title: Comparative analysis reveals amino acids critical for anticancer activity of peptide CIGB-552.
abstract: Because of resistance development by cancer cells against current anticancer drugs, there is a considerable interest in developing novel antitumor agents. We have previously demonstrated that CIGB-552, a novel cell-penetrating synthetic peptide, was effective in reducing tumor size and increasing lifespan in tumor-bearing mice. Studies of protein-peptide interactions have shown that COMMD1 protein is a major mediator of CIGB-552 antitumor activity. Furthermore, a typical serine-protease degradation pattern for CIGB-552 in BALB/c mice serum was identified, yielding peptides which differ from CIGB-552 in size and physical properties. In the present study, we show the results obtained from a comparative analysis between CIGB-552 and its main metabolites regarding physicochemical properties, cellular internalization, and their capability to elicit apoptosis in MCF-7 cells. None of the analyzed metabolites proved to be as effective as CIGB-552 in promoting apoptosis in MCF-7. Taking into account these results, it seemed important to examine their cell-penetrating capacity and interaction with COMMD1. We show that internalization, a lipid binding-dependent process, is impaired as well as metabolite-COMMD1 interaction, key component of the apoptotic mechanism. Altogether, our results suggest that features conferred by the amino acid sequence are decisive for CIGB-552 biological activity, turning it into the minimal functional unit. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.
authors.affiliation: Cell Biology Unit, Institut Pasteur de Montevideo, Mataojo 2020, 11400, Montevideo, Uruguay.
authors.forename: Soledad
authors.initials: S
authors.lastname: Astrada
authors.affiliation: Pharmaceutical Department, Center for Genetic Engineering and Biotechnology, Havana, Cuba.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Gomez
authors.affiliation: Biomolecular Simulations, Institut Pasteur Montevideo, Montevideo, Uruguay.
authors.forename: Exequiel
authors.initials: E
authors.lastname: Barrera
authors.affiliation: Protein Biophysics Unit, Institut Pasteur Montevideo, Montevideo, Uruguay.|Departamento de Inmunobiología, Facultad de Medicina, Universidad de la República, Avenida General Flores 2125, 11800, Montevideo, Uruguay.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Obal
authors.affiliation: Protein Biophysics Unit, Institut Pasteur Montevideo, Montevideo, Uruguay.
authors.forename: Otto
authors.initials: O
authors.lastname: Pritsch
authors.affiliation: Biomolecular Simulations, Institut Pasteur Montevideo, Montevideo, Uruguay.
authors.forename: Sergio
authors.initials: S
authors.lastname: Pantano
authors.affiliation: Pharmaceutical Department, Center for Genetic Engineering and Biotechnology, Havana, Cuba.
authors.forename: Maribel G
authors.initials: MG
authors.lastname: Vallespí
authors.affiliation: Cell Biology Unit, Institut Pasteur de Montevideo, Mataojo 2020, 11400, Montevideo, Uruguay.
authors.forename: Mariela
authors.initials: M
authors.lastname: Bollati-Fogolín
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001711:Biotransformation; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015870:Gene Expression; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D000970:Antineoplastic Agents; C000598873:CIGB-552 peptide; C480519:COMMD1 protein, human; D057846:Cell-Penetrating Peptides; C505520:CASP7 protein, human; D053179:Caspase 7
keywords: COMMD1; amino acids; apoptosis; cell penetrating peptide