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Peroxynitrite scavenger FeTPPS binds with hCT to effectively inhibit its amyloid aggregation

Xiao, Bin ; Xiao, Junhao ; Liu, Sisi ; Xiao, Xiaoying ; Dai, Shengping ; Sui, Yan ; Wu, Jinming LU and Ye, Huixian (2024) In Dalton Transactions 53(41). p.17036-17049
Abstract

Human calcitonin (hCT) is an endogenous polypeptide commonly employed in treating bone resorption-related illnesses, but its clinical application is limited due to its high aggregation tendency. Metalloporphyrins are effective in suppressing amyloid fibrillation, positioning them as potential drug candidates for amyloidogenic disorders like Alzheimer's and type 2 diabetes. In this work, we investigated the effects of Fe(iii) meso-tetra(4-sulfonatophenyl)porphine chloride (FeTPPS), a highly efficient ONOO− decomposition catalyst, on hCT aggregation. Our findings reveal that FeTPPS effectively precludes hCT fibrillation by stabilizing the monomers and delaying the structural transition from α-helix bundles to β-sheet-rich... (More)

Human calcitonin (hCT) is an endogenous polypeptide commonly employed in treating bone resorption-related illnesses, but its clinical application is limited due to its high aggregation tendency. Metalloporphyrins are effective in suppressing amyloid fibrillation, positioning them as potential drug candidates for amyloidogenic disorders like Alzheimer's and type 2 diabetes. In this work, we investigated the effects of Fe(iii) meso-tetra(4-sulfonatophenyl)porphine chloride (FeTPPS), a highly efficient ONOO− decomposition catalyst, on hCT aggregation. Our findings reveal that FeTPPS effectively precludes hCT fibrillation by stabilizing the monomers and delaying the structural transition from α-helix bundles to β-sheet-rich aggregates. The macrocyclic ring of FeTPPS plays a significant role in disrupting hCT self-associations. Among various porphyrin analogs, those with an iron center and negatively charged peripheral substituents exhibit a stronger inhibitory effect on hCT aggregation. Spectroscopic analyses and computational simulations indicate that FeTPPS binds to hCT's core aggregation region via complexation with His20 in a 1 : 1 molar ratio. Hydrophobic interaction, hydrogen bonding, and π-π stacking with the residues involving Tyr12, Phe19, and Ala26 also contribute to the interactions. Collectively, our study provides a promising approach for developing novel hCT drug formulations and offers theoretical guidance for designing metalloporphyrin-based inhibitors for various amyloidosis conditions.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Dalton Transactions
volume
53
issue
41
pages
14 pages
publisher
Royal Society of Chemistry
external identifiers
  • pmid:39355983
  • scopus:85205857106
ISSN
1477-9226
DOI
10.1039/d4dt02214a
language
English
LU publication?
yes
id
992ea253-0ce7-4cba-8c74-85be21ce218f
date added to LUP
2025-01-02 13:54:00
date last changed
2025-07-18 06:43:21
@article{992ea253-0ce7-4cba-8c74-85be21ce218f,
  abstract     = {{<p>Human calcitonin (hCT) is an endogenous polypeptide commonly employed in treating bone resorption-related illnesses, but its clinical application is limited due to its high aggregation tendency. Metalloporphyrins are effective in suppressing amyloid fibrillation, positioning them as potential drug candidates for amyloidogenic disorders like Alzheimer's and type 2 diabetes. In this work, we investigated the effects of Fe(iii) meso-tetra(4-sulfonatophenyl)porphine chloride (FeTPPS), a highly efficient ONOO<sup>−</sup> decomposition catalyst, on hCT aggregation. Our findings reveal that FeTPPS effectively precludes hCT fibrillation by stabilizing the monomers and delaying the structural transition from α-helix bundles to β-sheet-rich aggregates. The macrocyclic ring of FeTPPS plays a significant role in disrupting hCT self-associations. Among various porphyrin analogs, those with an iron center and negatively charged peripheral substituents exhibit a stronger inhibitory effect on hCT aggregation. Spectroscopic analyses and computational simulations indicate that FeTPPS binds to hCT's core aggregation region via complexation with His20 in a 1 : 1 molar ratio. Hydrophobic interaction, hydrogen bonding, and π-π stacking with the residues involving Tyr12, Phe19, and Ala26 also contribute to the interactions. Collectively, our study provides a promising approach for developing novel hCT drug formulations and offers theoretical guidance for designing metalloporphyrin-based inhibitors for various amyloidosis conditions.</p>}},
  author       = {{Xiao, Bin and Xiao, Junhao and Liu, Sisi and Xiao, Xiaoying and Dai, Shengping and Sui, Yan and Wu, Jinming and Ye, Huixian}},
  issn         = {{1477-9226}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{41}},
  pages        = {{17036--17049}},
  publisher    = {{Royal Society of Chemistry}},
  series       = {{Dalton Transactions}},
  title        = {{Peroxynitrite scavenger FeTPPS binds with hCT to effectively inhibit its amyloid aggregation}},
  url          = {{http://dx.doi.org/10.1039/d4dt02214a}},
  doi          = {{10.1039/d4dt02214a}},
  volume       = {{53}},
  year         = {{2024}},
}