Synthesis of six-membered carbocyclic ring α,α-disubstituted amino acids and arginine-rich peptides to investigate the effect of ring size on the properties of the peptide

Kato, Takuma; Kita, Yoshihiro; Iwanari, Kazuki; Asano, Akiko; Oba, Makoto; Tanaka, Masakazu; Doi, Mitsunobu

doi:10.1016/j.bmc.2021.116111

Cited by 12 publications

(5 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A stable helical structure of the arginine-rich peptide is necessary for their cell-penetrating abilities [ 81 , 82 ], causing the formation of the α-helical structure to decrease the polarity and the free energy cost of transfer to the hydrophobic membranes for peptide bonds in the peptide molecule [ 83 ]. To gain insight into the significance of α-helix formation for transcellular cargo delivery, Komin et al [ 72 ] designed a peptide (RLLrLLR, CLr) with the same sequence as the CL peptide (RLLRLLR).…”

Section: Peptide Design Of the Arginine-rich Cppsmentioning

confidence: 99%

Membrane Internalization Mechanisms and Design Strategies of Arginine-Rich Cell-Penetrating Peptides

Hao

Zhang

Chen

2022

IJMS

View full text Add to dashboard Cite

Cell-penetrating peptides (CPPs) have been discovered to deliver chemical drugs, nucleic acids, and macromolecules to permeate cell membranes, creating a novel route for exogenous substances to enter cells. Up until now, various sequence structures and fundamental action mechanisms of CPPs have been established. Among them, arginine-rich peptides with unique cell penetration properties have attracted substantial scientific attention. Due to the positively charged essential amino acids of the arginine-rich peptides, they can interact with negatively charged drug molecules and cell membranes through non-covalent interaction, including electrostatic interactions. Significantly, the sequence design and the penetrating mechanisms are critical. In this brief synopsis, we summarize the transmembrane processes and mechanisms of arginine-rich peptides; and outline the relationship between the function of arginine-rich peptides and the number of arginine residues, arginine optical isomers, primary sequence, secondary and ternary structures, etc. Taking advantage of the penetration ability, biomedical applications of arginine-rich peptides have been refreshed, including drug/RNA delivery systems, biosensors, and blood-brain barrier (BBB) penetration. Understanding the membrane internalization mechanisms and design strategies of CPPs will expand their potential applications in clinical trials.

show abstract

Section: Peptide Design Of the Arginine-rich Cppsmentioning

confidence: 99%

Membrane Internalization Mechanisms and Design Strategies of Arginine-Rich Cell-Penetrating Peptides

Hao

Zhang

Chen

2022

IJMS

View full text Add to dashboard Cite

show abstract

“…X-ray crystallographic analysis suggested that peptide 2a , composed of (1 S ,3 S )-Ac 5 c 3OAll and (1 R ,3 S )-Ac 5 c 3OAll , possessed a right-handed α-helical structure, while peptide 4a , composed of ( S )-Ala(4-Pte), comprises a mixture of right-handed 3 10 - and α-helical segment conformations. Further studies, including mechanistic investigation and application to helical foldamer organocatalysts and biologically active peptides, are in the progress in our laboratory.…”

mentioning

confidence: 99%

E-Selective Ring-Closing Metathesis in α-Helical Stapled Peptides Using Carbocyclic α,α-Disubstituted α-Amino Acids

et al. 2022

Self Cite

View full text Add to dashboard Cite

We present an E-selective ring-closing metathesis reaction in α-helical stapled peptides at positions i and i + 4. The use of two chiral carbocyclic α,α-disubstituted α-amino acids, (1S,3S)-Ac5c3OAll and (1R,3S)-Ac5c3OAll, provides a high E-selectivity of a ≤59:1 E:Z ratio, while mixtures with E:Z ratios of 2.1–0.5:1 were produced with standard acyclic (S)-(4-pentenyl)alanine amino acids. A stapled octapeptide composed of (1S,3S)- and (1R,3S)-Ac5c3OAll amino acids showed a right-handed α-helical crystal structure.

show abstract

“…16,17) It has also been reported that they improve the function of cationic CPPs. [18][19][20][21] In our previous studies, we investigated the effects of replacing various hydrophobic amino acids in the pep-1 sequence with dAAs and confirmed that replacing the three glutamic acid (Glu) residues in the hydrophobic domain with a dAA (1-aminocyclopentanecarboxylic acid (Ac 5 c)) results in high cell membrane permeability. 22) For the present study, we synthesized and evaluated four peptide analogs to investigate in more detail the effects of replacing Glu with a dAA on cell membrane permeability.…”

Section: Introductionmentioning

confidence: 87%

Effects of Substituting Disubstituted Amino Acids into the Amphipathic Cell Penetrating Peptide Pep-1

Kato

Numa

Nakamachi

et al. 2022

CHEMICAL & PHARMACEUTICAL BULLETIN

Self Cite

View full text Add to dashboard Cite

Amphipathic cell-penetrating peptides based on the pep-1 sequence were synthesized by replacing the three hydrophilic glutamic acid residues with disubstituted, non-proteinogenic, hydrophobic amino acids. These substitutions facilitated maintenance of the peptides' secondary structure in a helical conformation, even in aqueous solution. Stability against enzymatic degradation was improved through the use of disubstituted amino acids. The resultant peptides exhibited high membrane permeability that remained relatively stable during prolonged incubation times. The results of this study indicate that the use of non-proteinogenic amino acids may be an effective approach to improve the cell membrane permeability for existing amphiphilic peptides.

show abstract

Synthesis of six-membered carbocyclic ring α,α-disubstituted amino acids and arginine-rich peptides to investigate the effect of ring size on the properties of the peptide

Cited by 12 publications

References 46 publications

Membrane Internalization Mechanisms and Design Strategies of Arginine-Rich Cell-Penetrating Peptides

Membrane Internalization Mechanisms and Design Strategies of Arginine-Rich Cell-Penetrating Peptides

E-Selective Ring-Closing Metathesis in α-Helical Stapled Peptides Using Carbocyclic α,α-Disubstituted α-Amino Acids

Effects of Substituting Disubstituted Amino Acids into the Amphipathic Cell Penetrating Peptide Pep-1

Contact Info

Product

Resources

About