- The effects of conformational constraints and steric bulk in the amino acid moiety of philanthotoxins on AMPAR antagonism
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Philanthotoxin-343 (PhTX-343), a synthetic analogue of wasp toxin PhTX-433, is a noncompetitive antagonist at ionotropic receptors (e.g., AChR or iGluR). To determine possible effects of variations of the amino acid side chain, a library consisting of seventeen PhTX-343 analogues was prepared. Thus, tyrosine was replaced by either apolar, conformationally constrained, or bulky amino acids, whereas the acyl unit and the polyamine moiety were kept unchanged. Analogues with tertiary amide groups were prepared for the first time. Pentafluorophenyl esters were employed for amide bond formation, establishing general protocols for philanthotoxin solution- and solid-phase synthesis (39-90% and 42-54% overall yields, respectively). The analogues were tested for their ability to antagonize kainate-induced currents of 2-amino-3-(3-hydroxy-5-methyl- 4-isoxazoyl)propanoic acid receptors (AMPAR) expressed in Xenopus oocytes from rat brain mRNA. This showed that steric bulk in the amino acid moiety is well tolerated and suggests that binding to AMPAR does not involve the α-NHCO group as a donor in hydrogen bonding.
- J?rgensen, Malene R.,Olsen, Christian A.,Mellor, Ian R.,Usherwood, Peter N. R.,Witt, Matthias,Franzyk, Henrik,Jaroszewski, Jerzy W.
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- Therapeutic and diagnostic ligand systems comprising transport molecule binding properties and medicaments containing the same
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The invention relates to transport molecule binding ligand compounds which comprise a therapeutically and/or diagnostically active substance and a carrier molecule-affine substance with a high association constant to the carrier molecule. The invention also relates to medicaments containing these ligand compounds and to diagnostic kits.
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- Solid-phase synthesis and utilization of side-chain reactive unnatural amino acids
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Alkylation of the benzophenone imine of glycine Wang resin with α,ω-dihaloalkanes yielded valuable reactive intermediates. These racemic ω-chloro or ω-bromo intermediates were converted to α-amino acids containing diverse side-chain functionalities (e.g.
- O'Donnell, Martin J.,Alsina, Jordi,Scott, William L.
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p. 8403 - 8406
(2007/10/03)
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- 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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- Development of highly potent inhibitors of Ras farnesyltransferase possessing cellular and in vivo activity
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Analogs of CVFM (a known nonsubstrate farnesyltransferase (FT) inhibitor derived from a CA2A2X sequence where C is cysteine, A is an aliphatic residue, and X is any residue) were prepared where phenylalanine was replaced by (Z)-dehyd
- Leftheris, Katerina,Kline, Toni,Vite, Gregory D.,Cho, Young H.,Bhide, Rajeev S.,Patel, Dinesh V.,Patel, Manorama M.,Schmidt, Robert J.,Weller, Harold N.,Andahazy, Mary L.,Carboni, Joan M.,Gullo-Brown, Johnni L.,Lee, Francis Y. F.,Ricca, Carol,Rose, William C.,Yan, Ning,Barbacid, Mariano,Hunt, John T.,Meyers, Chester A.,Seizinger, Bernd R.,Zahler, Robert,Manne, Veeraswamy
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p. 224 - 236
(2007/10/03)
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