- Novel selective inhibitors of the interaction of individual nuclear hormone receptors with a mutually shared steroid receptor coactivator 2
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Nuclear hormone receptor (NR) signaling, currently a therapeutic target in multiple diseases, involves an ordered series of protein interactions to regulate transcription in response to changing hormone levels. Later steps in the process of ligand-dependent signaling are driven by a highly conserved interaction between the NRs and the steroid receptor coactivators (SRCs) that is effected by a conserved interaction motif (L1XXL2L3), known as an NR box. Using computational design and combinatorial chemistry, we have produced novel ∞-helical proteomimetics of the second NR box of SRC2 that exploit structural differences between human estrogen receptor ∞ (hER∞), human estrogen receptor β (hERβ), and human thyroid hormone receptor β (hTRβ). The resulting library sequentially replaced each leucine with non-natural side chains. Screening this library using a quantitative competition assay revealed compounds that selectively inhibit the interaction of SRC2-2 with each individual NR in preference to its interaction with the other NR. This approach generated highly selective compounds from one that had no specificity for a particular family member. These compounds represent the first family-member-selective competitive inhibitors of the protein interactions of transcription factors. Copyright
- Geistlinger, Timothy R.,Guy, R. Kiplin
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p. 6852 - 6853
(2007/10/03)
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- THE 1- AND 2-NAPHTHYLALANINE ANALOGS OF OXYTOCIN AND VASOPRESSIN
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Solid phase technique on p-methylbenzhydrylamine resin was used for the synthesis of four analogs of oxytocin and four analogs of vasopressin with the non-coded amino acids L- or D- and 1- or 2-naphthylalanine and D-homoarginine. 2>oxytocin, 2>oxytocin, 2>oxytocin, 2>oxytocin, 2, D-Har8>vasopressin, 2, D-Har8>vasopressin, 2, D-Har8>vasopressin and 2, D-Har8>vasopressin were synthesized.All eight analogs were found to be uterotonuc inhibitors in vitro and in vivo.Analogs with 2-naphthylalanine are stronger inhibitors, particularly in the vasopressin series than the analogs with 1-naphthylalanine.Analogs with 1-naphthylalanine have no activity in the pressor test, analogs with 2-naphthylalanine are weak pressor inhibitors.
- Prochazka, Zdenko,Slaninova, Jirina
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p. 2170 - 2177
(2007/10/03)
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- Cyclic peptides as selective tachykinin antagonists
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Twenty homodetic cyclic peptides based on the C-terminal sequence of substance P were prepared (Table I) by a combination of solid-phase techniques and cyclizations using azide coupling procedures. Incorporation of dipeptide mimics based on substituted γ-
- Williams,Curtis,McKnight,Maguire,Young,Veber,Baker
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