A Novel Cell-Penetrating Peptide Sequence Derived by Structural Minimization of a Snake Toxin Exhibits Preferential Nucleolar Localization

Structural simplification of a 42-residue venom peptide by N-to-C-terminal splicing led to two sequences [YKQCHKKG-GXKKGSG, where X = nil (1) or 6-aminohexanoyl (2)], both efficiently uptaken by HeLa cells and, most interestingly, specifically localized at the nucleolus. Retro-2 was uptaken less efficiently, but a single (His -> Ile) replacement recovered the translocation ability. None of the peptides were cytotoxic up to 100 mu M. Enantio-1 did not translocate, suggesting that peptide uptake was receptor-mediated.