Figure 3: Screening for novel SF-22 analogues and effect of SF-22 and MK6-83 on TRPML1 channel activity in WT- and mutant isoform-expressing lysosomes.
From: A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV
(a) Shown are the main strategies of chemical modifications of SF-22 and the chemical structure of the novel lead compound MK6-83. For further details, refer to Supplementary Methods section and Supplementary Figs 3 and 4. (b) Shown are representative calcium imaging measurements of HEK293 cells transiently transfected with the PM variant TRPML1(NC)-YFP and loaded with fura-2 (mean values±s.e.m. of at least 10 cells, each). (c) Current–voltage relations of whole-lysosome planar patch-clamp experiments demonstrating activation of hTRPML1 and MLIV causing mutant isoforms by MK6-83 (10 μM). (d) Bar diagram summarizing data at −200 mV from experiments shown in a in comparison to SF-22 effects. (e) Dose–response curves showing potency of MK6-83 on TRPML1 WT- and mutant isoform-expressing lysosomes.
