title: The rational search for selective anticancer derivatives of the peptide Trichogin GA IV: a multi-technique biophysical approach.
abstract: Peptaibols are peculiar peptides produced by fungi as weapons against other microorganisms. Previous studies showed that peptaibols are promising peptide-based drugs because they act against cell membranes rather than a specific target, thus lowering the possibility of the onset of multi-drug resistance, and they possess non-coded α-amino acid residues that confer proteolytic resistance. Trichogin GA IV (TG) is a short peptaibol displaying antimicrobial and cytotoxic activity. In the present work, we studied thirteen TG analogues, adopting a multidisciplinary approach. We showed that the cytotoxicity is tuneable by single amino-acids substitutions. Many analogues maintain the same level of non-selective cytotoxicity of TG and three analogues are completely non-toxic. Two promising lead compounds, characterized by the introduction of a positively charged unnatural amino-acid in the hydrophobic face of the helix, selectively kill T67 cancer cells without affecting healthy cells. To explain the determinants of the cytotoxicity, we investigated the structural parameters of the peptides, their cell-binding properties, cell localization, and dynamics in the membrane, as well as the cell membrane composition. We show that, while cytotoxicity is governed by the fine balance between the amphipathicity and hydrophobicity, the selectivity depends also on the expression of negatively charged phospholipids on the cell surface.
authors.affiliation: Dipartimento di Chimica, Università di Padova, via Marzolo 1, 35131, Padova, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Dalzini
authors.affiliation: Dipartimento di Farmacia e Biotecnologie, Università di Bologna, via Irnerio 48, 40126, Bologna, Italy.
authors.forename: Christian
authors.initials: C
authors.lastname: Bergamini
authors.affiliation: Dipartimento di Chimica, Università di Padova, via Marzolo 1, 35131, Padova, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Biondi
authors.affiliation: Dipartimento di Chimica, Università di Padova, via Marzolo 1, 35131, Padova, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: De Zotti
authors.affiliation: Dipartimento di Chimica, Università di Padova, via Marzolo 1, 35131, Padova, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Panighel
authors.affiliation: Dipartimento di Farmacia e Biotecnologie, Università di Bologna, via Irnerio 48, 40126, Bologna, Italy.
authors.forename: Romana
authors.initials: R
authors.lastname: Fato
authors.affiliation: Dipartimento di Chimica, Università di Padova, via Marzolo 1, 35131, Padova, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Peggion
authors.affiliation: Dipartimento di Chimica, Università di Padova, via Marzolo 1, 35131, Padova, Italy.|Dipartimento di Scienza dei Materiali, Università degli Studi di Milano Bicocca, 20126, Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Bortolus
authors.affiliation: Dipartimento di Chimica, Università di Padova, via Marzolo 1, 35131, Padova, Italy.
authors.forename: Anna Lisa
authors.initials: AL
authors.lastname: Maniero
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D055666:Lipopeptides / Q000737:chemistry*; D054848:Peptaibols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D055666:Lipopeptides; D054848:Peptaibols; C116419:trichogin GA IV