Targeting protein–protein interactions, a wide open field for drug design

Abstract Targeting protein–protein interactions has long been considered as a very difficult if impossible task, but over the past decade, front lines have moved. The number of successful examples is exponentially growing. This review presents a rapid overview of recent advances in this field considering the strengths and weaknesses of the small molecule approaches and alternative strategies such as the selection or design of artificial antibodies, peptides or peptidomimetics.

[1]  Philippe Roche,et al.  2P2Idb: a structural database dedicated to orthosteric modulation of protein–protein interactions , 2012, Nucleic Acids Res..

[2]  A. Hamilton,et al.  Aryl-linked imidazolidin-2-ones as non-peptidic β-strand mimetics. , 2012, Chemical communications.

[3]  S. Lowe,et al.  RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia , 2011, Nature.

[4]  A. Hamilton,et al.  Toward proteomimetics: terphenyl derivatives as structural and functional mimics of extended regions of an alpha-helix. , 2001, Journal of the American Chemical Society.

[5]  Robert B. Russell,et al.  PepSite: prediction of peptide-binding sites from protein surfaces , 2012, Nucleic Acids Res..

[6]  S. Warriner,et al.  Synthesis of functionalised aromatic oligamide rods. , 2008, Organic & biomolecular chemistry.

[7]  Qinjian Zhao,et al.  Utilizing ELISA to monitor protein-protein interaction. , 2015, Methods in molecular biology.

[8]  Bridget E. Begg,et al.  A Proteome-Scale Map of the Human Interactome Network , 2014, Cell.

[9]  M. Ultsch,et al.  Human growth hormone and extracellular domain of its receptor: crystal structure of the complex. , 1992, Science.

[10]  R. Young,et al.  BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc , 2011, Cell.

[11]  Dima Kozakov,et al.  The FTMap family of web servers for determining and characterizing ligand-binding hot spots of proteins , 2015, Nature Protocols.

[12]  Oliver Zerbe,et al.  Using a β‐Hairpin To Mimic an α‐Helix: Cyclic Peptidomimetic Inhibitors of the p53–HDM2 Protein–Protein Interaction , 2004 .

[13]  T. Klabunde,et al.  Understanding drugs and diseases by systems biology? , 2013, Bioorganic & medicinal chemistry letters.

[14]  Haim J. Wolfson,et al.  PepCrawler: a fast RRT-based algorithm for high-resolution refinement and binding affinity estimation of peptide inhibitors , 2011, Bioinform..

[15]  N. Cherradi,et al.  A novel concept in antiangiogenic and antitumoral therapy: multitarget destabilization of short-lived mRNAs by the zinc finger protein ZFP36L1 , 2010, Oncogene.

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

[17]  S. Gellman,et al.  Targeting diverse protein–protein interaction interfaces with α/β-peptides derived from the Z-domain scaffold , 2015, Proceedings of the National Academy of Sciences.

[18]  L. Ouyang,et al.  Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery , 2015, Oncotarget.

[19]  Erinna F. Lee,et al.  Structure‐Guided Rational Design of α/β‐Peptide Foldamers with High Affinity for BCL‐2 Family Prosurvival Proteins , 2013, Chembiochem : a European journal of chemical biology.

[20]  David Nemazee,et al.  Rational immunogen design to target specific germline B cell receptors , 2012, Retrovirology.

[21]  I B Dawid,et al.  The bromodomain: a conserved sequence found in human, Drosophila and yeast proteins. , 1992, Nucleic acids research.

[22]  Dominique Durand,et al.  Design, production and molecular structure of a new family of artificial alpha-helicoidal repeat proteins (αRep) based on thermostable HEAT-like repeats. , 2010, Journal of molecular biology.

[23]  Marko Hyvönen,et al.  Targeting protein-protein interactions and fragment-based drug discovery. , 2012, Topics in current chemistry.

[24]  Benjamin A. Shoemaker,et al.  IBIS (Inferred Biomolecular Interaction Server) reports, predicts and integrates multiple types of conserved interactions for proteins , 2011, Nucleic Acids Res..

[25]  M. C. Cardoso,et al.  Covalent attachment of cyclic TAT peptides to GFP results in protein delivery into live cells with immediate bioavailability. , 2015, Angewandte Chemie.

[26]  Joost Schymkowitz,et al.  Computational design of peptide ligands. , 2011, Trends in biotechnology.

[27]  C. Douat,et al.  Isosteric substitutions of urea to thiourea and selenourea in aliphatic oligourea foldamers: site-specific perturbation of the helix geometry. , 2015, Chemistry.

[28]  Martin H. Schaefer,et al.  Characterizing Protein Interactions Employing a Genome-Wide siRNA Cellular Phenotyping Screen , 2014, PLoS Comput. Biol..

[29]  Dima Kozakov,et al.  Ligand deconstruction: Why some fragment binding positions are conserved and others are not , 2015, Proceedings of the National Academy of Sciences.

[30]  Marc Graille,et al.  Selection of Specific Protein Binders for Pre-Defined Targets from an Optimized Library of Artificial Helicoidal Repeat Proteins (alphaRep) , 2013, PloS one.

[31]  F. Guerlesquin,et al.  Protein–protein interaction inhibition (2P2I) combining high throughput and virtual screening: Application to the HIV-1 Nef protein , 2007, Proceedings of the National Academy of Sciences.

[32]  Alicia P. Higueruelo,et al.  Atomic Interactions and Profile of Small Molecules Disrupting Protein–Protein Interfaces: the TIMBAL Database , 2009, Chemical biology & drug design.

[33]  S. Benkovic,et al.  A systematic method for identifying small-molecule modulators of protein-protein interactions. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[34]  William B. Smith,et al.  Selective inhibition of BET bromodomains , 2010, Nature.

[35]  S. Warriner,et al.  Solid-Phase Methodology for Synthesis of O-Alkylated Aromatic Oligoamide Inhibitors of α-Helix-Mediated Protein–Protein Interactions , 2013, Chemistry.

[36]  Tom L. Blundell,et al.  TIMBAL v2: update of a database holding small molecules modulating protein–protein interactions , 2013, Database J. Biol. Databases Curation.

[37]  J. McCafferty The long and winding road to antibody therapeutics , 2010, mAbs.

[38]  S. Gellman,et al.  α-Helix mimicry with α/β-peptides. , 2013, Methods in enzymology.

[39]  Matthew Mort,et al.  A Massively Parallel Pipeline to Clone DNA Variants and Examine Molecular Phenotypes of Human Disease Mutations , 2014, PLoS genetics.

[40]  Philippe Roche,et al.  Atomic Analysis of Protein-Protein Interfaces with Known Inhibitors: The 2P2I Database , 2010, PloS one.

[41]  G. Guichard,et al.  Microwave-enhanced solid-phase synthesis of N,N'-linked aliphatic oligoureas and related hybrids. , 2012, Organic letters.

[42]  S. Sagan,et al.  Cell‐penetrating peptides: 20 years later, where do we stand? , 2013, FEBS letters.

[43]  A. Gingras,et al.  Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family , 2012, Cell.

[44]  Ozlem Keskin,et al.  HotPoint: hot spot prediction server for protein interfaces , 2010, Nucleic Acids Res..

[45]  T. Blundell,et al.  Structural biology in fragment-based drug design. , 2010, Current opinion in structural biology.

[46]  Andreas Plückthun,et al.  Structural and functional analysis of phosphorylation-specific binders of the kinase ERK from designed ankyrin repeat protein libraries , 2012, Proceedings of the National Academy of Sciences.

[47]  R. Hartmann,et al.  RNA interference as a gene-specific approach for molecular medicine. , 2005, Current medicinal chemistry.

[48]  S. Muyldermans,et al.  Nanobody-based products as research and diagnostic tools. , 2014, Trends in biotechnology.

[49]  P. Colas,et al.  Yeast two-hybrid methods and their applications in drug discovery. , 2012, Trends in pharmacological sciences.

[50]  M. Vogel,et al.  Accelerated Disassembly of IgE:Receptor Complexes by a Disruptive Macromolecular Inhibitor , 2012, Nature.

[51]  M. C. Cardoso,et al.  Fundamental Molecular Mechanism for the Cellular Uptake of Guanidinium-Rich Molecules , 2014, Journal of the American Chemical Society.

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

[53]  James R Horn,et al.  Shotgun Alanine Scanning Shows That Growth Hormone Can Bind Productively to Its Receptor through a Drastically Minimized Interface* , 2005, Journal of Biological Chemistry.

[54]  Timothy A. Whitehead,et al.  Computational Design of Proteins Targeting the Conserved Stem Region of Influenza Hemagglutinin , 2011, Science.

[55]  István A. Kovács,et al.  Widespread Macromolecular Interaction Perturbations in Human Genetic Disorders , 2015, Cell.

[56]  Asher Mullard,et al.  2013 FDA drug approvals , 2014, Nature Reviews Drug Discovery.

[57]  Ora Schueler-Furman,et al.  Rosetta FlexPepDock web server—high resolution modeling of peptide–protein interactions , 2011, Nucleic Acids Res..

[58]  N. Pavletich,et al.  Crystal structure of the tetramerization domain of the p53 tumor suppressor at 1.7 angstroms , 1995, Science.

[59]  Vasant Honavar,et al.  Characterization of Protein–Protein Interfaces , 2008, The protein journal.

[60]  S. Futaki,et al.  Methodological and cellular aspects that govern the internalization mechanisms of arginine-rich cell-penetrating peptides. , 2008, Advanced drug delivery reviews.

[61]  Rumin Zhang,et al.  Fluorescence-based thermal shift assays. , 2010, Current opinion in drug discovery & development.

[62]  Daniel A Erlanson,et al.  Making drugs on proteins: site-directed ligand discovery for fragment-based lead assembly. , 2004, Current opinion in chemical biology.

[63]  J. Opferman,et al.  A competitive stapled peptide screen identifies a selective small molecule that overcomes MCL-1-dependent leukemia cell survival. , 2012, Chemistry & biology.

[64]  T. Clackson,et al.  A hot spot of binding energy in a hormone-receptor interface , 1995, Science.

[65]  Harren Jhoti,et al.  High-throughput crystallography for lead discovery in drug design , 2002, Nature Reviews Drug Discovery.

[66]  Jean-Luc Poyet,et al.  Drug-Like Protein–Protein Interaction Modulators: Challenges and Opportunities for Drug Discovery and Chemical Biology , 2014, Molecular informatics.

[67]  Asher Mullard,et al.  Protein–protein interaction inhibitors get into the groove , 2012, Nature Reviews Drug Discovery.

[68]  Jorge Becerril,et al.  Design and application of an alpha-helix-mimetic scaffold based on an oligoamide-foldamer strategy: antagonism of the Bak BH3/Bcl-xL complex. , 2003, Angewandte Chemie.

[69]  J. Wells,et al.  Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. , 2014, Chemistry & biology.

[70]  W. S. Horne,et al.  Folding and function in α/β-peptides: targets and therapeutic applications. , 2015, Current opinion in chemical biology.

[71]  Chong Li,et al.  D-peptide inhibitors of the p53–MDM2 interaction for targeted molecular therapy of malignant neoplasms , 2010, Proceedings of the National Academy of Sciences.

[72]  A. Barabasi,et al.  Uncovering disease-disease relationships through the incomplete interactome , 2015, Science.

[73]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings , 1997 .

[74]  Cyril Couturier,et al.  The BRET technology and its application to screening assays , 2008, Biotechnology journal.

[75]  I. Wilson,et al.  Crystal structure of the principal neutralization site of HIV-1. , 1994, Science.

[76]  David Baker,et al.  Proof of principle for epitope-focused vaccine design , 2014, Nature.

[77]  Kwok-Ho Chan,et al.  A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes , 2014, Science.

[78]  David Baker,et al.  Removing T-cell epitopes with computational protein design , 2014, Proceedings of the National Academy of Sciences.

[79]  Pinak Chakrabarti,et al.  PRICE (PRotein Interface Conservation and Energetics): a server for the analysis of protein–protein interfaces , 2011, Journal of Structural and Functional Genomics.

[80]  L. Vassilev,et al.  In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2 , 2004, Science.

[81]  C. Barbas,et al.  Phage display of combinatorial antibody libraries. , 1997, Current opinion in biotechnology.

[82]  Dan Peer,et al.  Omics-based nanomedicine: the future of personalized oncology. , 2014, Cancer letters.

[83]  S. Gellman,et al.  Extending foldamer design beyond α-helix mimicry: α/β-peptide inhibitors of vascular endothelial growth factor signaling. , 2012, Journal of the American Chemical Society.

[84]  A. Hamilton,et al.  Disrupting protein-protein interactions with non-peptidic, small molecule alpha-helix mimetics. , 2010, Current opinion in chemical biology.

[85]  Erinna F. Lee,et al.  α/β-Peptide Foldamers Targeting Intracellular Protein-Protein Interactions with Activity in Living Cells. , 2015, Journal of the American Chemical Society.

[86]  A. Marchand,et al.  Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. , 2010, Nature chemical biology.

[87]  C. Lavoie,et al.  Macrocyclic cell penetrating peptides: a study of structure-penetration properties. , 2015, Bioconjugate chemistry.

[88]  G. Verdine,et al.  Stapled peptides for intracellular drug targets. , 2012, Methods in enzymology.

[89]  S. Vajda,et al.  Anchor residues in protein-protein interactions. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[90]  N. Tatonetti,et al.  Connecting the Dots: Applications of Network Medicine in Pharmacology and Disease , 2013, Clinical pharmacology and therapeutics.

[91]  A. Schepartz,et al.  Minimally cationic cell-permeable miniature proteins via alpha-helical arginine display. , 2008, Journal of the American Chemical Society.

[92]  Andreas Plückthun,et al.  Designed ankyrin repeat proteins (DARPins): binding proteins for research, diagnostics, and therapy. , 2015, Annual review of pharmacology and toxicology.

[93]  Henning Hermjakob,et al.  Analyzing protein-protein interaction networks. , 2012, Journal of proteome research.

[94]  S. Gellman,et al.  Backbone modification of a polypeptide drug alters duration of action in vivo , 2014, Nature Biotechnology.

[95]  M. Smit,et al.  GPCR-targeting nanobodies: attractive research tools, diagnostics, and therapeutics. , 2014, Trends in pharmacological sciences.

[96]  P. Hajduk,et al.  NMR-based screening in drug discovery , 1999, Quarterly Reviews of Biophysics.

[97]  Nir London,et al.  The structural basis of peptide-protein binding strategies. , 2010, Structure.

[98]  S. Warriner,et al.  2-O-alkylated para-benzamide α-helix mimetics: the role of scaffold curvature. , 2012, Organic & biomolecular chemistry.

[99]  Haian Fu,et al.  Protein–Protein Interactions , 1952 .

[100]  Christoph Patsch,et al.  The FASEB Journal Research Communication Cargo-dependent mode of uptake and bioavailability of TAT-containing proteins and peptides in living cells , 2022 .

[101]  A. Levine,et al.  Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain , 1996, Science.

[102]  G. McKenzie,et al.  From Crystal Packing to Molecular Recognition: Prediction and Discovery of a Binding Site on the Surface of Polo-Like Kinase 1** , 2011, Angewandte Chemie.

[103]  D. Rognan,et al.  Stable helical secondary structure in short-chain N,N'-linked oligoureas bearing proteinogenic side chains. , 2002, Angewandte Chemie.

[104]  T Neumann,et al.  SPR-based fragment screening: advantages and applications. , 2007, Current topics in medicinal chemistry.

[105]  G. Weiss,et al.  Optimizing the affinity and specificity of proteins with molecular display. , 2006, Molecular bioSystems.

[106]  G Schreiber,et al.  Energetics of protein-protein interactions: analysis of the barnase-barstar interface by single mutations and double mutant cycles. , 1995, Journal of molecular biology.

[107]  Raymond E. Moellering,et al.  Direct inhibition of the NOTCH transcription factor complex , 2009, Nature.

[108]  D. Hoelzer,et al.  Far-Western based protein-protein interaction screening of high-density protein filter arrays. , 2001, Journal of biotechnology.

[109]  S. Dowdy,et al.  TAT transduction: the molecular mechanism and therapeutic prospects. , 2007, Trends in molecular medicine.

[110]  J. Wells,et al.  Systematic mutational analyses of protein-protein interfaces. , 1991, Methods in enzymology.

[111]  I. Wilson,et al.  Stapled HIV-1 Peptides Recapitulate Antigenic Structures and Engage Broadly Neutralizing Antibodies , 2014, Nature Structural &Molecular Biology.

[112]  Michelle R Arkin,et al.  Probing structural adaptivity at PPI interfaces with small molecules. , 2013, Drug discovery today. Technologies.

[113]  A. Prochiantz,et al.  Penetratin story: an overview. , 2011, Methods in molecular biology.

[114]  Asher Mullard 2014 FDA drug approvals , 2015, Nature Reviews Drug Discovery.

[115]  M. Laguerre,et al.  Structure of a complex formed by a protein and a helical aromatic oligoamide foldamer at 2.1 Å resolution. , 2014, Angewandte Chemie.

[116]  C. Ottmann,et al.  Modulators of protein-protein interactions. , 2014, Chemical reviews.

[117]  A. Hamilton,et al.  Strategies for targeting protein-protein interactions with synthetic agents. , 2005, Angewandte Chemie.

[118]  Timothy W. Craven,et al.  A Rotamer Library to Enable Modeling and Design of Peptoid Foldamers , 2014, Journal of the American Chemical Society.

[119]  H. Lehrach,et al.  A Human Protein-Protein Interaction Network: A Resource for Annotating the Proteome , 2005, Cell.

[120]  T. Spicer,et al.  Assay strategies for identification of therapeutic leads that target protein trafficking. , 2015, Trends in pharmacological sciences.

[121]  Nir Hacohen,et al.  Genome-scale loss-of-function screening with a lentiviral RNAi library , 2006, Nature Methods.

[122]  Michelle R. Arkin,et al.  Binding of small molecules to an adaptive protein–protein interface , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[123]  David Ryan Koes,et al.  Small-molecule inhibitor starting points learned from protein–protein interaction inhibitor structure , 2011, Bioinform..

[124]  Harry Jubb,et al.  Protein-protein interactions as druggable targets: recent technological advances. , 2013, Current opinion in pharmacology.

[125]  Erinna F. Lee,et al.  Evaluation of diverse α/β-backbone patterns for functional α-helix mimicry: analogues of the Bim BH3 domain. , 2012, Journal of the American Chemical Society.

[126]  D R Burton,et al.  Generation of a large combinatorial library of the immunoglobulin repertoire in phage lambda. , 1989, Science.

[127]  John A. Robinson,et al.  Protein ligand design: from phage display to synthetic protein epitope mimetics in human antibody Fc-binding peptidomimetics. , 2006, Journal of the American Chemical Society.

[128]  A. Marcus,et al.  Förster resonance energy transfer (FRET) microscopy for monitoring biomolecular interactions. , 2015, Methods in molecular biology.

[129]  Shuxing Zhang,et al.  Computational prediction of protein hot spot residues. , 2012, Current pharmaceutical design.

[130]  Olivier Sperandio,et al.  iPPI-DB: a manually curated and interactive database of small non-peptide inhibitors of protein-protein interactions. , 2013, Drug discovery today.

[131]  T. O'Brien,et al.  Fragment-based drug discovery. , 2004, Journal of medicinal chemistry.

[132]  S. Srinivasula,et al.  Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[133]  R&D productivity rides again? , 2015, Pharmaceutical statistics.

[134]  F. Pammolli,et al.  The productivity crisis in pharmaceutical R&D , 2011, Nature Reviews Drug Discovery.

[135]  L. Serrano,et al.  Predicting changes in the stability of proteins and protein complexes: a study of more than 1000 mutations. , 2002, Journal of molecular biology.

[136]  Thomas Madej,et al.  Modulating protein-protein interactions with small molecules: the importance of binding hotspots. , 2012, Journal of molecular biology.

[137]  D. Janero The future of drug discovery: enabling technologies for enhancing lead characterization and profiling therapeutic potential , 2014, Expert opinion on drug discovery.

[138]  P. Jeffrey,et al.  Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. , 1994, Science.

[139]  A. Keating,et al.  Determinants of BH3 binding specificity for Mcl-1 versus Bcl-xL. , 2010, Journal of molecular biology.

[140]  Richard Bonneau,et al.  Rational Design of Topographical Helix Mimics as Potent Inhibitors of Protein–Protein Interactions , 2014, Journal of the American Chemical Society.

[141]  Philippe Roche,et al.  Chemical and structural lessons from recent successes in protein-protein interaction inhibition (2P2I). , 2011, Current opinion in chemical biology.

[142]  John B. O. Mitchell,et al.  D‐amino acid residues in peptides and proteins , 2003, Proteins.

[143]  David Baker,et al.  Computational design of novel protein binders and experimental affinity maturation. , 2013, Methods in enzymology.