structure β-sheets and antiparallel β-sheet also supported the aggregation of oxidized WPI. A direct quantitative relationship between physicochemical and structural changes and protein digestibility indicated that oxidation-related damage restricts the susceptibility of WPI to proteases. In conclusion, WPI had high susceptibility to oxidative stress, and both physicochemical and structural changes caused by severe oxidative stress could decrease the rate of in vitro digestibility of WPI.

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Section: In Vitro Digestibility Of Oxidized Wpimentioning

confidence: 99%

“…Both trypsin and α-chymotrypsin are serine endopeptidases (Asante et al, 2014). Trypsin exclusively cleaves Arg or Lys residues on the C terminal, and α-chymotrypsin preferentially cleaves peptide amide bonds and prefers hydrophobic residues, such as Tyr, Trp, or Phe (Kim et al, 2013;Asante et al, 2014).…”

Section: In Vitro Digestibility Of Oxidized Wpimentioning

confidence: 99%

Susceptibility of whey protein isolate to oxidation and changes in physicochemical, structural, and digestibility characteristics

Feng

Ullah

et al. 2015

Journal of Dairy Science

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“…In an attempt to better understand fluorine's impact on the proteolytic stability of peptides, our group initiated a systematic study and established a peptide library that contained amino acids with systematically changed fluorine content at different positions relative to the protease cleavage sites. A 10‐amino acid model peptide, referred to as FA, was designed to combine the substrate specificities of different serine and aspartate proteases . Substitutions of Ala with fluorinated amino acids were introduced at the P2, P1′, or P2′ positions, which are at or adjacent to the cleavage site and carry the key residues for the recognition of the substrate by the protease (Figure ).…”

Section: Fluorinated Amino Acids For Influencing the Stability Of mentioning

confidence: 99%

“…Comparison with corresponding peptides containing the fluorine‐free amino acid 2‐aminobutanoic acid (Abu) enabled conclusions to be made about the role of electronic vs. steric effects. The proteolytic stability of the 10 different peptides of that library was investigated in the context of human blood plasma and elastase,[21a] as well as α‐chymotrypsin and pepsin. [21b]…”

Section: Fluorinated Amino Acids For Influencing the Stability Of mentioning

confidence: 99%

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Fine‐Tuning the Proteolytic Stability of Peptides with Fluorinated Amino Acids

Huhmann

Koksch

2018

Eur J Org Chem

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The decoration of organic compounds with fluorine substituents is a strategy well‐known to medicinal chemists. Around 25 % of drugs on the market contain at least one fluorine atom, as fluorine's unique properties very often produce effects that cannot be achieved by any other known functional group. The changes in molecular properties due to the incorporation of fluorine most relevant to medicinal chemistry are conformation, pKa values of neighboring functional groups, and interaction with proteins and membranes. The introduction of fluorine dramatically impacts these and in turn the pharmacokinetics and biological half‐lives of not only small molecules but peptides, which show high binding affinity and selectivity for their target and are, therefore, also desirable lead compounds in drug development. Unfortunately, several factors can limit the efficacy of peptides and biologicals including low bioavailability and protease digestion. Although the literature has numerous examples showing that fluorine can improve the latter aspect, there are also cases to the contrary. This review aims to provide an overview of the influence of fluorinated amino acids on the proteolytic stability of peptides.

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(R)‐α‐trifluoromethylalanine containing short peptide in the inhibition of amyloid peptide fibrillation

Botz

Gasparik²,

Devillers³

et al. 2015

Biopolymers

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The extracellular deposition of insoluble amyloid fibrils resulting from the aggregation of the amyloid-β (Aβ) is a pathological feature of neuronal loss in Alzheimer's disease (AD). Numerous small molecules have been reported to interfere with the process of Aβ aggregation. Compounds containing aromatic structures, hydrophobic amino acids and/or the α-aminoisobutyric acid (Aib) as β-sheet breaker elements have been reported to be effective inhibitors of Aβ aggregation. We synthesized two peptides, one containing the Aib amino acid and the other including its trifluoromethylated analog (R)-α-Trifluoromethylalanine ((R)-Tfm-Alanine) and we evaluated the impact of these peptides on Aβ amyloid formation. The compounds were tested by standard methods such as thioflavin-T fluorescence spectroscopy and transmission electron microscopy but also by circular dichroism, liquid state nuclear magnetic resonance (NMR) and NMR saturation transfer difference (STD) experiments to further characterize the effect of the two molecules on Aβ structure and on the kinetics of depletion of monomeric, soluble Aβ. Our results demonstrate that the peptide containing Aib reduces the quantity of aggregates containing β-sheet structure but slightly inhibits Aβ fibril formation, while the molecule including the trifluoromethyl (Tfm) group slows down the kinetics of Aβ fibril formation, delays the random coil to β-sheet structure transition and induces a change in the oligomerization pathway. These results suggest that the hydrophobic Tfm group has a better affinity with Aβ than the methyl groups of the Aib and that this Tfm group is effective and important in preventing the Aβ aggregation.

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Impact of fluorination on proteolytic stability of peptides: a case study with α-chymotrypsin and pepsin

Cited by 39 publications

References 76 publications

Susceptibility of whey protein isolate to oxidation and changes in physicochemical, structural, and digestibility characteristics

Susceptibility of whey protein isolate to oxidation and changes in physicochemical, structural, and digestibility characteristics

Fine‐Tuning the Proteolytic Stability of Peptides with Fluorinated Amino Acids

(R)‐α‐trifluoromethylalanine containing short peptide in the inhibition of amyloid peptide fibrillation

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