Rational design of vitamin D3 analogues which selectively restore activity to a vitamin D receptor mutant associated with rickets.
[formula: see text] Vitamin D3-resistant rickets (VDRR) is associated with mutations to the Vitamin D receptor (VDR) which effect ligand-dependent transactivation. Some VDRR associated mutants directly disrupt ligand binding. Using the reported VDR-1,25-dihydroxy vitamin D3 (1,25(OH)2D3) cocrystal structure, three 1,25(OH)2D3 analogues were designed to uniquely complement the rickets associated mutant VDR(Arg274-->Leu). The three analogues were 17 to 286 times more potent than 1,25(OH)2D3 with the mutant in cell-based assays and did not substantially activate cellular calcium influx.
Swann
Steve L
SL
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, USA.
Bergh
Joel J
JJ
Farach-Carson
M Cindy
MC
Koh
John T
JT
D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002762:Cholecalciferol / Q000031:analogs & derivatives*; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D018167:Receptors, Calcitriol / Q000187:drug effects* / Q000235:genetics; D012279:Rickets / Q000188:drug therapy* / Q000235:genetics; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects
D008024:Ligands; D018167:Receptors, Calcitriol; D002762:Cholecalciferol; D002118:Calcium