Structure-activity studies in a family of beta-hairpin protein epitope mimetic inhibitors of the p53-HDM2 protein-protein interaction

Chembiochem : a European Journal of Chemical Biology
Rudi FasanJohn A Robinson

Abstract

Inhibitors of the interaction between the p53 tumor-suppressor protein and its natural human inhibitor HDM2 are attractive as potential anticancer agents. In earlier work we explored designing beta-hairpin peptidomimetics of the alpha-helical epitope on p53 that would bind tightly to the p53-binding site on HDM2. The beta-hairpin is used as a scaffold to display energetically hot residues in an optimal array for interaction with HDM2. The initial lead beta-hairpin mimetic, with a weak inhibitory activity (IC(50)=125 microM), was optimized to afford cyclo-(L-Pro-Phe-Glu-6ClTrp-Leu-Asp-Trp-Glu-Phe-D-Pro) (where 6ClTrp=L-6-chlorotryptophan), which has an affinity almost 1,000 times higher (IC(50)=140 nM). In this work, insights into the origins of this affinity maturation based on structure-activity studies and an X-ray crystal structure of the inhibitor/HDM2(residues 17-125) complex at 1.4 A resolution are described. The crystal structure confirms the beta-hairpin conformation of the bound ligand, and also reveals that a significant component of the affinity increase arises through new aromatic/aromatic stacking interactions between side chains around the hairpin and groups on the surface of HDM2.

References

Jul 28, 1986·FEBS Letters·S K Burley, G A Petsko
Jan 20, 1995·Science·T Clackson, J A Wells
Dec 20, 1993·Journal of Molecular Biology·M C Lawrence, P M Colman
Jan 9, 1996·Proceedings of the National Academy of Sciences of the United States of America·J A Wells
Feb 1, 1996·Journal of Molecular Graphics·R KoradiK Wüthrich
Nov 21, 1997·Journal of Molecular Biology·P GüntertK Wüthrich
Apr 1, 1997·Journal of Molecular Graphics & Modelling·R M Esnouf
Jul 7, 1998·Journal of Molecular Biology·A A Bogan, K S Thorn
Oct 3, 1998·Acta Crystallographica. Section D, Biological Crystallography·J NavazaC Martin
Jan 23, 1999·Current Opinion in Chemical Biology·S H Gellman
Feb 2, 1999·Journal of Molecular Biology·L Lo ConteJ Janin
Mar 25, 1999·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Sep 1, 2000·Journal of Medicinal Chemistry·C García-EcheverríaP Furet
Oct 14, 2000·Archives of Biochemistry and Biophysics·Z LaiR A Copeland
Feb 24, 2001·Quarterly Reviews of Biophysics·P J HajdukS W Fesik
Jul 18, 2001·Journal of the American Chemical Society·S J DuncanM Moore
Aug 22, 2001·Bioorganic & Medicinal Chemistry Letters·C García-EcheverríaP Chène
Oct 19, 2001·Proceedings of the National Academy of Sciences of the United States of America·M KanovskyM R Pincus
Mar 29, 2002·Chembiochem : a European Journal of Chemical Biology·Milton T StubbsHanns Wurziger
Apr 5, 2002·Journal of Medicinal Chemistry·Peter L Toogood
Apr 5, 2002·Chembiochem : a European Journal of Chemical Biology·Anne DescoursJohn A Robinson
Jul 3, 2002·Journal of Peptide Science : an Official Publication of the European Peptide Society·Mario RainaldiGiorgio Cavicchioni
Jul 10, 2002·The Journal of Peptide Research : Official Journal of the American Peptide Society·Raja BanerjeeSiddhartha Roy
Oct 17, 2002·Journal of Molecular Biology·Oliver SchonAlan R Fersht
Oct 31, 2002·Chembiochem : a European Journal of Chemical Biology·Sasalu C ShankarammaJohn A Robinson
Dec 27, 2002·Biochemistry·Marc AdlerMarc Whitlow
Jan 29, 2003·Proceedings of the National Academy of Sciences of the United States of America·Mark A McCoyDaniel F Wyss
Feb 4, 2003·Nature Reviews. Cancer·Patrick Chène
Mar 5, 2003·Chemical Communications : Chem Comm·Sara J DuncanDudley H Williams
Mar 20, 2003·Angewandte Chemie·Emmanuel A MeyerFrançois Diederich
Aug 23, 2003·Chemical Communications : Chem Comm·Sasalu C ShankarammaJohn A Robinson
Jan 6, 2004·Science·Lyubomir T VassilevEmily A Liu
Jan 6, 2004·Angewandte Chemie·Steve W Homans
Jan 27, 2004·Journal of Molecular Biology·Oliver SchonAlan R Fersht

❮ Previous
Next ❯

Citations

Jun 15, 2013·Journal of the American Chemical Society·Mayumi KudoIvan Huc
Apr 2, 2009·Journal of the American Chemical Society·Alex ShaginianDale L Boger
Jun 15, 2012·Journal of Medicinal Chemistry·Changyou ZhanWuyuan Lu
Apr 2, 2011·The Journal of Organic Chemistry·Pin-Nan Cheng, James S Nowick
Apr 21, 2012·The Journal of Physical Chemistry. a·J M C MarquesF Pirani
Jul 23, 2013·The Journal of Physical Chemistry. a·J M C MarquesF Pirani
Mar 4, 2009·Proceedings of the National Academy of Sciences of the United States of America·Marzena PazgierWuyuan Lu
Nov 17, 2009·The Journal of Biological Chemistry·Jason PhanJiandong Chen
Mar 3, 2010·BMC Genomics·Jagadeesh N MavinahalliChandra Verma
Apr 17, 2014·Chemical Reviews·Lech-Gustav MilroyChristian Ottmann
May 8, 2010·Organic & Biomolecular Chemistry·Frederick CampbellAndrew J Wilson
Mar 14, 2007·Médecine sciences : M/S·Béatrice LaudetClaude Cochet
Feb 21, 2013·Nature Chemistry·Valeria AzzaritoAndrew J Wilson
May 8, 2010·Chemical Society Reviews·Andrew J Wilson
Jan 15, 2016·Bioorganic & Medicinal Chemistry Letters·Paulina Wójcik, Łukasz Berlicki
Apr 1, 2012·Drug Discovery Today. Technologies
Aug 3, 2010·Tetrahedron Letters·Kaori Sakurai, Daniel Kahne
Nov 10, 2009·Seminars in Cancer Biology·Michael P DickensPeter M Fischer
Nov 3, 2009·Bioorganic & Medicinal Chemistry·Ryo HayashiDaniel H Appella
Aug 21, 2012·Journal of Chemical Theory and Computation·Elio A CinoMikko Karttunen
Feb 13, 2009·Bioorganic & Medicinal Chemistry·Elizabeth A HarkerAlanna Schepartz
Aug 30, 2008·Drug Discovery Today·John A RobinsonDaniel Obrecht
May 2, 2009·Chembiochem : a European Journal of Chemical Biology·Anja GrässlinJohn A Robinson
Jan 16, 2009·Chembiochem : a European Journal of Chemical Biology·Amanda L Stewart, Marcey L Waters
May 21, 2008·Chemistry : a European Journal·Bhaswati ChatterjeePadmanabhan Balaram
Apr 12, 2007·Biopolymers·Justin K Murray, Samuel H Gellman
Mar 10, 2009·Chembiochem : a European Journal of Chemical Biology·Martin HintersteinerManfred Auer
Mar 7, 2009·Chembiochem : a European Journal of Chemical Biology·John A Robinson
May 4, 2011·Angewandte Chemie·Laura M SalonenFrançois Diederich
Mar 17, 2016·Chemical Communications : Chem Comm·Anupam BandyopadhyayHosahudya N Gopi
Jan 26, 2013·Journal of Peptide Science : an Official Publication of the European Peptide Society·John A Robinson
Mar 5, 2013·Journal of Peptide Science : an Official Publication of the European Peptide Society·Daniel MeyerChad Tatko
Feb 21, 2013·Chemistry : a European Journal·Jui Thiang Brian KuehMargaret A Brimble
Dec 4, 2012·Chembiochem : a European Journal of Chemical Biology·John R FrostRudi Fasan
Oct 8, 2014·Angewandte Chemie·Timothy A HillDavid P Fairlie
Jul 17, 2015·Chembiochem : a European Journal of Chemical Biology·Nina Bionda, Rudi Fasan
Mar 22, 2008·Biochemical and Biophysical Research Communications·L Michel Espinoza-Fonseca, Jazmín García-Machorro
Dec 23, 2015·Chembiochem : a European Journal of Chemical Biology·Valeria AzzaritoAndrew John Wilson
Sep 8, 2011·Chemical Communications : Chem Comm·Maragani SatyanarayanaRudi Fasan

❮ Previous
Next ❯

Related Concepts

Related Feeds

Autoimmune Diseases

Autoimmune diseases occur as a result of an attack by the immune system on the body’s own tissues resulting in damage and dysfunction. There are different types of autoimmune diseases, in which there is a complex and unknown interaction between genetics and the environment. Discover the latest research on autoimmune diseases here.