Sequence-based design of alpha/beta-peptide foldamers that mimic BH3 domains.

The design of molecules that bind tightly and selectively to a specific site on a protein constitutes a fundamental challenge in molecular recognition. Finding high-affinity ligands for protein surfaces that bind to other proteins has proven to be particularly difficult.[1] Foldamers, oligomers with discrete folding propensities,[2] represent an unconventional source of ligands for protein-recognition surfaces,[3] but realizing this potential requires that we learn how to design sequences that contain unnatural building blocks and effectively mimic one of the surfaces involved in a given protein-protein interaction. Here we show that systematic backbone modification throughout a natural protein-binding domain, a process we refer to as sequence-based design, can expeditiously generate foldamers that bind tightly and selectively to target protein surfaces.

[1]  Joshua A. Kritzer,et al.  Helical β-Peptide Inhibitors of the p53-hDM2 Interaction , 2004 .

[2]  S. Armstrong,et al.  Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. , 2006, Cancer cell.

[3]  A. Beck‐Sickinger,et al.  Analogues of neuropeptide Y containing beta-aminocyclopropane carboxylic acids are the shortest linear peptides that are selective for the Y1 receptor. , 2003, Angewandte Chemie.

[4]  S. Cory,et al.  The Bcl-2 apoptotic switch in cancer development and therapy , 2007, Oncogene.

[5]  W. DeGrado,et al.  beta-Peptides: from structure to function. , 2001, Chemical reviews.

[6]  W. Ebeling,et al.  Proteinase K from Tritirachium album Limber. , 1974, European journal of biochemistry.

[7]  S. Gellman,et al.  Two Helical Conformations from a Single Foldamer Backbone: “Split Personality” in Short α/β‐Peptides , 2004 .

[8]  S. Korsmeyer,et al.  Activation of Apoptosis in Vivo by a Hydrocarbon-Stapled BH3 Helix , 2004, Science.

[9]  Oliver Reiser,et al.  Neuropeptid‐Y‐Analoga mit β‐Aminocyclopropancarbonsäure‐Einheiten sind die kürzesten linearen und selektiven Peptide am Y1‐Rezeptor , 2003 .

[10]  K. Ramakrishna,et al.  9/11 mixed helices in alpha/beta peptides derived from C-linked carbo-beta-amino acid and L-Ala repeats. , 2005, Angewandte Chemie.

[11]  H. Hauser,et al.  β‐Peptides as Inhibitors of Small‐Intestinal Cholesterol and Fat Absorption , 1999 .

[12]  R. Meadows,et al.  Structure of Bcl-xL-Bak Peptide Complex: Recognition Between Regulators of Apoptosis , 1997, Science.

[13]  Lin Chen,et al.  Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. , 2005, Genes & development.

[14]  Erinna F. Lee,et al.  Structural insights into the degradation of Mcl-1 induced by BH3 domains , 2007, Proceedings of the National Academy of Sciences.

[15]  O. Zerbe,et al.  Surprisingly stable helical conformations in alpha/beta-peptides by incorporation of cis-beta-aminocyclopropane carboxylic acids. , 2004, Angewandte Chemie.

[16]  Samuel H. Gellman,et al.  Rational Development of β-Peptide Inhibitors of Human Cytomegalovirus Entry* , 2006, Journal of Biological Chemistry.

[17]  P. Arora,et al.  Enhanced metabolic stability and protein-binding properties of artificial alpha helices derived from a hydrogen-bond surrogate: application to Bcl-xL. , 2005, Angewandte Chemie.

[18]  Michelle R. Arkin,et al.  Small-molecule inhibitors of protein–protein interactions: progressing towards the dream , 2004, Nature Reviews Drug Discovery.

[19]  D. Rognan,et al.  β-Amino Acid Scan of a Class I Major Histocompatibility Complex-restricted Alloreactive T-cell Epitope* , 2001, The Journal of Biological Chemistry.

[20]  J. Briand,et al.  Melanoma peptide MART-1(27-35) analogues with enhanced binding capacity to the human class I histocompatibility molecule HLA-A2 by introduction of a beta-amino acid residue: implications for recognition by tumor-infiltrating lymphocytes. , 2000, Journal of medicinal chemistry.

[21]  Shaomeng Wang,et al.  Chimeric (α/β + α)-Peptide Ligands for the BH3-Recognition Cleft of Bcl-xL: Critical Role of the Molecular Scaffold in Protein Surface Recognition , 2005 .

[22]  J. McCluskey,et al.  T Cell Determinants Incorporating β-Amino Acid Residues Are Protease Resistant and Remain Immunogenic In Vivo1 , 2005, The Journal of Immunology.

[23]  Y. Narahashi,et al.  Studies on proteolytic enzymes (pronase) of Streptomyces griseus K-1. II. Separation of exo- and endopeptidases of pronase. , 1968, Journal of biochemistry.

[24]  Oliver Reiser,et al.  Überraschend stabile helicale Strukturen in α-β-Peptiden durch Einbau von cis-β-Aminocyclopropancarbonsäuren† , 2004 .

[25]  Scott J. Shandler,et al.  Foldamers as versatile frameworks for the design and evolution of function. , 2007, Nature chemical biology.

[26]  P. Perlmutter,et al.  β-amino acids: Versatile peptidomimetics , 2002 .

[27]  I. Karle,et al.  Alpha,beta hybrid peptides: a polypeptide helix with a central segment containing two consecutive beta-amino acid residues. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Brian J. Smith,et al.  Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. , 2005, Molecular cell.

[29]  S. Gellman,et al.  Exploration of Backbone Space in Foldamers Containing α‐ and β‐Amino Acid Residues: Developing Protease‐Resistant Oligomers that Bind Tightly to the BH3‐Recognition Cleft of Bcl‐xL , 2007, Chembiochem : a European journal of chemical biology.

[30]  Samuel H. Gellman,et al.  Foldamers: A Manifesto , 1998 .

[31]  W Seth Horne,et al.  Helix bundle quaternary structure from alpha/beta-peptide foldamers. , 2007, Journal of the American Chemical Society.

[32]  W. D. Fairlie,et al.  (alpha/beta+alpha)-peptide antagonists of BH3 domain/Bcl-x(L) recognition: toward general strategies for foldamer-based inhibition of protein-protein interactions. , 2007, Journal of the American Chemical Society.