Novel pH-Sensitive Cyclic Peptides

作者：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^*

来源：Scientific Reports, 2016, 6(1): 31322.

DOI：10.1038/srep31322

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[E4W5C], 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[E4W5C], at 24 hours after intravenous administration. pH-insensitive cyclic peptide c[R4W5C], 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.

• 出版日期2016-8-12