Targeting protein−protein interfaces using macrocyclic peptides

Protein−protein interactions (PPIs) are critical in numerous biological processes including signaling transduction, function regulations, and disease development. To regulate PPIs has been thought to be challenging due to their highly dynamic and expansive interfacial areas. Nonetheless, successful examples have been reported of targeting PPIs using small molecules, peptides, and proteins. Peptides, especially macrocyclic peptides have proven to be a particularly useful tool to inhibit PPIs for their exquisite potency, stability and selectivity. Herein we review the recent developments of this area of research, focusing on the macrocyclic peptides isolated from natural products, identified from library screening, and rationally designed based on structures, as PPI regulators. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 104: 310–316, 2015.

[1]  H. Benyamini,et al.  Cyclic peptide inhibitors of HIV-1 integrase derived from the LEDGF/p75 protein. , 2010, Bioorganic & medicinal chemistry.

[2]  Zeger Debyser,et al.  HIV-1 Integrase Forms Stable Tetramers and Associates with LEDGF/p75 Protein in Human Cells* , 2003, The Journal of Biological Chemistry.

[3]  L. Watkins,et al.  An MD2 Hot‐Spot‐Mimicking Peptide that Suppresses TLR4‐Mediated Inflammatory Response in vitro and in vivo , 2011, Chembiochem : a European journal of chemical biology.

[4]  D. Williams,et al.  Isolation and structure elucidation of Chlorofusin, a novel p53-MDM2 antagonist from a Fusarium sp. , 2001, Journal of the American Chemical Society.

[5]  M. Finn,et al.  Click Chemistry: Diverse Chemical Function from a Few Good Reactions. , 2001 .

[6]  Bert Vogelstein,et al.  Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53 , 1993, Nature.

[7]  K. Aoki,et al.  A disulfide bond replacement strategy enables the efficient design of artificial therapeutic peptides , 2014 .

[8]  G. Storz,et al.  The Sm-like Hfq protein increases OxyS RNA interaction with target mRNAs. , 2002, Molecular cell.

[9]  A. Cerami,et al.  Studies of endotoxin-induced decrease in lipoprotein lipase activity , 1981, The Journal of experimental medicine.

[10]  Nir London,et al.  Rationally Designed Macrocyclic Peptides as Synergistic Agonists of LPS-Induced Inflammatory Response. , 2014, Tetrahedron.

[11]  Sumera H Rizvi,et al.  Sequence-specific Recruitment of Heterochromatin Protein 1 via Interaction with Krüppel-like Factor 11, a Human Transcription Factor Involved in Tumor Suppression and Metabolic Diseases , 2012, The Journal of Biological Chemistry.

[12]  Liu Liu,et al.  Structure-based design of high-affinity macrocyclic peptidomimetics to block the menin-mixed lineage leukemia 1 (MLL1) protein-protein interaction. , 2013, Journal of medicinal chemistry.

[13]  A. Levine,et al.  The p53 tumour suppressor gene , 1991, Nature.

[14]  D. Macmillan,et al.  Sunflower trypsin inhibitor (SFTI-1) analogues of synthetic and biological origin via N→S acyl transfer: potential inhibitors of human Kallikrein-5 (KLK5) , 2014 .

[15]  M. Vidal,et al.  Interactome: gateway into systems biology. , 2005, Human molecular genetics.

[16]  J. Clements,et al.  Substrate-guided design of a potent and selective kallikrein-related peptidase inhibitor for kallikrein 4. , 2009, Chemistry & biology.

[17]  D. Goeddel,et al.  TNF-R1 Signaling: A Beautiful Pathway , 2002, Science.

[18]  V. Hruby,et al.  Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities. , 2006, Journal of medicinal chemistry.

[19]  Mark R Hutchinson,et al.  Application of a novel in silico high-throughput screen to identify selective inhibitors for protein-protein interactions. , 2010, Bioorganic & medicinal chemistry letters.

[20]  A. Butler.  The melanocortin system and energy balance , 2006, Peptides.

[21]  Hyo-Eon Jin,et al.  Cyclic RGD peptide incorporation on phage major coat proteins for improved internalization by HeLa cells. , 2014, Bioconjugate chemistry.

[22]  R. Khanna,et al.  Neuroexcitatory effects of morphine-3-glucuronide are dependent on Toll-like receptor 4 signaling , 2012, Journal of Neuroinflammation.

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

[24]  Weisi Wang,et al.  Small molecule agents targeting the p53‐MDM2 pathway for cancer therapy , 2012, Medicinal research reviews.

[25]  James P. Cain,et al.  Solid-phase peptide head-to-side chain cyclodimerization: Discovery of C2-symmetric cyclic lactam hybrid α-melanocyte-stimulating hormone (MSH)/agouti-signaling protein (ASIP) analogues with potent activities at the human melanocortin receptors , 2010, Peptides.

[26]  S. Rüdiger,et al.  Studying protein-protein interactions using peptide arrays. , 2011, Chemical Society reviews.

[27]  Chong Li,et al.  A left-handed solution to peptide inhibition of the p53-MDM2 interaction. , 2010, Angewandte Chemie.

[28]  P. Fischer.  Peptide, Peptidomimetic, and Small-molecule Antagonists of the p53–HDM2 Protein–Protein Interaction , 2006, International Journal of Peptide Research and Therapeutics.

[29]  Punit Upadhyaya,et al.  Screening bicyclic peptide libraries for protein-protein interaction inhibitors: discovery of a tumor necrosis factor-α antagonist. , 2013, Journal of the American Chemical Society.

[30]  Hadar Benyamini,et al.  Using peptides to study protein-protein interactions. , 2010, Future medicinal chemistry.

[31]  M. Martín-Martínez,et al.  De novo designed library of linear helical peptides: an exploratory tool in the discovery of protein-protein interaction modulators. , 2014, ACS combinatorial science.

[32]  M. Vidal.  A unifying view of 21st century systems biology , 2009, FEBS letters.

[33]  Arjel D. Bautista,et al.  Bridged beta(3)-peptide inhibitors of p53-hDM2 complexation: correlation between affinity and cell permeability. , 2010, Journal of the American Chemical Society.

[34]  Joshua A. Kritzer,et al.  Comprehensive Analysis of Loops at Protein-Protein Interfaces for Macrocycle Design , 2014, Nature chemical biology.

[35]  Hayyoung Lee,et al.  The structural basis of lipopolysaccharide recognition by the TLR4–MD-2 complex , 2009, Nature.

[36]  C. Ottmann,et al.  Constrained peptides with target-adapted cross-links as inhibitors of a pathogenic protein-protein interaction. , 2014, Angewandte Chemie.

[37]  Ali Tavassoli,et al.  A cyclic peptide inhibitor of C-terminal binding protein dimerization links metabolism with mitotic fidelity in breast cancer cells. , 2013, Chemical science.

[38]  B. Beutler,et al.  Inferences, questions and possibilities in Toll-like receptor signalling , 2004, Nature.

[39]  R. Norton,et al.  A potent cyclic peptide targeting SPSB2 protein as a potential anti-infective agent. , 2014, Journal of medicinal chemistry.

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

[41]  Peter S. Kutchukian,et al.  Structure of the stapled p53 peptide bound to Mdm2. , 2012, Journal of the American Chemical Society.

[42]  A. Friedler,et al.  Peptides that inhibit HIV‐1 integrase by blocking its protein–protein interactions , 2012, The FEBS journal.

[43]  M. Katze,et al.  Subversion of Cell Signaling Pathways by Hepatitis C Virus Nonstructural 5A Protein via Interaction with Grb2 and P85 Phosphatidylinositol 3-Kinase , 2002, Journal of Virology.

[44]  K. Gaus,et al.  Cyclic RGD peptides interfere with binding of the Helicobacter pylori protein CagL to integrins αVβ3 and α5β1 , 2011, Amino Acids.

[45]  W. DeGrado,et al.  The leech product saratin is a potent inhibitor of platelet integrin α2β1 and von Willebrand factor binding to collagen , 2007 .

[46]  P. Furet,et al.  Discovery of potent antagonists of the interaction between human double minute 2 and tumor suppressor p53. , 2000, Journal of medicinal chemistry.

[47]  M. Fleshner,et al.  Detection of highly curved membrane surfaces using a cyclic peptide derived from synaptotagmin-I. , 2012, ACS chemical biology.

[48]  T. Pawson,et al.  Protein-protein interactions define specificity in signal transduction. , 2000, Genes & development.

[49]  P. V. von Hippel,et al.  Theoretical aspects of DNA-protein interactions: co-operative and non-co-operative binding of large ligands to a one-dimensional homogeneous lattice. , 1974, Journal of molecular biology.

[50]  R. Cone.  Studies on the physiological functions of the melanocortin system. , 2006, Endocrine reviews.

[51]  G. Guillon,et al.  A Cyclic Peptide Mimicking the Third Intracellular Loop of the V2 Vasopressin Receptor Inhibits Signaling through Its Interaction with Receptor Dimer and G Protein* , 2004, Journal of Biological Chemistry.

[52]  Shaomeng Wang,et al.  Design of triazole-stapled BCL9 α-helical peptides to target the β-catenin/B-cell CLL/lymphoma 9 (BCL9) protein-protein interaction. , 2012, Journal of medicinal chemistry.

[53]  L. Watkins,et al.  A Peptide Antagonist of the TLR4–MD2 Interaction , 2009, Chembiochem : a European journal of chemical biology.

[54]  Xiaohui Wang,et al.  Discovery of small-molecule inhibitors of the TLR1/TLR2 complex. , 2012, Angewandte Chemie.

[55]  S. Akira,et al.  Pathogen Recognition and Innate Immunity , 2006, Cell.