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Synthesis and structure-activity relationship studies of IgG-binding peptides focused on the C-terminal histidine residue.

ABSTRACT: Currently, IgG-binding peptides are widely utilized as a research tool, as molecules that guide substrates to the Fc site for site-selective antibody modification, leading to preparation of a homogeneous antibody-drug conjugate. In this study, a structure-activity relationship study of an IgG-binding peptide, 15-IgBP, that is focused on its C-terminal His residue was performed in an attempt to create more potent peptides. A peptide with a substitution of His17 by 2-pyridylalanine (2-Pya) showed a good binding affinity (15-His17(2-Pya), K d = 75.7 nM). In combination with a previous result, we obtained 15-Lys8Leu/His17(2-Pya)-OH that showed a potent binding affinity (K d = 2.48 nM) and avoided three synthetic problems concerning the p-hydroxybenzyl amidation at the C-terminus, the difficulty associated with coupling at the His7 position and the racemization of 2-Pya.

SUBMITTER: Muguruma K

PROVIDER: S-EPMC6855313 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Synthesis and structure-activity relationship studies of IgG-binding peptides focused on the C-terminal histidine residue.

Muguruma Kyohei K Ito Mayu M Fukuda Akane A Kishimoto Satoshi S Taguchi Akihiro A Takayama Kentaro K Taniguchi Atsuhiko A Ito Yuji Y Hayashi Yoshio Y

MedChemComm 20190801 10

Currently, IgG-binding peptides are widely utilized as a research tool, as molecules that guide substrates to the Fc site for site-selective antibody modification, leading to preparation of a homogeneous antibody-drug conjugate. In this study, a structure-activity relationship study of an IgG-binding peptide, 15-IgBP, that is focused on its C-terminal His residue was performed in an attempt to create more potent peptides. A peptide with a substitution of His17 by 2-pyridylalanine (2-Pya) showed ...[more]

PMID: 31762965

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Project description:Linear (HR)n and cyclic [HR]n peptides (n = 4,5) containing alternate arginine and histidine residues were synthesized. The peptides showed 0⁻15% cytotoxicity at 5⁻100 µM in human ovarian adenocarcinoma (SK-OV-3) cells while they exhibited 0⁻12% toxicity in human leukemia cancer cell line (CCRF-CEM). Among all peptides, cyclic [HR]₄ peptide was able to improve the delivery of a cell impermeable fluorescence-labeled phosphopeptide by two-fold. Fatty acids of different alkyl chain length were attached at the N-terminal of the linear peptide (HR)₄ to improve the molecular transporter property. Addition of fatty acyl chains was expected to help with the permeation of the peptides through the cell membrane. Thus, we synthesized seven fatty acyl derivatives of the linear (HR)₄ peptide. The peptides were synthesized using Fmoc/tBu solid phase peptide chemistry, purified by reverse-phase high-performance liquid chromatography (RP-HPLC) and characterized by matrix-assisted laser desorption/ionization (MALDI) spectrometry. The fatty acyl peptides containing C₈, C12, C14, and C18 alkyl chain did not show cytotoxicity on SK-OV-3 or CCRF-CEM cell lines up to 50 µM concentration; however, at higher concentration (100 µM), they showed mild cytotoxicity. For example, C16-(HR)₄ was also found to reduce the proliferation of SK-OV-3 cells by 11% at 50 µM and C20-(HR)₄ showed mild toxicity at 10 µM, reducing the proliferation of SK-OV-3 cells by 21%. Increase in the length of alkyl chain showed cytotoxicity to the cell lines. C20-(HR)₄ peptide showed better efficiency in translocation of F′-GpYEEI to SK-OV-3 than the phosphopeptide alone. Further investigation of C20-(HR)₄ peptide efficacy showed that the peptide could deliver doxorubicin and epirubicin into SK-OV-3 and also improved the drug antiproliferative ability. These studies provided insights into understanding the structural requirements for optimal cellular delivery of the fatty acyl-(HR)₄ peptide conjugates.

Dataset Information

Synthesis and structure-activity relationship studies of IgG-binding peptides focused on the C-terminal histidine residue.

Publications

Synthesis and structure-activity relationship studies of IgG-binding peptides focused on the C-terminal histidine residue.

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