CHF5074 (CSP-1103) stabilizes human transthyretin in mice humanized at the transthyretin and retinol-binding protein loci.
Familial amyloidotic polyneuropathy is one type of protein misfolding disease. Transthyretin (TTR) tetramer dissociation is the limiting step for amyloid fibril formation. CHF5074 (CSP-1103) stabilizes TTR tetramer in vitro by binding to the T4 binding site. Here, we used three strains of double humanized mice (mTtr(hTTRVal30/hTTRVal30), mTtr(hTTRVal30/hTTRMet30), and mTtr(hTTRMet30/hTTRMet30)) to assess whether CHF5074 stabilizes TTR tetramers in vivo. Treatment of mice with CHF5074 increased serum TTR levels by stabilizing TTR tetramers. Although the binding affinities of CHF5074 and diflunisal with TTRMet30 were similar, CHF5074 bound TTRVal30 more strongly than did diflunisal, suggesting the potent TTR-stabilizing activity of CHF5074.
Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan; College of Life Sciences, Northeast Agriculture University, Harbin, China.
Yanshuang
Y
Mu
Division of Respiratory Disease, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
Shoude
S
Jin
Department of Histology and Embryology, Harbin Medical University, Harbin, China.
Jingling
J
Shen
Division of Medical Informatics and Bioinformatics, Kobe University Hospital, Kobe, Japan.
Aki
A
Sugano
Division of Medical Informatics and Bioinformatics, Kobe University Hospital, Kobe, Japan.
Yutaka
Y
Takaoka
Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
Lixia
L
Qiang
Research and Development, Chiesi Farmaceutici, Parma, Italy.
Bruno P
BP
Imbimbo
Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
Ken-ichi
K
Yamamura
Department of Histology and Embryology, Harbin Medical University, Harbin, China; Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan. Electronic address: liseika@kumamoto-u.ac.jp.
Zhenghua
Z
Li
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D003521:Cyclopropanes / Q000008:administration & dosage* / Q000494:pharmacology; D005480:Flurbiprofen / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D010949:Plasma / Q000378:metabolism; D011228:Prealbumin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects; D054839:Retinol-Binding Proteins, Plasma / Q000378:metabolism*; D014633:Valine / Q000378:metabolism
C522246:1-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid; D003521:Cyclopropanes; D011228:Prealbumin; D054839:Retinol-Binding Proteins, Plasma; D005480:Flurbiprofen; D014633:Valine
CHF5074 (CSP-1103); Familial amyloidotic polyneuropathy; Misfolding; Retinol binding protein; Transthyretin