The Effects of Combinatorial Chemistry and Technologies on Drug Discovery and Biotechnology – a Mini Review

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The review will focus on the aspects of combinatorial chemistry and technologies that are more relevant in the modern pharmaceutical process. An historical, critical introduction is followed by three chapters, dealing with the use of combinatorial chemistry/high throughput synthesis in medicinal chemistry; the rational design of combinatorial libraries using computer-assisted combinatorial drug design; and the use of combinatorial technologies in biotechnology. The impact of “combinatorial thinking” in drug discovery in general, and in the examples reported in details, is critically discussed. Finally, an expert opinion on current and future trends in combinatorial chemistry and combinatorial technologies is provided.

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  • ACEVEDO-ROCHA CG. HOEBENREICH S. REETZ MT.: Iterative saturation mutagenesis: a powerful approach to engineer proteins by systematically simulating Darwinian evolution. Methods Mol. Biol. 11792014 103-28.

  • AGRAFIOTIS D. K.: Multiobjective optimization of combinatorial libraries. J. Comput. Aided. Mol. Des. 16 2002 335-356.

  • ALDANA-MASANGKAY G. I. RODRIGUEZ-GONZALEZ A. LIN T. IKEDA A.K. HSIEH Y.T. KIM Y.M. LOMENICK B. OKEMOTO K. LANDAW E.M. WANG D. MAZITSCHEK R. BRADNER J.E. SAKAMOTO K.M.: Tubacin suppresses proliferation and induces apoptosis of acute lymphoblastic leukemia cells. Leuk. Lymphoma 52 2011 1544−1555.

  • ASHOK B.T. DAVID L. CHEN Y.G. GARIKAPATY V.P. CHANDER B. KANDUC D. MITTELMAN A. TIWARI R.K.: Peptide mimotopes of oncoproteins as therapeutic agents in breast cancer. Int. J. Mol. Med. 11 2003 465-71.

  • BANFI L. RIVA R.: The Passerini reaction. Org. React. 65 2005 1-140.

  • BEAVERS M.P. CHEN X.: Structure-based combinatorial library design: methodologies and applications. J. Mol. Graph. Model. 20 2002 463-468.

  • BIENAYMÉ H. BOUZID K.: A new heterocyclic multicomponent reaction for the combinatorial synthesis of fused 3-aminoimidazoles. Angew. Chem. Int. Ed. 37 1998 2234-2237.

  • BLACKWELL H. E. PEREZ L. STAVENGER R. A. STAVENGER R.A. TALLARICO J.A. COPE EATOUGH E. FOLEY M.A. SCHREIBER S.L.: A one bead one-stock solution approach to chemical genetics: part 1. Chem. Biol. 8 2001 1167-1182.

  • BLUNDELL T. L. PATEL S.: High-throughput X-ray crystallography for drug discovery. Curr. Opin. Pharmacol. 4 2004 490-496.

  • BOENS N. LEEN V. DEHAEN W.: Fluorescent indicators based on BODIPY. Chem. Soc. Rev. 41 2012 1130-1172.

  • BÖHM H. J. BANNER D. W. WEBER L.: Combinatorial docking and combinatorial chemistry: design of non-peptide thrombin inhibitors. J. Comput.- Aided Mol. Design 13 1999 51-56.

  • BÖHM H. J. STAHL M.: Structure-based library design: molecular modelling merges with combinatorial chemistry. Curr. Opin. Chem. Biol. 4 2000 283-286.

  • BUNIN B. A. PLUNKETT M. J. ELLMAN J. A.: The combinatorial synthesis and chemical and biological evaluation of a 14-benzodiazepine library. Proc. Natl. Acad. Sci. U.S.A. 91 1994 4708-4712.

  • BUTZ S. RAWER S. RAPP W. BIRSNER U.: Immunization and affinity purification of antibodies using resin-immobilized lysine-branched synthetic peptides. Pept. Res. 7 1994 20-23.

  • CASALI P. SCHETTINO E. W. Structure and function of natural antibodies. Curr. Top. Microbiol. Immunol. 1996 210 167-179.

  • CLEMONS P. A. KOEHLER A. N. WAGNER B. K. SPRIGINGS T.G. SPRING D.R. KING R.W. SCHREIBER S.L. FOLEY M.A.: A one-bead one-stock solution approach to chemical genetics: part 2. Chem. Biol. 8 2001 1183-1195.

  • COBB R. E. CHAO R. ZHAO H.: Directed evolution: Past present and future. AIChE J. 59 2013 1432-1440.

  • CORTHALS G. L. WASINGER V. C. HOCHSTRASSER D. F. SANCHEZ J. C.: The dynamic range of protein expression: A challenge for proteomic research. Electrophoresis 21 2000 1104-1115.

  • D’YDEWALLE C. KRISHNAN J. CHIHEB D. M. Van DAMME P. IROBI J. KOZIKOWSKI A.P. VANDEN BERGHE P. TIMMERMAN V. ROBBERECHT W. Van DEN BOSCH L.: HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease. Nat. Med. 17 2011 968-974.

  • DAWIS I. W. BAKER D.: RosettaLigand docking with full ligand and receptor flexibility. J. Mol. Biol. 385 2009 381-392.

  • DE ZOETEN E. F. WANG L. BUTLER K. BEIER U.H. AKIMOVA T. SAI H. BRADNER J.E. MAZITSCHEK R. KOZIKOWSKI A.P. MATTHIAS P. HANCOCK W.W.: Histone deacetylase 6 and heat shock protein 90 control the functions of Foxp3+ T-regulatory cells. Mol. Cell. Biol. 31 2011 2066-2078.

  • DOMINGUEZ J. M.: High throughput combinatorial methods for heterogeneous catalysts design and development. In: Fassina G Miertus S Eds. Combinatorial Chemistry and Technologies 2nd Edition. CLC Press LCC Boca Raton 2005 369-388.

  • DUFFY B. C. ZHU L. DECORNEZ H. KITCHEN D. B.: Early phase drug discovery: Cheminformatics and computational techniques in identifying lead series. Bioorg. Med. Chem. 20 2012 5324-5342.

  • ER J. C. TANG M. K. CHIA C. G. LIEW H. VENDRELL M. CHANG Y-T.: MegaStokes BODIPY-triazoles as environmentally sensitive turn-on fluorescent dyes. Chem. Sci. 4 2013 2168-2176.

  • ERLANSON D. A.: Fragment-based lead discovery: a chemical update. Curr. Opin. Biotech. 17 2006 643-652.

  • ESTIU G. GREENBERG E. HARRISON C. B. KWIATKOWSKI N.P. MAZITSCHEK R. BRADNER J.E. WIEST O.: Structural origin of selectivity in class II-selective histone deacetylase inhibitors. J. Med. Chem. 51 2008 2898-2906.

  • FASSINA G. SCARDINO P. RUVO M. FUCILE P. AMODEO P. CASSANI G.: Synthesis of conformationally constrained dimeric peptide libraries. In: Maia H Ed. Peptides 1994. Leiden ESCOM 1995 489-490.

  • FASSINA G. VERDOLIVA A. ODIERNA M. R. RUVO M. CASSINI G.: Protein A mimetic peptide ligand for affinity purification of antibodies. J. Mol. Recognit. 9 1996 564-569.

  • FASSINA G.: Oriented immobilization of peptide ligands on solid supports. J. Chromatogr. 591 1992 99-106.

  • FODOR S. P. A. READ J. L. PIRRUNG M. C. STRYER L. LIU A. T. SOLAS D.: Light-directed spatially addressable parallel chemical synthesis. Science 2511991 767.

  • FOURNIER A. COUVINEAU A. LABURTHE M.: Synthesis of a hydrophilic affinity matrix for the purification of the vasoactive intestinal peptide receptor. Anal. Biochem. 2111992 305-310.

  • FRECER V. BURELLO E. MIERTUS S.: Combinatorial design of nonsymmetrical cyclic urea inhibitors of aspartic protease of HIV-1. Bioorg. Med. Chem. 13 2005 5492-5501.

  • FRECER V. MEGNASSAN E. MIERTUS S.: Design and in silico screening of combinatorial library of antimalarial analogs of triclosan inhibiting Plasmodium falciparum enoyl-acyl carrier protein reductase. Eur. J. Med. Chem. 44 2009 3009-3019.

  • FRECER V. MIERTUS S. TOSSI A. ROMEO D.: Rational design of inhibitors for drug-resistant HIV-1 aspartic protease mutants. Drug Des. Disc. 15 1998 211-231.

  • FRECER V. MIERTUS S.: Design structure-based focusing and in silico screening of combinatorial library of peptidomimetic inhibitors of Dengue virus NS2B-NS3 protease. J. Comp.-Aided Mol. Des. 24 2010 195-212.

  • FRECER V. SENECI P. MIERTUS S.: Computer-assisted combinatorial design of bicyclic thymidine analogs as inhibitors of mycobacterium tuberculosis thymidine monophosphate kinase. J. Comp.-Aided Mol. Des. 252011 31-49.

  • FURKA A. SEBESTYEN F. ASGEDOM M. DIBO G.: Cornucopia of peptide synthesis. Highlights of Modern Biochemistry Proceedings of the 14th International Congress of Biochemistry VSP. Utrecht The Netherland 1988 Vol. 5 p. 47.

  • FURKA A. SEBESTYEN F. ASGEDOM M. DIBO G.: General method for rapid synthesis of multicomponent peptide mixtures. Int. J. Peptide Protein Res. 37 1991 487-493.

  • GAZOULI M. HAN Z. PAPADOPOULOS V.: Identification of a peptide antagonist to the peripheral type benzodiazepine receptor (PBR) that inhibits hormone stimulated Leydig cell steroid formation. J. Pharmacol. Exp. Ther. 303 2002 627-632.

  • GEYSEN H. M. BARTELING S. J. MELOEN R. H.: Small peptides induce antibodies with a sequence and structural requirement for binding antigen comparable to antibodies raised against the native protein. Proc. Natl. Acad. Sci. USA 82 1985 178-182.

  • GEYSEN H. M. MELOEN R. H. BARTELING S. J.: Use of peptide synthesis to probe viral antigens for epitopes to a resolution of a single amino acid. Proc. Natl. Acad. Sci. USA. 81 1984 3998-4002.

  • GILLET V. KHATIB W. WILLETT P. FLEMING P.J GREEN D.V.: Combinatorial library design using a multiobjective genetic algorithm. J. Chem. Inf. Comput. Sci. 42 2002 375-385.

  • GILLET V. J.: Reactant- and product-based approaches to the design of combinatorial libraries. J. Comp. Aided Mol. Des. 16 2002 371-380.

  • GREENBERG A. H.: Antibodies and natural immunity. Biomed. Pharmacother. 39 1985 4-6.

  • GRIFFITH R. LUU T. T. GARNER J. KELLER P. A.: Combining structurebased drug design and pharmacophores. J. Mol. Graph. Model. 23 2005 439-446.

  • GROZINGER C. M. SCHREIBER S. L.: Deacetylase enzymes: biological functions and the use of small-molecule inhibitors. Chem. Biol. 9 2002 3-16.

  • HAGGARTY S. J. KOELLER K. M. WONG J. C. GROZINGER C.M. SCHREIBER S.L.: Domain-selective small molecule inhibitor of HDAC6- mediated tubulin deacetylation. Proc. Natl. Acad. Sci. USA 100 2003 4389-4394.

  • HAGGARTY S. J. KOELLER K. M. WONG J. C. BUTCHER R.A. SCHREIBER S.L.: Multidimensional chemical genetic analysis of diversityoriented synthesis-derived deacetylase inhibitors using cell-based assays. Chem. Biol. 10 2003 383-396.

  • HAJDUK P. J. GREER J. A.: decade of fragment-based drug design: strategic advances and lesions learned. Nat. Rev. Drug Discov. 6 2007 211-219.

  • HEIKAMP K. BAJORATH J.: The future of virtual compound screening. Chem. Biol. Drug Des. 81 2013 33-40.

  • HOUGHTEN R. A. PINILLA C. BLONDELLE S. E. APPEL J. R. DOOLEY C. T. CUERVO J. H.: Generation and use of synthetic peptide combinatorial libraries for basic research and drug discovery. Nature 354 1991 84-86.

  • HOUGHTEN R. A.: General method for the rapid solid-phase synthesis of large numbers of peptides: specificity of antigen-antibody interaction at the level of individual amino acids. Proc. Natl. Acad. Sci. USA 82 1985 5131-5135.

  • HUBBARD R. E. CHEN I. DAVIS B.: Informatics and modeling challenges in fragment-based drug discovery. Curr. Opin. Drug. Discov. Devel. 10 2007 289-297.

  • JACOBSEN B. GÅRDSVOLL H. FUNCH G. J. ØSTERGAARD S. BARKHOLT V. PLOUG M.: One-step affinity purification of recombinant urokinase-type plasminogen activator receptor using a synthetic peptide developed by combinatorial chemistry. Prot. Expr. Purific. 52 2007 286-296.

  • JOSE J.: Autodisplay: efficient bacterial surface display of recombinant proteins. Appl. Microbiol. Biot. 69 2006 607-617.

  • KALIN J. H. BERGMAN J. A.: Development and therapeutic implications of selective histone deacetylase 6 inhibitors. J. Med. Chem. 56 2013 6297-6313.

  • KASAIAN M. T. CASALI P.: Autoimmunity-prone B-1 (CD5 B) cells natural antibodies and self recognition. Autoimmunity 15 1993 315-329.

  • KASAIAN M. T. IKEMATSU H. CASALI P.: Identification and analysis of a novel human surface CD5- B lymphocyte subset producing natural antibodies. J. Immunol. 148 1992 2690-2702.

  • KIJIMA M. YOSHIDA M. SUGITA K. HORINOUCHI S. BEPPU T.: Trapoxin an antitumor cyclic tetrapeptide is an irreversible inhibitor of mammalian histone deacetylase. J. Biol. Chem. 268 1993 22429-22435.

  • KITCHEN D. B. DECORNEZ H. FURR J. R. BAJORATH J.: Docking and scoring in virtual screening for drug discovery: methods and applications. Nat. Rev. Drug Discov. 3 2004 935-949.

  • KOCHETKOV N. K.: Catalytic antibodies: prospects for the use in organic synthesis. Russ. Chem. Rev. 67 1998 999-1029.

  • KODADEK T.: The rise fall and reinvention of combinatorial chemistry. Chem. Commun. 47 2011 9757-9763.

  • KUBINYI H.: The design of combinatorial libraries. Drug Discov. Today 7 2002 503-504.

  • LAM K. S. SALMON S. E. HERSH E. M. HRUBY V. J. KAZMIERSKI W. M. KNAPP R. J.: A new type of synthetic peptide library for identifying ligandbinding activity. Nature 354 1991 82-84.

  • LEACH A. R. HANN M. M. The in silico world of virtual libraries. Drug Discov. Today 2000 5 326-336.

  • LEE J. S. KANG N. Y. KIM Y. K. SAMANTA A. FENG S. KIM H.K. VENDRELL M. PARK J.H. CHANG Y.T.: Synthesis of a BODIPY library and its application to the development of live cell glucagon imaging probe. J. Am. Chem. Soc. 131 2009 10077-10082.

  • LEE J. S. KIM H. K. FENG S. VENDRELL M. CHANG Y-T.: Accelerating fluorescent sensor discovery: unbiased screening of a diversity-oriented BODIPY library. Chem. Commun. 47 2011 2339−2341.

  • LEVIN A. M. WEISS G. A.: Optimizing the affinity and specificity of proteins with molecular display. Mol. Bio. Syst. 2 2006 49-57.

  • LOPEZ M. F.: Better approaches to finding the needle in a haystack: Optimizing proteome analysis through automation. Electrophoresis 21 2000 1082-1093.

  • LOUDET A. BURGESS K.: BODIPY dyes and their derivatives: Syntheses and spectroscopic properties. Chem. Rev. 107 2007 4891-4932.

  • MA B. KUMAR S. TSAI C. J. NUSSINOV R.: Folding funnels and binding mechanisms. Protein Eng. 12 1999 713-720.

  • MAIER W. STOEWE K. SIEG S.: Combinatorial and high-throughput materials science. Angew. Chem. Int. Ed. 46 2007 6016-6067.

  • MARINO M. CAMPANILE M. N. IPPOLITO A. SCARALLO A. RUVO M. FASSINA G.: Structurally constrained selective ligands for mouse immunoglobulins. In: S. BAJUSZ and F. HUDECZ Eds. Peptides 98 Academia Kiado Budapest 1999 776-777.

  • MARINO M. RUVO M. DE FALCO S. FASSINA G.: Prevention of systemic lupus erythematosus in MRL/lpr mice by administration of an immunoglobulinbinding peptide. Nat. Biotechnol. 18 2000 735-739.

  • MCINNES C.: Virtual screening strategies in drug discovery. Curr. Opin. Chem. Biol. 11 2007 494-502.

  • MENEGATTI S. WARD K. L. NAIK A. D. KISH W. S. BLACKBURN R. K. CARBONELL R. G.: Reversible cyclic peptide libraries for the discovery of affinity ligands. Anal. Chem. 85 2013 9229-9237.

  • MERRITT A.: High throughput chemistry in drug discovery. RSC Drug Discovery Series 2012 11 (New synthetic technologies in medicinal chemistry) 6-41.

  • MORTIER J. RAKERS C. FREDERICK R. WOLBER G.: Computational tools for in silico fragment-based drug design. Curr. Top. Med. Chem. 12 2012 1935-1943.

  • NAIK A. D. MENEGATTI S. GURGEL P. V. CARBONELL R. G.: Performance of hexamer peptide ligands for affinity purification of immunoglobulin G from commercial cell culture media. J. Chromatogr. A 1218 2011 1691-700.

  • NIXON A.E.: Phage Display as a Tool for Protease Ligand Discovery. Curr. Pharm. Biotechnol. 3 2002 1-12.

  • NOPPE W. PLIEVA F. M. GALAEV I. Y. VANHOORELBEKE K. MATTIASSON B. DECKMYN H.: Immobilised peptide displaying phages as affinity ligands: Purification of lactoferrin from defatted milk. J. Chromatogr. A 1101 2006 79-85.

  • OPREA T. I.: Current trends in lead discovery: are we looking forthe appropriate properties? J. Comput. Aided Mol. Des. 16 2002 371-380.

  • PALOMBO G. ROSSI M. CASSANI G. FASSINA G.: Affinity purification of mouse monoclonal IgE using a protein A mimetic ligand (TG19318) immobilized on solid supports. J. Mol. Recognit. 11 1998 247-249.

  • RASMUSSEN U. B. SCHREIBER V. SCHULTZ H. MISCHLER F. SCHUGHART K.:Tumor cell-targeting by phage-displayed peptides. Cancer Gene Ther. 9 2002 606-612.

  • ROLLINGER J. M. STUPPNER H. LANGER T.: Virtual screening for the discovery of bioactive natural products. Prog. Drug Res. 65 2008 213-249.

  • ROSE S. STEVENS A.: Computational design strategies for combinatorial libraries. Curr. Opin. Chem. Biol. 7 2003 331-339.

  • RUNGROTMONGKOL T. FRECER V. DE-EKNAMKUL W. HANNONGBUA S. MIERTUS S.: Design of oseltamivir analogs inhibiting neuraminidase of avian influenza virus H5N1. Antivir. Res. 82 2009 51-58.

  • RUPASINGHE C. N. SPALLER M. R.: The interplay between structure-based design and combinatorial chemistry. Curr. Opin. Chem. Biol. 10 2006 188-193.

  • RUVO M. SCARDINO P. CASSANI G. FASSINA G.: Facile manual synthesis of peptide libraries. Protein Pept. Lett. 1 1994 187-192.

  • SANCINETO L. MASSARI S. IRACI N. TABARRINI O.: From small to powerful: the fragments universe and its "chem-appeal". Curr. Med. Chem. 20 2013 1355-1381.

  • SHERMAN W. BEARD H. S. FARID R.: Use of an induced fit receptor structure in virtual screening. Chem. Biol. Drug Des. 67 2006 83-84.

  • SINKO W. LINDERT S. MCCAMMON A. J.: Accounting for receptor flexibility and enhanced sampling methods in computer-aided drug design. Chem. Biol. Drug. Des. 81 2013 41-49.

  • SMITH G. P. PETRENKO V. A.: Phage display. Chem. Rev. 97 1997 391-410.

  • SMITH G. P.: Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science 228 1985 1315-1317.

  • STEMBERG N. HOESS R. H.: Display of peptides and proteins on the surface of bacteriophage lambda. Proc. Nat. Acad. Sci. USA 92 1995 1609-1613.

  • STERNSON S. M. WONG J. C. GROZINGER C. M. SCHREIBER S. L.: Synthesis of 7200 small molecules based on a substructural analysis of the histone deacetylase inhibitors trichostatin and trapoxin. Org. Lett. 3 2001 4239-4242.

  • STRATMANN J. STROMMENGER B. STEVENSON K. GERLACH G. F.: Development of a peptide-mediated capture PCR for detection of Mycobacterium avium subsp. paratuberculosis in milk. J. Clin Microb. 40 2002 4244-4250.

  • TAM J. P.: Synthetic peptide vaccine design: synthesis and properties of a highdensity multiple antigenic peptide system. Proc. Natl. Acad. Sci. USA 85 1988 5409-5413.

  • TANAKA F.: Catalytic antibodies as designer proteases and esterases. Chem. Rev. 102 2002 4885-4905.

  • TIAM F. TSAO M. L. SCHULTZ P. G.: A phage display system with unnatural amino acids. J. Am. Chem. Soc. 126 2004 15962-15963.

  • TINOCO L. W. DA SILVA J. R. A. LEITE A. VALENTE A.P. ALMEIDA F.C.: NMR structure of PW2 bound to SDS micelles. A tryptophan-rich anticoccidial peptide selected from phage display libraries. J. Biol Chem. 277 2002 36351-36356.

  • TSUJI N. KOBAYASHI M. NAGASHIMA K. WAKISAKA Y. KOIZUMI K.: A new antifungal antibiotic trichostatin. J. Antibiot. 29 1976 1-6.

  • UGI I. GOEBEL M. GRUBER B. HEILINGBRUNNER M. HEIß C. HÖRL W. KERN O. STARNECKER M. DÖMLING A.: Molecular libraries in liquid phase via Ugi-MCR. Res. Chem. Interm. 22 1996 625-644.

  • VAZQUEZ-ROMERO A. KIELLAND N. ARÉVALO M. J. PRECIADO S. MELLANBY R.J. FENG Y. LAVILLA R. VENDRELL M.: Multicomponent reactions for de novo synthesis of BODIPY probes: In vivo imaging of phagocytic macrophages. J. Am. Chem. Soc. 135 2013 16018−16021.

  • VENDRELL M. KRISHNA G. G. GHOSH K. K. ZHAI D. LEE J.S. ZHU Q. YAU Y.H. SHOCHAT S.G. KIM H. CHUNG J. CHANG Y.T.: Solid-phase synthesis of BODIPY dyes and development of an immunoglobulin fluorescent sensor. Chem. Commun. 47 2011 8424−8426.

  • VERDOLIVA A. BASILE G. FASSINA G.: Affinity purification of immunoglobulins from chicken egg yolk using a new synthetic ligand. J. Chromat. B 749 2000 233-242.

  • VILLAR H. O. YAN J. HANSEN M. R.: Using NMR for ligand discovery and optimization. Curr. Opin. Chem. Biol. 8 2004 387-391.

  • WOLBER G. LANGER T.: CombiGen: A novel software package for the rapid generation of virtual combinatorial libraries. In: HÖLTJE H. D. SIPPL W. Eds. Rational Approaches to Drug Design Prous Science Barcelona Spain 2001 pp. 390-399.

  • WONG J. C. HONG R. SCHREIBER S. L.: Structural biasing elements for in-cell histone deacetylase paralog selectivity. J. Am. Chem. Soc. 125 2003 5586-5587.

  • WOO L. K.: Combinatorial approaches and molecular evolution of homogeneous catalysts . In: NARASIMHAN B. MALLAPRAGADA S. K. PORTER M. D. Eds. Combinatorial materials science. John Wiley and Sons Hoboken 2007 121-162.

  • ZHAI D. LEE S. C. VENDRELL M. LEONG L.P. CHANG Y-T.: Synthesis of a novel BODIPY library and its application in the discovery of a fructose sensor. ACS Combi. Science 14 2012 81-84.

  • ZHOU J. Z.: Structure-directed combinatorial library design. Curr. Opin. Chem. Biol. 12 2008 379-385.

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