期刊
AMYLOID-JOURNAL OF PROTEIN FOLDING DISORDERS
卷 24, 期 1, 页码 42-51出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/13506129.2017.1308348
关键词
Amyloidosis; stabilization; genetic disease; treatment
资金
- Chiesi Farmaceutici, Parma, Italy
- Japan Society for the Promotion of Science [24590404, 21220010]
- National Natural Science Foundation of China [81670028]
- Natural Science Foundation of Heilongjiang Province of China [ZD2016014]
- Dean Foundation of the Fourth Hospital of Harbin Medical University
- Foster Foundation of the Fourth Hospital of Harbin Medical University
- Ministry of Education, Culture, Sports, Science and Technology [221S0001]
- CREST (Japan Science and Technology Agency)
- Grants-in-Aid for Scientific Research [24590404, 21220010] Funding Source: KAKEN
Hereditary amyloid polyneuropathy is a type of protein misfolding disease. Transthyretin (TTR) is a homotetrameric serum protein and TTR tetramer dissociation is the limiting step in amyloid fibril formation. Thus, prevention of TTR dissociation is a promising therapeutic approach and some TTR stabilizers have been approved for the treatment of TTR amyloidosis. CSP-1103 (CHF5074) is a non-steroidal anti-inflammatory derivative that lacks cyclooxygenase inhibitory activity. In vitro, CSP-1103 stabilizes the TTR tetramer by binding to the thyroxine (T4) binding site. We have previously shown that serum TTR levels were increased by oral CSP-1103 administration through stabilization of TTR tetramers in humanized mice at both the Ttr locus and the Rbp4 locus. To determine whether CSP-1103 stabilizes TTR tetramers in humans, multiple CSP-1103 oral doses were administered for two weeks to 48 healthy human volunteers in a double-blind, placebo-controlled, parallel-group study. CSP-1103 treatment stabilized TTR tetramers in a dose-dependent manner under normal or denaturing stress conditions, thereby increasing serum TTR levels. Preincubation of serum with CSP-1103 or diflunisal in vitro increased the TTR tetramer stability. Computer simulation analysis revealed that the binding affinities of CSP-1103 with TTR at pH 7.0 were similar to those of tafamidis, thus confirming that CSP-1103 has potent TTR-stabilizing activity.
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