Dataset Information

Synthesis, Profiling, and in Vivo Evaluation of Cyclopeptides Containing N-Methyl Amino Acids as Antiplasmodial Agents.

ABSTRACT: Malaria is a major tropical disease where important needs are to mitigate symptoms and to prevent the establishment of infection. Cyclopeptides containing N-methyl amino acids with in vitro activity against erythrocytic forms as well as liver stage are presented. The synthesis, parasitological characterization, physicochemical properties, in vivo evaluation, and mice pharmacokinetics are described.

SUBMITTER: Fagundez C

PROVIDER: S-EPMC6331169 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

Synthesis, Profiling, and in Vivo Evaluation of Cyclopeptides Containing N-Methyl Amino Acids as Antiplasmodial Agents.

Fagundez Catherine C Sellanes Diver D Peña Stella S Scarone Laura L Aguiar Anna C C ACC de Souza Juliana O JO Guido Rafael V C RVC Stewart Lindsay L Yardley Vanessa V Ottilie Sabine S Winzeler Elizabeth A EA Gamo Francisco-J FJ Sanz Laura M LM Serra Gloria L GL

ACS medicinal chemistry letters 20181226 1

Malaria is a major tropical disease where important needs are to mitigate symptoms and to prevent the establishment of infection. Cyclopeptides containing N-methyl amino acids with in vitro activity against erythrocytic forms as well as liver stage are presented. The synthesis, parasitological characterization, physicochemical properties, in vivo evaluation, and mice pharmacokinetics are described. ...[more]

PMID: 30655961

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Project description:A series of cyclic peptides, [(DipR)(WR)4], [(DipR)2(WR)3], [(DipR)3(WR)2], [(DipR)4(WR)], and [DipR]5, and their linear counterparts containing arginine (R) as positively charged residues and tryptophan (W) or diphenylalanine (Dip) as hydrophobic residues, were synthesized and evaluated for their molecular transporter efficiency. The in vitro cytotoxicity of the synthesized peptides was determined in human epithelial ovary adenocarcinoma cells (SK-OV-3), human lymphoblast peripheral blood cells (CCRF-CEM), human embryonic epithelial kidney healthy cells (HEK-293), human epithelial mammary gland adenocarcinoma cells (MDA-MB-468), pig epithelial kidney normal cells (LLC-PK1), and human epithelial fibroblast uterine sarcoma cells (MES-SA). A concentration of 5-10 µM and 3 h incubation were selected in uptake studies. The cellular uptake of a fluorescent-labeled phosphopeptide, stavudine, lamivudine, emtricitabine, and siRNA was determined in the presence of peptides via flow cytometry. Among the peptides, [DipR]5 (10 µM) was found to be the most efficient transporter and significantly improved the uptake of F'-GpYEEI, i.e., by approximately 130-fold after 3 h incubation in CCRF-CEM cells. Confocal microscopy further confirmed the improved delivery of fluorescent-labeled [DipR]5 (F'-[K(DipR)5]) alone and F'-GpYEEI in the presence of [DipR]5 in MDA-MB-231 cells. The uptake of fluorescent-labeled siRNA (F'-siRNA) in the presence of [DipR]5 with N/P ratios of 10 and 20 was found to be 30- and 50-fold higher, respectively, compared with the cells exposed to F'-siRNA alone. The presence of endocytosis inhibitors, i.e., nystatin, chlorpromazine, chloroquine, and methyl β-cyclodextrin, did not completely inhibit the cellular uptake of F'-[K(DipR)5] alone or F'-GpYEEI in the presence of [DipR]5, suggesting that a combination of mechanisms contributes to uptake. Circular dichroism was utilized to determine the secondary structure, while transmission electron microscopy was used to evaluate the particle sizes and morphology of the peptides. The data suggest the remarkable membrane transporter property of [DipR]5 for improving the delivery of various small molecules and cell-impermeable negatively charged molecules (e.g., siRNA and phosphopeptide).

Dataset Information

Synthesis, Profiling, and in Vivo Evaluation of Cyclopeptides Containing N-Methyl Amino Acids as Antiplasmodial Agents.

Publications

Synthesis, Profiling, and in Vivo Evaluation of Cyclopeptides Containing <i>N</i>-Methyl Amino Acids as Antiplasmodial Agents.

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