New perspectives for pharmacological chaperoning treatment in methylmalonic aciduria cblB type

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1864

Article

Brasil, S.^1,2  Briso-Montiano, A.^1,2  Gamez, A.^1,2  Underhaug, J.³  Flydai, M. I.⁴  Desviat, L.^1,2  Merinero, B.^1,2  Ugarte, M.^1,2  Martinez, A.^4,5  Perez, B.^1,2 

[1] Univ Autonoma Madrid, CSIC, Ctr Biol Mol SO, Ctr Diagnost Enfermedades Mol, Campus Cantoblanco, E-28049 Madrid, Spain

[2] Inst Invest Sanitaria IdiPAZ, CIBERER, Madrid, Spain

[3] Univ Bergen, Dept Chem, Bergen, Norway

[4] Univ Bergen, Dept Biomed, Bergen, Norway

[5] Univ Bergen, KG Jebsen Ctr Neuropsychiat Disorders, Bergen, Norway

关键词: Pharmacological chaperones;    MMA cblB type;    ATR;    MMAB;    Destabilizing mutations;   

DOI  :  10.1016/j.bbadis.2017.11.024

来源: Elsevier

【 摘 要 】

Methylmalonic aciduria cblB type (MMA cblB) is caused by the impairment of ATP:cob(I)alamin adenosyltransferase (ATR), the enzyme responsible for the synthesis of adenosylcobalamin (AdoCbl) from cob(I)alamin. No definitive treatment is available for patients with this condition and novel therapeutic strategies are therefore much needed. Recently, we described a proof-of-concept regarding the use of pharmacological chaperones as a treatment. This work describes the effect of two potential pharmacological chaperones - compound V (N-{[(4-chlorophenyl)carbamothioyl]amino}-2-phenylacetamide) and compound VI (4-(4-(4-fluorophenyl)-5-methyl-1H-pyrazol-3-yl)benzene-1,3-diol) - on six ATR mutants, including the most common, p.Arg186Trp. Comprehensive functional analysis identified destabilizing (p.Arg186Gln, p.Arg190Cys, p.Arg190His, p.Arg191Gln and p.Glu193Lys) and oligomerization (p.Arg186Trp and p.Arg191Gln) mutations. In a cellular model overexpressing the destabilizing/oligomerization mutations, compounds V and VI had a positive effect on the stability and activity of all ATR variants. When provided in combination with hydroxocobalamin a more positive effect was obtained than with the compounds alone, even in mutations previously described as B-12 nonresponsive. In addition, a normal oligomerization profile was recovered after treatment of the p.Arg186Trp mutant with both compounds. These promising results confirm MMA cblB type as a conformational disorder and hence, pharmacological chaperones as a new therapeutic option alone or in combination with hydroxocobalamin for many patients with MMA cblB.

【 授权许可】

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