Open AccessA “ligand-targeting” peptide-drug conjugate: Targeted intracellular drug delivery by VEGF-binding helix-loop-helix peptides via receptor-mediated endocytosis
Author(s) -
Masataka Michigami,
Kentaro Takahashi,
Haruna Yamashita,
Zhengmao Ye,
Ikuhiko Nakase,
Ikuo Fujii
Publication year - 2021
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0247045
Subject(s) - endocytosis , peptide , endocytic cycle , drug delivery , microbiology and biotechnology , intracellular , chemistry , ligand (biochemistry) , internalization , targeted drug delivery , peptide library , receptor , biology , biochemistry , biophysics , peptide sequence , organic chemistry , gene
As a new alternative to antibody-drug conjugates, we generated “ligand-targeting” peptide-drug conjugates (PDCs), which utilize receptor-mediated endocytosis for targeted intracellular drug delivery. The PDC makes a complex with an extracellular ligand and then binds to the receptor on the cell surface to stimulate intracellular uptake via the endocytic pathway. A helix-loop-helix (HLH) peptide was designed as the drug carrier and randomized to give a conformationally constrained peptide library. The phage-displayed library was screened against vascular endothelial growth factor (VEGF) to yield the binding peptide M49, which exhibited strong binding affinity ( K D = 0.87 nM). The confocal fluorescence microscopy revealed that peptide M49 formed a ternary complex with VEGF and its receptor, which was then internalized into human umbilical vein endothelial cells (HUVECs) via VEGF receptor-mediated endocytosis. The backbone-cyclized peptide M49K was conjugated with a drug, monomethyl auristatin E, to afford a PDC, which inhibited VEGF-induced HUVEC proliferation. HLH peptides and their PDCs have great potential as a new modality for targeted molecular therapy.