New Insight into Isoprenoids Biosynthesis Process and Future Prospects for Drug Designing in Plasmodium.
The MEP (Methyl Erythritol Phosphate) isoprenoids biosynthesis pathway is an attractive drug target to combat malaria, due to its uniqueness and indispensability for the parasite. It is functional in the apicoplast of Plasmodium and its products get transported to the cytoplasm, where they participate in glycoprotein synthesis, electron transport chain, tRNA modification and several other biological processes. Several compounds have been tested against the enzymes involved in this pathway and amongst them Fosmidomycin, targeted against IspC (DXP reductoisomerase) enzyme and MMV008138 targeted against IspD enzyme have shown good anti-malarial activity in parasite cultures. Fosmidomycin is now-a-days prescribed clinically, however, less absorption, shorter half-life, and toxicity at higher doses, limits its use as an anti-malarial. The potential of other enzymes of the pathway as candidate drug targets has also been determined. This review details the various drug molecules tested against these targets with special emphasis to Plasmodium. We corroborate that MEP pathway functional within the apicoplast of Plasmodium is a major drug target, especially during erythrocytic stages. However, the major bottlenecks, bioavailability and toxicity of the new molecules needs to be addressed, before considering any new molecule as a potent antimalarial.
Molecular Parasitology and Systems Biology Laboratory, Department of Biological Sciences, Birla Institute of Technology and Science Pilani, India.
Gagandeep S
GS
Saggu
Molecular Parasitology and Systems Biology Laboratory, Department of Biological Sciences, Birla Institute of Technology and Science Pilani, India.
Zarna R
ZR
Pala
Molecular Parasitology and Systems Biology Laboratory, Department of Biological Sciences, Birla Institute of Technology and Science Pilani, India.
Shilpi
S
Garg
Molecular Parasitology and Systems Biology Laboratory, Department of Biological Sciences, Birla Institute of Technology and Science Pilani, India.
Vishal
V
Saxena
MEP pathway; Plasmodium; anti-malarial; apicoplast; isoprenoids
ChemMedChem. 2015 Dec;10 (12 ):2090-8
26435072
J Bacteriol. 2001 Apr;183(8):2411-6
11274098
FEBS Lett. 2001 Jun 15;499(1-2):37-40
11418107
FEBS Lett. 2005 Nov 21;579(28):6433-8
16289098
Eur J Biochem. 2001 Jun;268(11):3190-7
11389720
Biochemistry. 2004 Sep 28;43(38):12189-97
15379557
J Med Chem. 2014 Dec 11;57(23):9740-63
25210872
Bioorg Med Chem Lett. 2008 Oct 1;18(19):5320-3
18783951
J Biol Chem. 2011 Oct 21;286(42):36522-31
21878632
J Am Chem Soc. 2008 Dec 24;130(51):17206-7
19035630
J Mol Biol. 2005 Jan 7;345(1):115-27
15567415
J Biol Chem. 2007 Jul 27;282(30):21573-7
17442674
J Antibiot (Tokyo). 2010 Oct;63(10):583-8
20808315
PLoS One. 2012;7(12):e52498
23285068
Bioorg Med Chem Lett. 2015 Apr 1;25(7):1515-9
25754494
Malar J. 2013 Jun 04;12:184
23734739
Proteins. 2005 Sep 1;60(4):787-96
16021622
J Med Chem. 2011 Jul 28;54(14):4964-76
21678907
J Am Chem Soc. 2011 May 4;133(17):6525-8
21486034
Eukaryot Cell. 2015 Feb;14(2):128-39
25446055
Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):11758-63
10518523
Chem Sci. 2014 Apr 1;5(4):1642-1649
24999381
J Biol Chem. 2002 Jun 28;277(26):23612-9
11976331
Acta Crystallogr D Biol Crystallogr. 2005 Jan;61(Pt 1):45-52
15608374
Acta Crystallogr D Biol Crystallogr. 2011 May;67(Pt 5):403-14
21543842
FEBS J. 2006 Mar;273(5):1065-73
16478479
J Biol Chem. 2003 May 16;278(20):18401-7
12621040
Protein Expr Purif. 2016 Apr;120:16-27
26699947
Angew Chem Int Ed Engl. 2006 Feb 6;45(7):1069-74
16392111
Proc Natl Acad Sci U S A. 2010 Jan 19;107(3):1077-81
20080550
Crit Rev Biochem Mol Biol. 1999;34(2):107-22
10333388
Org Lett. 2011 Nov 4;13(21):5912-5
21981393
Angew Chem Int Ed Engl. 2013 Feb 11;52(7):2118-21
23307751
PLoS Biol. 2011 Aug;9(8):e1001138
21912516
PLoS One. 2014 Aug 29;9(8):e106243
25171339
Acta Crystallogr D Biol Crystallogr. 2006 Jul;62(Pt 7):807-13
16790937
Nature. 1996 Jun 6;381(6582):482
8632819
Biochim Biophys Acta. 2004 Apr 8;1698(1):37-44
15063313
Bioorg Med Chem. 2011 Oct 1;19(19):5886-95
21903402
J Biol Chem. 2002 Mar 8;277(10):8667-72
11786530
J Mol Biol. 2015 Jun 19;427(12):2220-8
25868383
Int Rev Cytol. 2003;224:57-110
12722949
J Bacteriol. 2001 Jan;183(1):1-11
11114895
J Am Chem Soc. 2013 Feb 6;135(5):1816-22
23316732
ChemMedChem. 2012 Jan 2;7(1):151-8
22095896
J Med Chem. 2013 Aug 8;56(15):6190-9
23819803
FEBS Lett. 2011 Feb 4;585(3):447-51
21167158
J Mol Biol. 2010 Dec 10;404(4):600-10
20932974
FEBS J. 2008 Jun;275(11):2779-94
18422643
J Antibiot (Tokyo). 2014 Jan;67(1):77-83
24169798
Antimicrob Agents Chemother. 2003 Feb;47(2):735-8
12543685
Science. 1997 Sep 19;277(5333):1788-9
9324768
Biochemistry. 2004 Nov 23;43(46):14594-601
15544330
J Mol Biol. 2002 Feb 8;316(1):79-88
11829504
J Med Chem. 2013 Oct 24;56(20):8151-62
24032981
J Med Chem. 2014 Nov 13;57(21):8827-38
25254502
Chem Biol. 2009 Dec 24;16(12):1230-9
20064433
PLoS One. 2011 May 04;6(5):e19334
21573242
Angew Chem Int Ed Engl. 2014 Jul 1;53(27):7079-84
24895172
Bioorg Med Chem Lett. 2015;25(10):2112-6
25881827
ChemMedChem. 2007 Jun;2(6):806-10
17361977
BMC Struct Biol. 2007 Oct 23;7:68
17956607
FEBS Open Bio. 2013 Jan 28;3:124-9
23772383
Antimicrob Agents Chemother. 2014;58(2):811-9
24247137
J Biochem Mol Biol. 2007 Nov 30;40(6):911-20
18047786
Chemioterapia. 1987 Apr;6(2):113-9
3594633
Antimicrob Agents Chemother. 2015 Jan;59(1):356-64
25367906
Sci Rep. 2011;1:9
22355528
Chem Biodivers. 2004 Sep;1(9):1367-76
17191914
Nat Struct Biol. 2001 Jul;8(7):641-8
11427897
Protein Sci. 2007 Sep;16(9):2082-8
17660251
J Med Chem. 2011 Oct 13;54(19):6796-802
21866890
J Med Chem. 2012 Jul 26;55(14):6566-75
22731758
ACS Infect Dis. 2015 Apr 10;1(4):157-167
26783558
J Biol Chem. 2004 Dec 10;279(50):51749-59
15452112
Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1158-63
11818558
Proteins. 2002 Oct 1;49(1):135-8
12211023
Antimicrob Agents Chemother. 1982 Feb;21(2):224-30
7073262
FASEB J. 2011 May;25(5):1577-84
21282208
Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11189-93
20534554
ChemMedChem. 2010 Jul 5;5(7):1092-101
20480490
Angew Chem Int Ed Engl. 2014 Feb 17;53(8):2235-9
24446431
J Biomol Struct Dyn. 2015;33(6):1198-210
25011618
Science. 1999 Sep 3;285(5433):1573-6
10477522
Bioorg Med Chem Lett. 2003 Feb 24;13(4):737-9
12639570
Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):12857-62
9371765
Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8251-6
10880567
J Org Chem. 2008 Feb 15;73(4):1365-70
18211084
Antimicrob Agents Chemother. 2013 Oct;57(10):4689-98
23856773
Curr Top Med Chem. 2011;11(16):2048-59
21619509
J Biol Chem. 2003 Aug 8;278(32):30022-7
12771135
Nat Prod Rep. 2014 Aug;31(8):1043-55
24921065
Org Biomol Chem. 2008 Aug 7;6(15):2719-30
18633530
BMC Struct Biol. 2014 Jan 10;14:1
24410837
Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9572-7
16760253
J Biol Chem. 2007 Jan 26;282(4):2676-82
17135236
FEBS Lett. 2013 Dec 11;587(24):3968-72
24188825
J Exp Med. 2011 Jul 4;208(7):1547-59
21690250
Angew Chem Int Ed Engl. 2011 Aug 16;50(34):7931-5
21766403