title: Discovering new medicines targeting helicases: challenges and recent progress.
abstract: Helicases are ubiquitous motor proteins that separate and/or rearrange nucleic acid duplexes in reactions fueled by adenosine triphosphate (ATP) hydrolysis. Helicases encoded by bacteria, viruses, and human cells are widely studied targets for new antiviral, antibiotic, and anticancer drugs. This review summarizes the biochemistry of frequently targeted helicases. These proteins include viral enzymes from herpes simplex virus, papillomaviruses, polyomaviruses, coronaviruses, the hepatitis C virus, and various flaviviruses. Bacterial targets examined include DnaB-like and RecBCD-like helicases. The human DEAD-box protein DDX3 is the cellular antiviral target discussed, and cellular anticancer drug targets discussed are the human RecQ-like helicases and eIF4A. We also review assays used for helicase inhibitor discovery and the most promising and common helicase inhibitor chemotypes, such as nucleotide analogues, polyphenyls, metal ion chelators, flavones, polycyclic aromatic polymers, coumarins, and various DNA binding pharmacophores. Also discussed are common complications encountered while searching for potent helicase inhibitors and possible solutions for these problems.
authors.affiliation: Department of Chemistry & Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Shadrick
authors.forename: Jean
authors.initials: J
authors.lastname: Ndjomou
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kolli
authors.forename: Sourav
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Hanson
authors.forename: David N
authors.initials: DN
authors.lastname: Frick
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D004265:DNA Helicases / Q000037:antagonists & inhibitors* / Q000502:physiology; D004261:DNA Replication; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D011485:Protein Binding; D014176:Protein Biosynthesis; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D014764:Viral Proteins; D004265:DNA Helicases
keywords: ATPase; RNA binding proteins; antibiotic; anticancer; antivirals; molecular probes; motor protein
references.citation: Herpes. 2003 Aug;10(2):46-52
references.pmid: 14577954
references.citation: Arch Dermatol. 2005 May;141(5):617-20
references.pmid: 15897384
references.citation: Nature. 2003 May 29;423(6939):512-8
references.pmid: 12774115
references.citation: Biochem Pharmacol. 2012 Aug 15;84(4):459-67
references.pmid: 22687623
references.citation: Am J Manag Care. 2004 Mar;10(2 Suppl):S21-9
references.pmid: 15084064
references.citation: Nucleic Acids Res. 2012 Sep 1;40(17):8607-21
references.pmid: 22740655
references.citation: Biochemistry. 2010 Mar 9;49(9):1822-32
references.pmid: 20108979
references.citation: J Clin Invest. 2008 Jul;118(7):2651-60
references.pmid: 18551192
references.citation: J Med Chem. 1998 Dec 17;41(26):5219-46
references.pmid: 9857091
references.citation: Acta Pol Pharm. 2004 Dec;61 Suppl:26-8
references.pmid: 15909930
references.citation: J Nucleic Acids. 2011;2011:724215
references.pmid: 21977309
references.citation: J Biomol Screen. 2012 Feb;17(2):194-203
references.pmid: 21948801
references.citation: Annu Rev Genomics Hum Genet. 2000;1:409-59
references.pmid: 11701636
references.citation: Nat Struct Biol. 1997 Jun;4(6):463-7
references.pmid: 9187654
references.citation: Nat Rev Mol Cell Biol. 2008 May;9(5):391-401
references.pmid: 18414490
references.citation: Appl Microbiol. 1969 Mar;17(3):489-90
references.pmid: 4180993
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D400-12
references.pmid: 22140110
references.citation: Adv Exp Med Biol. 2013;767:161-84
references.pmid: 23161011
references.citation: Methods Enzymol. 2012;511:463-83
references.pmid: 22713333
references.citation: Nat Biotechnol. 2011 Nov 08;29(11):963-6
references.pmid: 22068526
references.citation: Acta Crystallogr Sect F Struct Biol Cryst Commun. 2007 Mar 1;63(Pt 3):193-5
references.pmid: 17329812
references.citation: Nat Med. 2002 Apr;8(4):386-91
references.pmid: 11927945
references.citation: Virology. 2004 Dec 20;330(2):471-80
references.pmid: 15567440
references.citation: Antimicrob Agents Chemother. 2012 Sep;56(9):4718-28
references.pmid: 22733076
references.citation: Biochemistry. 1994 Nov 29;33(47):14306-16
references.pmid: 7947840
references.citation: Nat Chem Biol. 2012 Nov;8(11):920-5
references.pmid: 23023261
references.citation: J Mol Biol. 2004 Dec 10;344(5):1287-309
references.pmid: 15561144
references.citation: J Struct Biol. 2004 Apr-May;146(1-2):11-31
references.pmid: 15037234
references.citation: J Mol Cell Biol. 2011 Feb;3(1):31-8
references.pmid: 21278449
references.citation: Prog Nucleic Acid Res Mol Biol. 2001;70:77-118
references.pmid: 11642367
references.citation: Antimicrob Agents Chemother. 2005 Dec;49(12):4834-42
references.pmid: 16304143
references.citation: J Gen Virol. 2003 Dec;84(Pt 12):3215-3225
references.pmid: 14645903
references.citation: Crit Rev Biochem Mol Biol. 2004 Mar-Apr;39(2):79-97
references.pmid: 15217989
references.citation: Nucleic Acids Res. 2010 Mar;38(5):1686-96
references.pmid: 20007598
references.citation: J Mol Biol. 2007 Jan 26;365(4):1017-32
references.pmid: 17084859
references.citation: J Cell Biochem. 2009 Apr 1;106(5):758-63
references.pmid: 19173305
references.citation: Curr Pharm Des. 2006;12(11):1315-38
references.pmid: 16611118
references.citation: Nat Biotechnol. 1996 Mar;14(3):303-8
references.pmid: 9630890
references.citation: Q Rev Biophys. 2002 Nov;35(4):431-78
references.pmid: 12621862
references.citation: Future Virol. 2009 May 1;4(3):277-293
references.pmid: 20161209
references.citation: EMBO J. 1982;1(8):945-51
references.pmid: 6329717
references.citation: Nat Rev Cancer. 2009 Sep;9(9):644-54
references.pmid: 19657341
references.citation: ACS Chem Biol. 2012 May 18;7(5):879-91
references.pmid: 22443934
references.citation: Annu Rev Biochem. 1992;61:55-85
references.pmid: 1323237
references.citation: Biochem Biophys Res Commun. 2004 Dec 17;325(3):670-5
references.pmid: 15541341
references.citation: Q Rev Biophys. 2003 Feb;36(1):1-69
references.pmid: 12643042
references.citation: Mol Biol Cell. 2009 Jan;20(1):114-23
references.pmid: 18987339
references.citation: Curr Top Microbiol Immunol. 2011;348:61-88
references.pmid: 20676971
references.citation: Curr Issues Mol Biol. 2007 Jan;9(1):1-20
references.pmid: 17263143
references.citation: Nucleic Acids Res. 2000 Jun 15;28(12):2420-30
references.pmid: 10871376
references.citation: J Virol. 2004 Jul;78(14):7833-8
references.pmid: 15220459
references.citation: Cell. 1997 Jul 11;90(1):77-86
references.pmid: 9230304
references.citation: Adv Exp Med Biol. 2013;767:145-59
references.pmid: 23161010
references.citation: Molecules. 2011 Aug 25;16(9):7210-23
references.pmid: 21869749
references.citation: Antiviral Res. 2000 Jun;46(3):181-93
references.pmid: 10867156
references.citation: Bioorg Med Chem Lett. 2009 Jun 1;19(11):2935-7
references.pmid: 19414257
references.citation: Biochemistry. 1999 Apr 20;38(16):5164-71
references.pmid: 10213622
references.citation: Nature. 1992 Jan 23;355(6358):318-25
references.pmid: 1731246
references.citation: J Virol. 2005 Aug;79(16):10268-77
references.pmid: 16051820
references.citation: J Med Chem. 2012 Dec 27;55(24):10896-908
references.pmid: 23231076
references.citation: J Biol Chem. 1992 Apr 15;267(11):7596-610
references.pmid: 1313807
references.citation: J Antimicrob Chemother. 2008 May;61(5):1044-7
references.pmid: 18299638
references.citation: Nat Rev Microbiol. 2004 Feb;2(2):123-40
references.pmid: 15040260
references.citation: Annu Rev Biophys. 2012;41:295-319
references.pmid: 22404684
references.citation: Chem Commun (Camb). 2007 Nov 14;(42):4413-5
references.pmid: 17957304
references.citation: J Biol Chem. 2006 May 5;281(18):12625-35
references.pmid: 16527808
references.citation: Curr Opin Struct Biol. 2000 Feb;10(1):124-8
references.pmid: 10679457
references.citation: Structure. 1999 Nov 15;7(11):1353-63
references.pmid: 10574797
references.citation: J Mol Biol. 2007 Aug 3;371(1):25-33
references.pmid: 17544443
references.citation: Annu Rev Biophys. 2008;37:317-36
references.pmid: 18573084
references.citation: Nat Genet. 1997 Sep;17(1):100-3
references.pmid: 9288107
references.citation: Nucleic Acids Res. 2001 Apr 15;29(8):1765-71
references.pmid: 11292849
references.citation: Cell. 2012 Oct 12;151(2):267-77
references.pmid: 23022319
references.citation: Arch Intern Med. 2008 Jun 9;168(11):1137-44
references.pmid: 18541820
references.citation: Anal Biochem. 2004 Jun 1;329(1):68-76
references.pmid: 15136168
references.citation: Cell. 1999 Apr 2;97(1):75-84
references.pmid: 10199404
references.citation: Nat Chem Biol. 2006 Apr;2(4):213-20
references.pmid: 16532013
references.citation: J Antimicrob Chemother. 2012 Aug;67(8):1884-94
references.pmid: 22535622
references.citation: Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5471-4
references.pmid: 8202510
references.citation: Bioorg Med Chem Lett. 2006 Mar 1;16(5):1286-90
references.pmid: 16343901
references.citation: J Biol Chem. 2011 May 6;286(18):15619-24
references.pmid: 21362621
references.citation: J Mol Biol. 2007 Sep 7;372(1):150-9
references.pmid: 17631897
references.citation: J Virol. 2008 Jan;82(1):173-83
references.pmid: 17942558
references.citation: Biol Pharm Bull. 2007 Oct;30(10):1958-61
references.pmid: 17917271
references.citation: Anticancer Agents Med Chem. 2008 May;8(4):390-401
references.pmid: 18473724
references.citation: J Med Chem. 2012 Apr 12;55(7):3319-30
references.pmid: 22409723
references.citation: J Virol. 1993 Oct;67(10):6152-8
references.pmid: 8396675
references.citation: Acta Biochim Pol. 2000;47(1):173-80
references.pmid: 10961691
references.citation: Biotechniques. 2008 Oct;45(4):433-40, 442
references.pmid: 18855770
references.citation: Eur J Med Chem. 2011 Nov;46(11):5698-704
references.pmid: 21925774
references.citation: RNA. 2004 Aug;10(8):1277-90
references.pmid: 15247433
references.citation: Virology. 2008 May 25;375(1):253-64
references.pmid: 18289627
references.citation: Mutat Res. 2013 Apr-Jun;752(2):138-152
references.pmid: 23276657
references.citation: Nat Med. 2004 Dec;10(12 Suppl):S98-109
references.pmid: 15577938
references.citation: J Mol Biol. 2000 Nov 10;303(5):773-95
references.pmid: 11061975
references.citation: Nucleic Acids Res. 1996 Apr 1;24(7):1179-86
references.pmid: 8614617
references.citation: FASEB J. 2000 Nov;14(14):2138-40
references.pmid: 11023999
references.citation: Bioorg Med Chem Lett. 2009 Aug 15;19(16):4538-41
references.pmid: 19625187
references.citation: Bioorg Med Chem Lett. 2012 Mar 1;22(5):2094-8
references.pmid: 22300661
references.citation: Eur Rev Med Pharmacol Sci. 2012 Aug;16(8):1039-44
references.pmid: 22913154
references.citation: J Gen Virol. 2011 Jan;92(Pt 1):101-11
references.pmid: 20881089
references.citation: FEBS Lett. 2004 Jun 4;567(2-3):253-8
references.pmid: 15178332
references.citation: J Biomol Screen. 2001 Feb;6(1):39-46
references.pmid: 11679164
references.citation: Chem Biol. 2013 Jan 24;20(1):55-62
references.pmid: 23352139
references.citation: Am J Pathol. 2004 Oct;165(4):1163-73
references.pmid: 15466383
references.citation: Nature. 2003 Jun 19;423(6942):893-7
references.pmid: 12815438
references.citation: Biochemistry. 2001 Oct 23;40(42):12628-38
references.pmid: 11601987
references.citation: Front Biosci (Schol Ed). 2013 Jan 01;5(1):206-16
references.pmid: 23277046
references.citation: Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1525-30
references.pmid: 21220316
references.citation: Mol Biotechnol. 2008 Jul;39(3):231-8
references.pmid: 18259889
references.citation: J Biomol Screen. 1999;4(5):239-248
references.pmid: 10838444
references.citation: Anal Biochem. 1998 Mar 15;257(2):120-6
references.pmid: 9514793
references.citation: J Biomol Screen. 2010 Dec;15(10):1211-9
references.pmid: 20926844
references.citation: PLoS One. 2008 Feb 13;3(2):e1583
references.pmid: 18270573
references.citation: Anal Biochem. 1979 Nov 15;100(1):95-7
references.pmid: 161695
references.citation: Oncogene. 2000 Jul 27;19(32):3570-5
references.pmid: 10951562
references.citation: Antiviral Res. 2012 Oct;96(1):70-81
references.pmid: 22898086
references.citation: Biochem Biophys Res Commun. 2010 Feb 26;393(1):131-6
references.pmid: 20117090
references.citation: Virology. 2005 Jun 5;336(2):299-307
references.pmid: 15892970
references.citation: J Am Chem Soc. 2001 Jun 27;123(25):5878-91
references.pmid: 11414820
references.citation: Open Virol J. 2011;5:80-95
references.pmid: 21769307
references.citation: Anal Biochem. 1997 Mar 1;246(1):86-95
references.pmid: 9056187
references.citation: J Bacteriol. 2009 Aug;191(16):5076-84
references.pmid: 19542287
references.citation: J Antimicrob Chemother. 2010 Aug;65(8):1733-41
references.pmid: 20534624
references.citation: J Biol Chem. 2002 Aug 9;277(32):21e
references.pmid: 12161449
references.citation: Antiviral Res. 2012 Feb;93(2):301-304
references.pmid: 22155691
references.citation: Anal Biochem. 1998 Dec 1;265(1):22-7
references.pmid: 9866703
references.citation: Curr Med Chem Anticancer Agents. 2005 May;5(3):183-99
references.pmid: 15992349
references.citation: Nucleic Acids Res. 2004 Feb 09;32(3):902-15
references.pmid: 14769948
references.citation: J Antimicrob Chemother. 2007 Aug;60(2):274-9
references.pmid: 17550887
references.citation: J Infect Dis. 2012 Apr 1;205(7):1100-10
references.pmid: 22351940
references.citation: J Biol Chem. 2004 Feb 20;279(8):6976-85
references.pmid: 14634007
references.citation: J Ocul Pharmacol Ther. 2008 Feb;24(1):34-42
references.pmid: 18201137
references.citation: J Med Chem. 2009 May 14;52(9):2716-23
references.pmid: 19419203
references.citation: J Med Chem. 2008 Nov 13;51(21):6635-8
references.pmid: 18834110
references.citation: Proc Natl Acad Sci U S A. 2002 May 28;99(11):7687-92
references.pmid: 12032344
references.citation: J Biochem. 2005 Mar;137(3):339-47
references.pmid: 15809335
references.citation: J Biol Chem. 2008 Apr 25;283(17):11516-25
references.pmid: 18283103
references.citation: J Biol Chem. 2007 Apr 20;282(16):12048-57
references.pmid: 17317667
references.citation: Anal Biochem. 2001 Jun 1;293(1):31-7
references.pmid: 11373075
references.citation: Chem Biol. 2006 Dec;13(12):1287-95
references.pmid: 17185224
references.citation: Bioorg Med Chem Lett. 2012 Jun 15;22(12):4049-54
references.pmid: 22578462
references.citation: Bioorg Med Chem. 2007 Nov 15;15(22):7203-8
references.pmid: 17851081
references.citation: Annu Rev Biophys. 2012;41:247-67
references.pmid: 22404686
references.citation: Adv Exp Med Biol. 2013;767:123-44
references.pmid: 23161009
references.citation: Nat Rev Drug Discov. 2005 Oct;4(10):845-53
references.pmid: 16184083
references.citation: Oncol Rep. 2012 Oct;28(4):1146-52
references.pmid: 22797812
references.citation: Cell. 2000 Jun 9;101(6):589-600
references.pmid: 10892646
references.citation: Nat Rev Cancer. 2002 May;2(5):342-50
references.pmid: 12044010
references.citation: Assay Drug Dev Technol. 2004 Apr;2(2):153-60
references.pmid: 15165511
references.citation: Bioorg Med Chem Lett. 2001 Jul 9;11(13):1647-50
references.pmid: 11425528
references.citation: J Mol Biol. 2007 Sep 14;372(2):444-55
references.pmid: 17658551
references.citation: Biochem Biophys Res Commun. 2012 Mar 30;420(1):24-8
references.pmid: 22390926
references.citation: Science. 1996 Apr 12;272(5259):258-62
references.pmid: 8602509
references.citation: Antivir Ther. 2012;17(3):467-76
references.pmid: 22293206
references.citation: Biochem Biophys Res Commun. 1998 Dec 30;253(3):594-9
references.pmid: 9918773
references.citation: Bioorg Med Chem. 2009 Jul 1;17(13):4466-76
references.pmid: 19477652
references.citation: J Infect Dev Ctries. 2012 Oct 19;6(10):692-4
references.pmid: 23103889
references.citation: Front Biosci (Landmark Ed). 2012 Jun 01;17(6):2070-88
references.pmid: 22652765
references.citation: Oncogene. 2013 Apr 25;32(17):2179-88
references.pmid: 22689062
references.citation: Cell. 2006 Nov 3;127(3):553-64
references.pmid: 17081977
references.citation: Bioorg Med Chem. 2001 Sep;9(9):2511-8
references.pmid: 11553493
references.citation: J Mol Biol. 2011 Feb 4;405(5):1139-53
references.pmid: 21145896
references.citation: Cell. 2004 Oct 29;119(3):381-92
references.pmid: 15507209
references.citation: Antivir Chem Chemother. 2004 May;15(3):135-40
references.pmid: 15266895
references.citation: Biochem Pharmacol. 2012 Nov 15;84(10):1351-8
references.pmid: 22935448
references.citation: J Med Chem. 2008 Aug 28;51(16):5043-51
references.pmid: 18680273
references.citation: Virology. 1993 Nov;197(1):265-73
references.pmid: 8212562
references.citation: Nature. 2006 Jul 20;442(7100):270-5
references.pmid: 16855583
references.citation: J Virol. 1993 Jul;67(7):4017-26
references.pmid: 7685406
references.citation: Annu Rev Biochem. 2007;76:23-50
references.pmid: 17506634
references.citation: Aliment Pharmacol Ther. 2010 Jul;32(1):14-28
references.pmid: 20374226
references.citation: Bioorg Med Chem Lett. 2011 Sep 15;21(18):5331-5
references.pmid: 21821416
references.citation: Nucleic Acids Res. 2003 Jul 15;31(14):e70
references.pmid: 12853647
references.citation: J Virol. 2004 May;78(10):5288-98
references.pmid: 15113910
references.citation: Bioorg Med Chem. 2007 Apr 1;15(7):2690-700
references.pmid: 17306550
references.citation: J Gen Virol. 2003 Sep;84(Pt 9):2323-2332
references.pmid: 12917452
references.citation: Nat Genet. 1999 May;22(1):82-4
references.pmid: 10319867
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10460-5
references.pmid: 16030146
references.citation: Nature. 2011 May 25;474(7350):S18-9
references.pmid: 21613999
references.citation: Virus Res. 2009 Apr;141(1):71-80
references.pmid: 19200446
references.citation: Antivir Ther. 2007;12(1):1-6
references.pmid: 17503741
references.citation: Antiviral Res. 2012 Nov;96(2):245-55
references.pmid: 22940425
references.citation: Antimicrob Agents Chemother. 2012 Jul;56(7):3587-91
references.pmid: 22526302
references.citation: J Med Chem. 2004 Jan 1;47(1):18-21
references.pmid: 14695816
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):521-8
references.pmid: 20080715
references.citation: Science. 2001 Mar 9;291(5510):1959-62
references.pmid: 11239155
references.citation: J Med Genet. 2006 Feb;43(2):148-52
references.pmid: 15964893
references.citation: Nature. 2004 Nov 11;432(7014):187-93
references.pmid: 15538360
references.citation: Drug News Perspect. 2003 Jul-Aug;16(6):355-62
references.pmid: 12973446
references.citation: Curr Med Chem. 2007;14(8):883-915
references.pmid: 17430143
references.citation: J Virol. 2009 Dec;83(24):12895-906
references.pmid: 19793813
references.citation: Genes Dev. 2003 Jul 1;17(13):1569-74
references.pmid: 12842909
references.citation: Nat Struct Mol Biol. 2006 Mar;13(3):242-9
references.pmid: 16474403
references.citation: Antiviral Res. 2008 Nov;80(2):94-101
references.pmid: 18674567
references.citation: Antivir Chem Chemother. 2007;18(1):35-48
references.pmid: 17354650
references.citation: Curr HIV/AIDS Rep. 2008 Aug;5(3):112-9
references.pmid: 18627659
references.citation: Nucleic Acids Res. 2001 Dec 15;29(24):5058-66
references.pmid: 11812837
references.citation: Nat Med. 2002 Apr;8(4):392-8
references.pmid: 11927946
references.citation: ACS Chem Biol. 2012 Feb 17;7(2):403-10
references.pmid: 22026461