Recent advances in the discovery of haem-targeting drugs for malaria and schistosomiasis.
Haem is believed to be the target of some of the historically most important antimalarial drugs, most notably chloroquine. This target is almost ideal as haem is host-derived and the process targeted, haemozoin formation, is a physico-chemical process with no equivalent in the host. The result is that the target remains viable despite resistance to current drugs, which arises from mutations in parasite membrane transport proteins. Recent advances in high-throughput screening methods, together with a better understanding of the interaction of existing drugs with this target, have created new prospects for discovering novel haem-targeting chemotypes and for target-based structural design of new drugs. Finally, the discovery that Schistosoma mansoni also produces haemozoin suggests that new drugs of this type may be chemotherapeutic not only for malaria, but also for schistosomiasis. These recent developments in the literature are reviewed.
de Villiers
Katherine A
KA
University of Stellenbosch, Private Bag X1, Matieland 7602, South Africa. kchen@sun.ac.za
Egan
Timothy J
TJ
D000962:Antimalarials / Q000737:chemistry* / Q000627:therapeutic use*; D015195:Drug Design; D006801:Humans; D008288:Malaria / Q000188:drug therapy*; D015394:Molecular Structure; D012552:Schistosomiasis / Q000188:drug therapy*; D012556:Schistosomicides / Q000737:chemistry* / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
D000962:Antimalarials; D012556:Schistosomicides
J Inorg Biochem. 1997 Nov 1;68(2):137-45
9336973
J Inorg Biochem. 2008 Aug;102(8):1660-7
18508124
Nature. 2002 Feb 7;415(6872):686-93
11832957
Curr Med Chem. 2005;12(21):2539-49
16250876
J Inorg Biochem. 1996 Oct;64(1):7-23
8837498
Exp Parasitol. 1997 Nov;87(3):293-304
9371097
Exp Parasitol. 2007 Apr;115(4):344-51
17083933
Mol Biochem Parasitol. 2000 Nov;111(1):217-21
11087932
Travel Med Infect Dis. 2008 Sep;6(5):253-8
18760248
FEBS Lett. 1994 Sep 19;352(1):54-7
7925942
Anal Biochem. 2005 Mar 15;338(2):306-19
15745752
Biochem J. 2007 Feb 15;402(1):197-204
17044814
Nature. 2009 May 14;459(7244):270-3
19357645
Am J Trop Med Hyg. 2001 Jul;65(1):19-20
11504401
Biochem Pharmacol. 1981 Dec 15;30(24):3323-7
7326041
Nature. 1992 Jan 9;355(6356):167-9
1729651
J Inorg Biochem. 2008 May-Jun;102(5-6):1288-99
18226838
Exp Parasitol. 2006 Sep;114(1):47-56
16828746
Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):1143-7
8302844
J Biol Chem. 1995 Oct 20;270(42):24876-83
7559611
Lancet. 2005 Apr 23-29;365(9469):1474-80
15850631
Nature. 1967 May 27;214(5091):935-6
4964195
FEBS Lett. 2000 Jul 14;477(1-2):95-8
10899317
Mol Microbiol. 2004 Sep;53(5):1291-305
15387810
J Cell Biol. 1985 Dec;101(6):2302-9
3905824
Mol Cell. 2000 Oct;6(4):861-71
11090624
J Pharmacol Exp Ther. 1997 Jul;282(1):108-12
9223546
J Med Chem. 2008 Mar 13;51(5):1278-94
18278860
Antimicrob Agents Chemother. 2009 Jun;53(6):2564-8
19307367
J Exp Med. 1911 Feb 1;13(2):290-9
19867409
J Clin Invest. 1980 Oct;66(4):856-8
7419723
Antimicrob Agents Chemother. 1992 Jul;36(7):1538-44
1510452
J Postgrad Med. 2006 Oct-Dec;52(4):271-6
17102545
Biochim Biophys Acta. 1991 May 24;1074(1):19-24
2043670
Mol Biochem Parasitol. 2008 Feb;157(2):127-36
18083247
Int J Parasitol. 2002 Dec 4;32(13):1645-53
12435449
Biochem J. 2002 Jul 15;365(Pt 2):343-7
12033986
Nature. 1967 May 27;214(5091):937-9
4861556
Naunyn Schmiedebergs Arch Pharmacol. 1978 Oct;304(3):309-15
714190
Biochem Pharmacol. 1998 Mar 15;55(6):727-36
9586944
J Inorg Biochem. 1999 Jan-Feb;73(1-2):101-7
10212997
Comb Chem High Throughput Screen. 2005 Feb;8(1):63-79
15720198
FEBS Lett. 2006 Sep 18;580(21):5105-10
16956610
Biochem Pharmacol. 2003 Dec 1;66(11):2201-12
14609745
Curr Opin Chem Biol. 2007 Aug;11(4):433-9
17652008
Biochemistry. 1980 Apr 15;19(8):1543-9
6990976
Wkly Epidemiol Rec. 1993 Sep 10;68(37):269-70
8217579
Antimicrob Agents Chemother. 1998 Nov;42(11):2973-7
9797235
J Infect Dis. 2004 Aug 15;190(4):843-52
15272414
Comb Chem High Throughput Screen. 2002 May;5(3):241-8
11966432
FEBS Lett. 2005 Nov 7;579(27):6010-6
16229843
J Cell Sci. 2006 Mar 15;119(Pt 6):1016-25
16492710
Antimicrob Agents Chemother. 1998 Mar;42(3):682-6
9517951
Biochem Pharmacol. 1998 Mar 15;55(6):737-47
9586945
Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11865-70
8876229
J Med Chem. 2009 Jan 22;52(2):502-13
19113955
J Med Chem. 2004 Apr 8;47(8):1997-2009
15055999
Acta Trop. 2005 Oct;96(1):16-23
16054105
Mol Microbiol. 2004 Oct;54(1):109-22
15458409
Bioorg Med Chem. 2008 Jan 15;16(2):771-82
17967541
Nature. 2000 Mar 16;404(6775):307-10
10749217
Parasitol Int. 2008 Jun;57(2):89-96
18373972
Biochem J. 1999 Apr 15;339 ( Pt 2):363-70
10191268
J Inorg Biochem. 2006 May;100(5-6):916-26
16384600
Antimicrob Agents Chemother. 2000 Oct;44(10):2638-44
10991837
J Chem Inf Comput Sci. 2002 Sep-Oct;42(5):1212-20
12377011
Antimicrob Agents Chemother. 2007 Nov;51(11):4133-40
17846138
Eur J Med Chem. 2008 Dec;43(12):2840-52
18395298
Life Sci. 1991;49(17):1213-9
1943436