Novel pH-Sensitive Cyclic Peptides

Dhammika Weerakkody, Anna Moshnikova, Naglaa Salem El-Sayed, Ramona Cosmina Adochite, Gregory Slaybaugh, Jovana Golijanin, Rakesh K. Tiwari, Oleg A. Andreev, Keykavous Parang, Yana K. Reshetnyak

Research output: Contribution to journalArticle

Abstract

A series of cyclic peptides containing a number of tryptophan (W) and glutamic acid (E) residues were synthesized and evaluated as pH-sensitive agents for targeting of acidic tissue and pH-dependent cytoplasmic delivery of molecules. Biophysical studies revealed the molecular mechanism of peptides action and localization within the lipid bilayer of the membrane at high and low pHs. The symmetric, c[(WE)4 WC], and asymmetric, c[E4 W5 C], cyclic peptides translocated amanitin, a polar cargo molecule of similar size, across the lipid bilayer and induced cell death in a pH-and concentration-dependent manner. Fluorescently-labelled peptides were evaluated for targeting of acidic 4T1 mammary tumors in mice. The highest tumor to muscle ratio (5.6) was established for asymmetric cyclic peptide, c[E4 W5 C], at 24 hours after intravenous administration. pH-insensitive cyclic peptide c[R4 W5 C], where glutamic acid residues (E) were replaced by positively charged arginine residues (R), did not exhibit tumor targeting. We have introduced a novel class of cyclic peptides, which can be utilized as a new pH-sensitive tool in investigation or targeting of acidic tissue.

Original languageEnglish (US)
Article number31322
JournalScientific Reports
Volume6
DOIs
StatePublished - Aug 12 2016
Externally publishedYes

Fingerprint

Cyclic Peptides
Lipid Bilayers
Glutamic Acid
Amanitins
Peptides
Tryptophan
Intravenous Administration
Arginine
Neoplasms
Cell Death
Breast Neoplasms
Muscles
Membranes

ASJC Scopus subject areas

  • General

Cite this

Weerakkody, D., Moshnikova, A., El-Sayed, N. S., Adochite, R. C., Slaybaugh, G., Golijanin, J., ... Reshetnyak, Y. K. (2016). Novel pH-Sensitive Cyclic Peptides. Scientific Reports, 6, [31322]. https://doi.org/10.1038/srep31322

Novel pH-Sensitive Cyclic Peptides. / Weerakkody, Dhammika; Moshnikova, Anna; El-Sayed, Naglaa Salem; Adochite, Ramona Cosmina; Slaybaugh, Gregory; Golijanin, Jovana; Tiwari, Rakesh K.; Andreev, Oleg A.; Parang, Keykavous; Reshetnyak, Yana K.

In: Scientific Reports, Vol. 6, 31322, 12.08.2016.

Research output: Contribution to journalArticle

Weerakkody, D, Moshnikova, A, El-Sayed, NS, Adochite, RC, Slaybaugh, G, Golijanin, J, Tiwari, RK, Andreev, OA, Parang, K & Reshetnyak, YK 2016, 'Novel pH-Sensitive Cyclic Peptides', Scientific Reports, vol. 6, 31322. https://doi.org/10.1038/srep31322
Weerakkody D, Moshnikova A, El-Sayed NS, Adochite RC, Slaybaugh G, Golijanin J et al. Novel pH-Sensitive Cyclic Peptides. Scientific Reports. 2016 Aug 12;6. 31322. https://doi.org/10.1038/srep31322
Weerakkody, Dhammika ; Moshnikova, Anna ; El-Sayed, Naglaa Salem ; Adochite, Ramona Cosmina ; Slaybaugh, Gregory ; Golijanin, Jovana ; Tiwari, Rakesh K. ; Andreev, Oleg A. ; Parang, Keykavous ; Reshetnyak, Yana K. / Novel pH-Sensitive Cyclic Peptides. In: Scientific Reports. 2016 ; Vol. 6.
@article{fc7fc44552d9410abbdf331faffe28a7,
title = "Novel pH-Sensitive Cyclic Peptides",
abstract = "A series of cyclic peptides containing a number of tryptophan (W) and glutamic acid (E) residues were synthesized and evaluated as pH-sensitive agents for targeting of acidic tissue and pH-dependent cytoplasmic delivery of molecules. Biophysical studies revealed the molecular mechanism of peptides action and localization within the lipid bilayer of the membrane at high and low pHs. The symmetric, c[(WE)4 WC], and asymmetric, c[E4 W5 C], cyclic peptides translocated amanitin, a polar cargo molecule of similar size, across the lipid bilayer and induced cell death in a pH-and concentration-dependent manner. Fluorescently-labelled peptides were evaluated for targeting of acidic 4T1 mammary tumors in mice. The highest tumor to muscle ratio (5.6) was established for asymmetric cyclic peptide, c[E4 W5 C], at 24 hours after intravenous administration. pH-insensitive cyclic peptide c[R4 W5 C], where glutamic acid residues (E) were replaced by positively charged arginine residues (R), did not exhibit tumor targeting. We have introduced a novel class of cyclic peptides, which can be utilized as a new pH-sensitive tool in investigation or targeting of acidic tissue.",
author = "Dhammika Weerakkody and Anna Moshnikova and El-Sayed, {Naglaa Salem} and Adochite, {Ramona Cosmina} and Gregory Slaybaugh and Jovana Golijanin and Tiwari, {Rakesh K.} and Andreev, {Oleg A.} and Keykavous Parang and Reshetnyak, {Yana K.}",
year = "2016",
month = "8",
day = "12",
doi = "10.1038/srep31322",
language = "English (US)",
volume = "6",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Novel pH-Sensitive Cyclic Peptides

AU - Weerakkody, Dhammika

AU - Moshnikova, Anna

AU - El-Sayed, Naglaa Salem

AU - Adochite, Ramona Cosmina

AU - Slaybaugh, Gregory

AU - Golijanin, Jovana

AU - Tiwari, Rakesh K.

AU - Andreev, Oleg A.

AU - Parang, Keykavous

AU - Reshetnyak, Yana K.

PY - 2016/8/12

Y1 - 2016/8/12

N2 - A series of cyclic peptides containing a number of tryptophan (W) and glutamic acid (E) residues were synthesized and evaluated as pH-sensitive agents for targeting of acidic tissue and pH-dependent cytoplasmic delivery of molecules. Biophysical studies revealed the molecular mechanism of peptides action and localization within the lipid bilayer of the membrane at high and low pHs. The symmetric, c[(WE)4 WC], and asymmetric, c[E4 W5 C], cyclic peptides translocated amanitin, a polar cargo molecule of similar size, across the lipid bilayer and induced cell death in a pH-and concentration-dependent manner. Fluorescently-labelled peptides were evaluated for targeting of acidic 4T1 mammary tumors in mice. The highest tumor to muscle ratio (5.6) was established for asymmetric cyclic peptide, c[E4 W5 C], at 24 hours after intravenous administration. pH-insensitive cyclic peptide c[R4 W5 C], where glutamic acid residues (E) were replaced by positively charged arginine residues (R), did not exhibit tumor targeting. We have introduced a novel class of cyclic peptides, which can be utilized as a new pH-sensitive tool in investigation or targeting of acidic tissue.

AB - A series of cyclic peptides containing a number of tryptophan (W) and glutamic acid (E) residues were synthesized and evaluated as pH-sensitive agents for targeting of acidic tissue and pH-dependent cytoplasmic delivery of molecules. Biophysical studies revealed the molecular mechanism of peptides action and localization within the lipid bilayer of the membrane at high and low pHs. The symmetric, c[(WE)4 WC], and asymmetric, c[E4 W5 C], cyclic peptides translocated amanitin, a polar cargo molecule of similar size, across the lipid bilayer and induced cell death in a pH-and concentration-dependent manner. Fluorescently-labelled peptides were evaluated for targeting of acidic 4T1 mammary tumors in mice. The highest tumor to muscle ratio (5.6) was established for asymmetric cyclic peptide, c[E4 W5 C], at 24 hours after intravenous administration. pH-insensitive cyclic peptide c[R4 W5 C], where glutamic acid residues (E) were replaced by positively charged arginine residues (R), did not exhibit tumor targeting. We have introduced a novel class of cyclic peptides, which can be utilized as a new pH-sensitive tool in investigation or targeting of acidic tissue.

UR - http://www.scopus.com/inward/record.url?scp=84982112149&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84982112149&partnerID=8YFLogxK

U2 - 10.1038/srep31322

DO - 10.1038/srep31322

M3 - Article

C2 - 27515582

AN - SCOPUS:84982112149

VL - 6

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 31322

ER -