What is the potential of Lumacaftor as a chemical chaperone in promoting
hERG trafficking?
Abstract
Lumacaftor (LUM), approved by the FDA for the treatment of cystic
fibrosis(CF), has shown great therapeutic potential in protein
conformational diseases. As a chemical chaperone, LUM corrects the
F508del CFTR mutation and increases the expression of chloride channels
on the alveolar cell membrane. After Mehta et al’s research, the
selectivity of LUM has been challenged. In human induced pluripotent
stem cell-derived cardiomyocytes (hiPSC-CMs), LUM has been also
confirmed to be effective against heterozygous mutants (type II
mutations) that cause cardiac hERG protein trafficking defects, which
can clinically lead to long QT syndrome type 2 (LQT2). The effect of LUM
in hERG protein reverses the clinical phenotype of LQT2. Recent studies
have shown that LUM has an effect on more similar mutants in the
hiPSC-CMs cells rather than heterologous TSA201 cells, among which may
lead to more severe clinical phenotypes. Besides, comparing the negative
effects of LUM in other hERG mutants and the different effects on
mutations at the same site, what is the therapeutic potential and
stereoselectivity of LUM for protein conformational diseases? And what
this therapeutic effect should be attributed to requires further
understanding.