Module assembly for protein-surface recognition: geranylgeranyltransferase I bivalent inhibitors for simultaneous targeting of interior and exterior protein surfaces

Chemistry : a European Journal
Shinnosuke MachidaJunko Ohkanda

Abstract

Synthetic chemical probes designed to simultaneously targeting multiple sites of protein surfaces are of interest owing to their potential application as site specific modulators of protein-protein interactions. A new approach toward bivalent inhibitors of mammalian type I geranylgeranyltransferase (GGTase I) based on module assembly for simultaneous recognition of both interior and exterior protein surfaces is reported. The inhibitors synthesized in this study consist of two modules linked by an alkyl spacer; one is the tetrapeptide CVIL module for binding to the interior protein surface (active pocket) and the other is a 3,4,5-alkoxy substituted benzoyl motif that contains three aminoalkyl groups designed to bind to the negatively charged protein exterior surface near the active site. The compounds were screened by two distinct enzyme inhibition assays based on fluorescence spectroscopy and incorporation of a [(3)H]-labeled prenyl group onto a protein substrate. The bivalent inhibitors block GGTase I enzymatic activity with K(i) values in the submicromolar range and are approximately one order of magnitude and more than 150 times more effective than the tetrapeptide CVIL and the methyl benzoate derivatives, respectively. The ...Continue Reading

References

Nov 1, 1991·Proceedings of the National Academy of Sciences of the United States of America·W W EpsteinH C Rilling
Nov 1, 1995·Molecular and Cellular Biology·R Khosravi-FarC J Der
Jun 1, 1997·Molecular and Cellular Biology·R G QiuM Symons
May 30, 1997·The Journal of Biological Chemistry·C A RowellA M Garcia
May 30, 1997·The Journal of Biological Chemistry·D B WhyteJ K Pai
Nov 1, 2001·Proceedings of the National Academy of Sciences of the United States of America·S B LongL S Beese
Jan 31, 2002·Proceedings of the National Academy of Sciences of the United States of America·Bartosz A GrzybowskiEugene I Shakhnovich
Apr 18, 2002·Proceedings of the National Academy of Sciences of the United States of America·Hyung Soon ParkAndrew D Hamilton
Feb 4, 2003·Nature Biotechnology·Daniel A ErlansonTom O'Brien
Nov 12, 2003·The EMBO Journal·Jeffrey S TaylorLorena S Beese
Nov 20, 2003·Journal of the American Chemical Society·Stacey E RutledgeAlanna Schepartz
Dec 12, 2003·Proceedings of the National Academy of Sciences of the United States of America·Jin YeMichael Gale
Dec 25, 2003·Journal of the American Chemical Society·Kui Shen, Philip A Cole
Apr 3, 2004·Nature Reviews. Drug Discovery·Michelle R Arkin, James A Wells
Jun 15, 2004·Current Opinion in Structural Biology·Peer BorkEdward M Marcotte
Aug 4, 2004·Current Opinion in Chemical Biology·Len PagliaroSteven Butcher
Sep 2, 2004·Journal of the American Chemical Society·Abir L BanerjeeD K Srivastava
Oct 8, 2004·Journal of the American Chemical Society·Kevin GrovesAndrew D Hamilton
Oct 14, 2004·Journal of the American Chemical Society·Bidhan C RoyD K Srivastava
Dec 14, 2004·Chembiochem : a European Journal of Chemical Biology·Norbert SchaschkeChristian P Sommerhoff
Jun 14, 2005·Cancer Cell·Kian-Huat LimChristopher M Counter
Jun 15, 2005·Angewandte Chemie·Hang Yin, Andrew D Hamilton
Oct 26, 2005·Current Opinion in Chemical Biology·Steven Fletcher, Andrew D Hamilton
Nov 10, 2005·Journal of Lipid Research·Andrea D BassoW Robert Bishop
Jan 7, 2006·Chembiochem : a European Journal of Chemical Biology·Joshua A KritzerAlanna Schepartz
Feb 16, 2006·Journal of the American Chemical Society·Huchen ZhouAndrew D Hamilton
Feb 24, 2006·Journal of the American Chemical Society·Ricardo L A DiasJohn A Robinson

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Citations

Jun 15, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Haoling GaoQun Jiang
Nov 12, 2009·Chemical Communications : Chem Comm·Junko OhkandaNobuo Kato
Mar 27, 2019·Chemistry : a European Journal·Thomas Marmin, Yves L Dory
Aug 9, 2019·Chemistry : a European Journal·Junko OhkandaJiazhi Sun
Dec 17, 2010·Journal of the American Chemical Society·Shinnosuke MachidaJunko Ohkanda

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