research10(1) - ORGANIC LETTERS Rational Design of Vitamin...

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Rational Design of Vitamin D 3 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 V ersity of Delaware, Newark, Delaware 19716 johnkoh@udel.edu Received August 7, 2002 ABSTRACT Vitamin D 3 -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 3 (1,25(OH) 2 D 3 ) cocrystal structure, three 1,25(OH) 2 D 3 analogues were designed to uniquely complement the rickets associated mutant VDR(Arg274 f Leu). The three analogues were 17 to 286 times more potent than 1,25(OH) 2 D 3 with the mutant in cell-based assays and did not substantially activate cellular calcium influx. A few recent examples have shown that small molecules (MW < 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, 1 or recover activity to mutated forms of nuclear hormone receptors associated with refractory forms of prostate cancer, 2 resis- tance to thyroid hormone (RTH), 3 and type II rickets. 4 These 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 (VDRR). 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. 5,6 The NHRs bind to specific DNA sequences (response elements) Department of Biological Sciences, University of Delaware, Newark, DE 19716. (1) Foster, B. A.; Coffey, H. A.; Mornin, M. J.; Rastinejad, F. Science 1999 , 286 , 2507 - 2510. (2) Taplin, M.-E.; Bubley, G. J.; Ko, Y.-L.; Small, E.; Upton, M.; Rajeshkumar, B.; Balk, S. P. Cancer Res. 1999 , 59 , 2511 - 2515. (3) Takeda, T.; Suzuki, S.; Lui, R. T.; DeGroot, L. J. J. Clin. Endocrinol. Metab. 1995 , 80 , 2033 - 2040. (4) Gardezi, S. A.; Nguyen, C.; Malloy, P. J.; Posner, G. H.; Feldman, D.; Peleg, S. J. Biol. Chem. 2001 , 276 , 29148 - 29156. (5) Aranda, A.; Pascual, A.
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research10(1) - ORGANIC LETTERS Rational Design of Vitamin...

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