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Inhibition of the fibrillation of highly amyloidogenic human calcitonin by cucurbit[7]uril with improved bioactivity

Shang, Hui ; Zhou, Anna ; Jiang, Jian ; Liu, Yanpeng ; Xie, Jing ; Li, Sheyu ; Chen, Yantao ; Zhu, Xiaofeng ; Tan, Hong ; Li, Jianshu

Acta biomaterialia, 2018-09, Vol.78, p.178-188 [Peer Reviewed Journal]

England: Elsevier Ltd

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Title:
Inhibition of the fibrillation of highly amyloidogenic human calcitonin by cucurbit[7]uril with improved bioactivity
Author: Shang, Hui ; Zhou, Anna ; Jiang, Jian ; Liu, Yanpeng ; Xie, Jing ; Li, Sheyu ; Chen, Yantao ; Zhu, Xiaofeng ; Tan, Hong ; Li, Jianshu
Subjects: Alkaline Phosphatase - metabolism ; Amino Acid Sequence ; Amyloid ; Amyloid - antagonists & inhibitors ; Amyloid beta-peptides ; Amyloidogenesis ; Animals ; Bioavailability ; Biocompatibility ; Biocompatible Materials - pharmacology ; Biological activity ; Biomedical materials ; Bridged-Ring Compounds - pharmacology ; Calcitonin ; Calcitonin - antagonists & inhibitors ; Calcitonin - chemistry ; Calcitonin - metabolism ; Calcium ; Calcium - blood ; Cell Line ; Cell proliferation ; Cell Proliferation - drug effects ; Cucurbituril ; Cytotoxicity ; Drug development ; Female ; Fibrillation ; Fibrils ; Human behavior ; Human calcitonin ; Humans ; Hypercalcemia ; Imidazoles - pharmacology ; Immune response ; Immunogenicity ; Immunoglobulin G - metabolism ; Immunosuppressive agents ; Inhibitor ; Kinetics ; Male ; Medical treatment ; Mice, Inbred C57BL ; Osteoporosis ; Peptides ; Protein Conformation ; Proteins ; Rats, Sprague-Dawley ; Supramolecular chemistry ; Toxicity
Is Part Of: Acta biomaterialia, 2018-09, Vol.78, p.178-188
Notes: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Description: [Display omitted] Protein/peptide fibrillation is an important challenge for biotechnological drug development. Salmon calcitonin (sCT) is currently used in the clinical treatment of bone-related diseases such as osteoporosis and hypercalcemia, but it still has the risk of immune responses. Although human calcitonin (hCT) would be a better choice in terms of immunogenicity, it has a strong tendency to irreversibly aggregate in aqueous solutions and form long amyloid fibrils, which significantly reduces its bioavailability and therapeutic potency. Here, we demonstrate that cucurbit[7]uril (CB[7]) can inhibit hCT fibrillation by supramolecular interaction with its aromatic groups (affinity: Phe16 > Tyr12 > Phe19 > Phe22). The hCT-CB[7] complex exhibits low cytotoxicity, even promotes osteoblast proliferation and osteogenic capacity of MC3T3 cells. Meanwhile the hCT-CB[7] complexes shows higher bioactivity compared to hCT in reducing blood calcium levels in rats, and also decreases the immunogenicity of hCT. These results suggest that CB[7] has the potential to improve the therapeutic potency of amyloidogenic protein/peptide drugs such as hCT.
Publisher: England: Elsevier Ltd
Language: English

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Inhibition of the fibrillation of highly amyloidogenic human calcitonin by cucurbit[7]uril with improved bioactivity

Shang, Hui ; Zhou, Anna ; Jiang, Jian ; Liu, Yanpeng ; Xie, Jing ; Li, Sheyu ; Chen, Yantao ; Zhu, Xiaofeng ; Tan, Hong ; Li, Jianshu

England: Elsevier Ltd

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