Abstract
Peptaibols, by disturbing the permeability of phospholipid membranes, can overcome anticancer drug resistance, but their natural hydrophobicity hampers their administration. By a green peptide synthesis protocol, we produced two water-soluble analogs of the peptaibol trichogin GA IV, termed K6-Lol and K6-NH2. To reduce production costs, we successfully explored the possibility of changing the naturally occurring 1,2-aminoalcohol leucinol to a C-terminal amide. Peptaibol activity was evaluated in ovarian cancer (OvCa) and Hodgkin lymphoma (HL) cell lines. Peptaibols exerted comparable cytotoxic effects in cancer cell lines that were sensitive—and had acquired resistance—to cisplatin and doxorubicin, as well as in the extrinsic-drug-resistant OvCa 3-dimensional spheroids. Peptaibols, rapidly taken up by tumor cells, deeply penetrated and killed OvCa-spheroids. They led to cell membrane permeabilization and phosphatidylserine exposure and were taken up faster by cancer cells than normal cells. They were resistant to proteolysis and maintained a stable helical structure in the presence of cancer cells. In conclusion, these promising results strongly point out the need for further preclinical evaluation of our peptaibols as new anticancer agents.
Highlights
Characterizations are reported in the Supporting Information
We found that both peptaibols decreased tumor growth of cHL and ovarian cancer (OvCa) cell lines in a dose dependent manner, with IC50 ranging from 7.2 to 13.2 μM in cHL cells and from 7.5 to 10.5 μM in OvCa cells (Table 1)
We evaluated the fluorescent calcein released in culture medium from cHL and OvCa cells treated or not with peptaibols
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. They have target specificity, rarely show off-target toxicity, are far cheaper than biological molecules (therapeutic proteins), have better tissue penetration ability and reduced immunogenicity than antibodies [2] In this context, naturally occurring, bioactive peptides are the first choice for the development of active agents. We propose the substitution of the naturally occurring C-terminal Leucinol for the far cheaper Leucine amide and test if this modification affects the bioactivity of the peptide analogs To this end, we synthesized two water-soluble analogs of the short-length peptaibol trichogin GA IV, termed K6-Lol and K6-NH2. We describe the synthesis (by green synthesis) of the water-soluble peptaibol analogs K6-Lol and K6-NH2, and determine/compare (i) their proteolytic and plasma stability, (ii) their mechanism of action and (iii) cytotoxicity in cisplatin and doxorubicinresistant cancer cells from HL lymphoma (Hodgkin Reed Sternberg, HRS) and from OvCa
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