title: Hemozoin and antimalarial drug discovery.
abstract: Recent initiatives to develop more effective and affordable drugs, controlling mosquitoes and development of a preventative vaccine have been launched with the goal of completely eradicating malaria. To this end, Novartis (Surrey, UK) and GlaxoSmithKline (Middlesex, UK) screened their chemical libraries of approximately two million small molecules for antimalarial properties, which resulted in a set of over 20,000 'highly druggable' initial hits. Efforts in academia are centered on specific pathway targets. One such high-throughput screening effort has been focused on hemozoin formation, a unique heme detoxification pathway found in the malaria parasite. This review discusses the current approaches and limitations of high-throughput screening discovery of hemozoin inhibitors. In the future, new methods must be developed to validate the mechanism of action of these hit compounds within the parasite.
authors.affiliation: Vanderbilt University, 2201 West End Avenue, Nashville, TN 37235, USA.
authors.forename: Kim Y
authors.initials: KY
authors.lastname: Fong
authors.forename: David W
authors.initials: DW
authors.lastname: Wright
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D006418:Heme / Q000737:chemistry; D006420:Hemeproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects
chemical_list: D000962:Antimalarials; D006420:Hemeproteins; C020753:hemozoin; D006418:Heme
references.citation: Antimicrob Agents Chemother. 2003 Mar;47(3):1175
references.pmid: 12604568
references.citation: Inorg Chem. 2004 Dec 13;43(25):8078-84
references.pmid: 15578847
references.citation: Mol Biochem Parasitol. 2008 Feb;157(2):127-36
references.pmid: 18083247
references.citation: PLoS Pathog. 2008 Apr 25;4(4):e1000053
references.pmid: 18437218
references.citation: Am J Respir Cell Mol Biol. 1996 Jul;15(1):9-19
references.pmid: 8679227
references.citation: Curr Med Chem. 2005;12(21):2539-49
references.pmid: 16250876
references.citation: Trends Parasitol. 2003 Jan;19(1):23-6
references.pmid: 12488222
references.citation: Mol Microbiol. 2007 Apr;64(2):407-20
references.pmid: 17493125
references.citation: Am J Trop Med Hyg. 2000 Jan;62(1):77-81
references.pmid: 10761728
references.citation: Nat Rev Microbiol. 2006 Nov;4(11):849-56
references.pmid: 17041632
references.citation: ACS Chem Biol. 2012 Apr 20;7(4):666-71
references.pmid: 22276975
references.citation: Comb Chem High Throughput Screen. 2010 Mar;13(3):285-92
references.pmid: 20230372
references.citation: Biochem J. 2007 Feb 15;402(1):197-204
references.pmid: 17044814
references.citation: BMC Cell Biol. 2009 Jun 10;10:45
references.pmid: 19515257
references.citation: Malar J. 2011 May 24;10:144
references.pmid: 21609473
references.citation: BMC Infect Dis. 2012 Jan 03;12:1
references.pmid: 22214291
references.citation: Nature. 1992 Jan 9;355(6356):167-9
references.pmid: 1729651
references.citation: Med Trop (Mars). 2002;62(3):219-24
references.pmid: 12244914
references.citation: Am J Med Sci. 1999 Oct;318(4):241-56
references.pmid: 10522552
references.citation: Chem Rev. 2008 Nov;108(11):4899-914
references.pmid: 19006402
references.citation: Br J Clin Pharmacol. 2006 Jun;61(6):666-70
references.pmid: 16722826
references.citation: J Med Chem. 1999 Nov 4;42(22):4630-9
references.pmid: 10579825
references.citation: Int J Biochem Cell Biol. 2011 Jun;43(6):839-42
references.pmid: 21458590
references.citation: Parasitology. 2001 Aug;123(Pt 2):125-31
references.pmid: 11510677
references.citation: Trends Parasitol. 2012 Nov;28(11):504-14
references.pmid: 23020971
references.citation: J Inorg Biochem. 2008 Aug;102(8):1660-7
references.pmid: 18508124
references.citation: J Biol Inorg Chem. 2006 Oct;11(7):917-29
references.pmid: 16868743
references.citation: Cell Host Microbe. 2009 Feb 19;5(2):191-9
references.pmid: 19218089
references.citation: J Phys Chem B. 2009 Jun 18;113(24):8391-401
references.pmid: 19472980
references.citation: Science. 1996 Jan 12;271(5246):219-22
references.pmid: 8539625
references.citation: Antimicrob Agents Chemother. 2009 Jun;53(6):2564-8
references.pmid: 19307367
references.citation: J Med Chem. 2011 Dec 8;54(23):8207-13
references.pmid: 22023506
references.citation: Nature. 2010 May 20;465(7296):305-10
references.pmid: 20485427
references.citation: Drug Discov Today. 2005 Jan 15;10(2):139-47
references.pmid: 15718163
references.citation: Biochem Biophys Res Commun. 2003 Sep 5;308(4):736-43
references.pmid: 12927780
references.citation: Antimicrob Agents Chemother. 2007 Jun;51(6):1926-33
references.pmid: 17371812
references.citation: Biochem Pharmacol. 2009 Feb 1;77(3):322-36
references.pmid: 19022224
references.citation: J Bioenerg Biomembr. 2011 Feb;43(1):93-9
references.pmid: 21301942
references.citation: Antimicrob Agents Chemother. 2004 Jul;48(7):2370-8
references.pmid: 15215083
references.citation: Biochemistry. 2010 Nov 30;49(47):10107-16
references.pmid: 20979358
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9059-64
references.pmid: 18579783
references.citation: Comb Chem High Throughput Screen. 2012 Sep;15(8):595-610
references.pmid: 22480238
references.citation: Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11405-10
references.pmid: 21709259
references.citation: J Biol Chem. 2012 Nov 2;287(45):37793-807
references.pmid: 22992734
references.citation: J Inorg Biochem. 2001 Sep;86(2-3):617-25
references.pmid: 11566335
references.citation: FEBS Lett. 2006 Sep 18;580(21):5105-10
references.pmid: 16956610
references.citation: Biochem Pharmacol. 2003 Dec 1;66(11):2201-12
references.pmid: 14609745
references.citation: Parasitol Today. 1986 Dec;2(12):330-1
references.pmid: 15462754
references.citation: Antimicrob Agents Chemother. 2007 Jan;51(1):350-3
references.pmid: 17088494
references.citation: Dalton Trans. 2010 Feb 7;39(5):1235-44
references.pmid: 20104349
references.citation: Mol Biochem Parasitol. 1991 Dec;49(2):181-9
references.pmid: 1775162
references.citation: J Biol Chem. 2009 Mar 20;284(12):7687-96
references.pmid: 19117944
references.citation: Antimicrob Agents Chemother. 2011 Jul;55(7):3363-9
references.pmid: 21518844
references.citation: Lancet Infect Dis. 2002 Apr;2(4):209-18
references.pmid: 11937421
references.citation: Ann N Y Acad Sci. 2008;1136:32-7
references.pmid: 18579874
references.citation: Exp Parasitol. 2005 Oct;111(2):105-14
references.pmid: 16098967
references.citation: EMBO J. 2002 Apr 2;21(7):1597-606
references.pmid: 11927544
references.citation: Antimicrob Agents Chemother. 2002 Jan;46(1):144-50
references.pmid: 11751125
references.citation: Malar J. 2012 Nov 05;11:366
references.pmid: 23126583
references.citation: Biochemistry. 2010 Aug 10;49(31):6804-11
references.pmid: 20593810
references.citation: ACS Chem Biol. 2013 Jan 18;8(1):133-7
references.pmid: 23043646
references.citation: J Inorg Biochem. 2005 Jul;99(7):1532-9
references.pmid: 15927260
references.citation: Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11865-70
references.pmid: 8876229
references.citation: Biochim Biophys Acta. 1999 May 31;1454(1):31-7
references.pmid: 10354512
references.citation: Exp Parasitol. 2007 Jul;116(3):311-3
references.pmid: 17336296
references.citation: J Am Chem Soc. 2007 Mar 7;129(9):2615-27
references.pmid: 17290993
references.citation: J Antimicrob Chemother. 1998 Jul;42(1):55-60
references.pmid: 9700528
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11188-93
references.pmid: 22745164
references.citation: FEBS Lett. 1997 Jun 2;409(1):67-73
references.pmid: 9199506
references.citation: Antimicrob Agents Chemother. 2000 Oct;44(10):2638-44
references.pmid: 10991837
references.citation: Proc Natl Acad Sci U S A. 1990 Apr;87(8):2931-5
references.pmid: 2183218
references.citation: Science. 2009 Sep 25;325(5948):1680-2
references.pmid: 19779197
references.citation: Mol Biochem Parasitol. 1994 Jan;63(1):121-8
references.pmid: 8183310