Journal Article

Novel pH-Sensitive Cyclic Peptides

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

2016

Overview

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[E 4 W 5 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[E 4 W 5 C], at 24 hours after intravenous administration. pH-insensitive cyclic peptide c[R 4 W 5 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/154/152 / 692/4028/67 / Amanitin / Arginine / Breast cancer / Cell death / Glutamic acid / Humanities and Social Sciences / Intravenous administration / Localization / multidisciplinary / Peptides / pH effects / Science / Tryptophan / Tumors