Rational Design of Vitamin D
Analogues Which Selectively Restore
Activity to a Vitamin D Receptor Mutant
Associated with Rickets
Steve L. Swann,
Joel J. Bergh,
M. Cindy Farach-Carson, and John T. Koh*
Department of Chemistry and Biochemistry, Uni
ersity of Delaware,
Newark, Delaware 19716
Received August 7, 2002
-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 D
structure, three 1,25(OH)
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)
with the mutant in cell-based assays and did not substantially activate cellular
A few recent examples have shown that small molecules
600) can restore activity to mutationally impaired
proteins that are associated with genetic disease. For example,
compounds have been discovered which can help stabilize
mutant forms of p53 associated with cancer,
activity to mutated forms of nuclear hormone receptors
associated with refractory forms of prostate cancer,
tance to thyroid hormone (RTH),
and type II rickets.
examples illustrate that small molecules may be used to
restore activity to at least a subset of genetic mutations and
suggest a potentially new pharmacological approach to the
treatment of genetic disease. Thus far, mutant-complementing
molecules have almost exclusively been discovered by
screening existing compounds and compound libraries. In
this study, we evaluate the ability of structure-based design
to custom design hormone analogues for a vitamin D receptor
(VDR) mutation associated with vitamin D resistant rickets
The nuclear and steroid hormone receptors (NHR’s)
comprise a superfamily of ligand-dependent transcriptional
regulators that control the expression of specific eukaryotic
genes involved in development and homeostasis.
NHRs bind to specific DNA sequences (response elements)
Department of Biological Sciences, University of Delaware, Newark,
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