A brief history of artemisinin:Modes of action and mechanisms of resistance
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摘要
The cornerstone of antimalarial treatment, artemisinin, has reduced malaria associated morbidity and mortality worldwide. However, Plasmodium falciparum parasites with reduced sensitivity to artemisinin have emerged, and this threatens malaria control and elimination efforts. In this minireview, we describe the initial development of artemisinin as an antimalarial drug,its use both historically and currently, and our current understanding of its mode of action and the mechanisms by which malaria parasites achieve resistance.
The cornerstone of antimalarial treatment, artemisinin, has reduced malaria associated morbidity and mortality worldwide. However, Plasmodium falciparum parasites with reduced sensitivity to artemisinin have emerged, and this threatens malaria control and elimination efforts. In this minireview, we describe the initial development of artemisinin as an antimalarial drug,its use both historically and currently, and our current understanding of its mode of action and the mechanisms by which malaria parasites achieve resistance.
The cornerstone of antimalarial treatment, artemisinin, has reduced malaria associated morbidity and mortality worldwide. However, Plasmodium falciparum parasites with reduced sensitivity to artemisinin have emerged, and this threatens malaria control and elimination efforts. In this minireview, we describe the initial development of artemisinin as an antimalarial drug,its use both historically and currently, and our current understanding of its mode of action and the mechanisms by which malaria parasites achieve resistance.
引文
[1]WHO.World Malaria Report 2017[R].2017.
[2]Zhang JF,Zhou YQ,Shi LR,et al.A detailed chronological record of project 523 and the discovery and development of qinghaosu(artemisinin)[M].Guangzhou,China:Yangcheng Evening News Publishing Company,2006.
[3]O'Neill PM,Posner GH.A medicinal chemistry perspective on artemisinin and related endoperoxides[J].J Med Chem,2004,47(12):2945-2964.
[4]White NJ.Qinghaosu(artemisinin):the price of success[J].Science,2008,320(5874):330-334.
[5]White NJ,Pukrittayakamee S,Hien TT,et al.Malaria[J].Lancet,2014,383(9918):723-735.
[6]Dondorp AM,Nosten F,Yi P,et al.Artemisinin resistance in Plasmodium falciparum malaria[J].N Engl J Med,2009361(5):455-467.
[7]Jiang JB,Li GQ,Guo XB,et al.Antimalarial activity of mefloquine and qinghaosu[J].Lancet,1982,2(8293):285-288.
[8]Li GQ,Arnold K,Guo XB,et al.Randomised comparative study of mefloquine,qinghaosu,and pyrimethamine-sulfadoxine in patients with falciparum malaria[J].Lancet,1984,2(8416):1360-1361.
[9]White N.Antimalarial drug resistance and combination chemotherapy[J].Philos Trans R Soc Lond B Biol Sci,1999,354(1384):739-749.
[10]Nosten F,Luxemburger C,ter Kuile FO,et al.Treatment of multidrug-resistant Plasmodium falciparum malaria with 3-day artesunate-mefloquine combination[J].J Infect Dis,1994,170(4):971-977.
[11]Hastings IM,Watkins WM,White NJ.The evolution of drug-resistant malaria:the role of drug elimination half-life[J].Philos Trans R Soc Lond B Biol Sci,2002,357(1420):505-519.
[12]Yeung S,Pongtavornpinyo W,Hastings IM,et al.Antimalarial drug resistance,artemisinin-based combination therapy,and the contribution of modeling to elucidating policy choices[J].Am J Trop Med Hyg,2004,71(2 Suppl):179-186.
[13]Noedl H,Se Y,Schaecher K,et al.Evidence of artemisinin-resistant malaria in western Cambodia[J].N Engl J Med,2008,359(24):2619-2620.
[14]Ferreira PE,Culleton R,Gil JP,et al.Artemisinin resistance in Plasmodium falciparum:what is it really?[J].Trends Parasitol,2013,29(7):318-320.
[15]Tun KM,Imwong M,Lwin KM,et al.Spread of artemisinin-resistant Plasmodium falciparum in Myanmar:a crosssectional survey of the K13 molecular marker[J].Lancet Infect Dis,2015,15(4):415-421.
[16]Das S,Saha B,Hati AK,et al.Evidence of artemisinin-resistant Plasmodium falciparum malaria in eastern India[J].N Engl JMed,2018,379(20):1962-1964.
[17]Grist EP,Flegg JA,Humphreys G,et al.Optimal health and disease management using spatial uncertainty:a geographic characterization of emergent artemisinin-resistant Plasmodium falciparum distributions in Southeast Asia[J].Int J Health Geogr,2016,15(1):37.
[18]Huang F,Takala-Harrison S,Jacob CG,et al.A single mutation in K13 predominates in Southern China and is associated with delayed clearance of Plasmodium falciparum following artemisinin treatment[J].J Infect Dis,2015,212(10):1629-1635.
[19]Lu F,Culleton R,Zhang M,et al.Emergence of Indigenous Artemisinin-Resistant Plasmodium falciparum in Africa[J].NEngl J Med,2017,376(10):991-993.
[20]Ikeda M,Kaneko M,Tachibana SI,et al.Artemisinin-resistant Plasmodium falciparum with high survival rates,Uganda,2014-2016[J].Emerg Infect Dis,2018,24(4):718-726.
[21]WHO.World Malaria Report 2014[R].2014.
[22]Marsh K.Malaria disaster in Africa[J].Lancet,1998,352(9132):924.
[23]Eastman RT,Fidock DA.Artemisinin-based combination therapies:a vital tool in efforts to eliminate malaria[J].Nat Rev Microbiol,2009,7(12):864-874.
[24]Meunier B,Robert A.Heme as trigger and target for trioxane-containing antimalarial drugs[J].Acc Chem Res,2010,43(11):1444-1451.
[25]Egan TJ.Haemozoin formation[J].Mol Biochem Parasitol,2008,157(2):127-136.
[26]Combrinck JM,Mabotha TE,Ncokazi KK,et al.Insights into the role of heme in the mechanism of action of antimalarials[J]ACS Chem Biol,2013,8(1):133-137.
[27]Clark M,Fisher NC,Kasthuri R,et al.Parasite maturation and host serum iron influence the labile iron pool of erythrocyte stage Plasmodium falciparum[J].Br J Haematol,2013,161(2):262-269.
[28]Wang J,Zhang CJ,Chia WN,et al.Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum[J].Nat Commun,2015,6:10111.
[29]Ke H,Sigala PA,Miura K,et al.The heme biosynthesis pathway is essential for Plasmodium falciparum development in mosquito stage but not in blood stages[J].J Biol Chem,2014,289(50):34827-34837.
[30]Klonis N,Xie SC,McCaw JM,et al.Altered temporal response of malaria parasites determines differential sensitivity to artemisinin[J].Proc Natl Acad Sci USA,2013,110(13):5157-5162.
[31]Adjalley SH,Johnston GL,Li T,et al.Quantitative assessment of Plasmodium falciparum sexual development reveals potent transmission-blocking activity by methylene blue[J].Proc Natl Acad Sci USA,2011,108(47):E1214-1223.
[32]Meister S,Plouffe DM,Kuhen KL,et al.Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery[J].Science,2011,334(6061):1372-1377.
[33]Ismail HM,Barton VE,Panchana M,et al.A click chemistrybased proteomic approach reveals that 1,2,4-trioxolane and artemisinin antimalarials share a common protein alkylation profile[J].Angew Chem Weinheim Bergstr Ger,2016,128(22):6511-6515.
[34]Bridgford JL,Xie SC,Cobbold SA,et al.Artemisinin kills malaria parasites by damaging proteins and inhibiting the proteasome[J].Nat Commun,2018,9(1):3801.
[35]Mbengue A,Bhattacharjee S,Pandharkar T,et al.A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria[J].Nature,2015,520(7549):683-687.
[36]Straimer J,Gnadig NF,Witkowski B,et al.Drug resistance.K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates[J].Science,2015,347(6220):428-431.
[37]WHO:Artemisinin Resistance and Artemisinin-based Combination Therapy Efficacy[R].http://apps.who.int/iris/bitstream/handle/10665/274362/WHO-CDS-GMP-2018.18-eng.pdf?ua=1,Status report August 2018.
[38]Bhattacharjee S,Coppens I,Mbengue A,et al.Remodeling of the malaria parasite and host human red cell by vesicle amplification that induces artemisinin resistance[J].Blood,2018,131(11):1234-1247.
[39]Nascimbeni AC,Codogno P,Morel E.Phosphatidylinositol-3-phosphate in the regulation of autophagy membrane dynamics[J].FEBS J,2017,284(9):1267-1278.
[40]Mok S,Ashley EA,Ferreira PE,et al.Drug resistance.Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance[J].Science,2015347(6220):431-435.
[41]Suresh N,Haldar K.Mechanisms of artemisinin resistance in Plasmodium falciparum malaria[J].Curr Opin Pharmacol,2018,42:46-54.
[42]Rocamora F,Zhu L,Liong KY,et al.Oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites[J].PLoS Pathog,2018,14(3):e1006930.
[43]Cowell AN,Istvan ES,Lukens AK,et al.Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics[J].Science,2018,359(6372):191-199.
[44]Hanscheid T,Hardisty DW.How"resistant"is artemisinin resistant malaria?-The risks of ambiguity using the term"resistant"malaria[J].Travel Med Infect Dis,2018,24:23-24.
[45]Rosenthal PJ.Artefenomel:a promising new antimalarial drug[J].Lancet Infect Dis,2016,16(1):6-8.
[46]Cao J,Sturrock HJ,Cotter C,et al.Communicating and monitoring surveillance and response activities for malaria elimination:China's"1-3-7"strategy[J].PLoS Med,2014,11(5):e1001642.
[2]Zhang JF,Zhou YQ,Shi LR,et al.A detailed chronological record of project 523 and the discovery and development of qinghaosu(artemisinin)[M].Guangzhou,China:Yangcheng Evening News Publishing Company,2006.
[3]O'Neill PM,Posner GH.A medicinal chemistry perspective on artemisinin and related endoperoxides[J].J Med Chem,2004,47(12):2945-2964.
[4]White NJ.Qinghaosu(artemisinin):the price of success[J].Science,2008,320(5874):330-334.
[5]White NJ,Pukrittayakamee S,Hien TT,et al.Malaria[J].Lancet,2014,383(9918):723-735.
[6]Dondorp AM,Nosten F,Yi P,et al.Artemisinin resistance in Plasmodium falciparum malaria[J].N Engl J Med,2009361(5):455-467.
[7]Jiang JB,Li GQ,Guo XB,et al.Antimalarial activity of mefloquine and qinghaosu[J].Lancet,1982,2(8293):285-288.
[8]Li GQ,Arnold K,Guo XB,et al.Randomised comparative study of mefloquine,qinghaosu,and pyrimethamine-sulfadoxine in patients with falciparum malaria[J].Lancet,1984,2(8416):1360-1361.
[9]White N.Antimalarial drug resistance and combination chemotherapy[J].Philos Trans R Soc Lond B Biol Sci,1999,354(1384):739-749.
[10]Nosten F,Luxemburger C,ter Kuile FO,et al.Treatment of multidrug-resistant Plasmodium falciparum malaria with 3-day artesunate-mefloquine combination[J].J Infect Dis,1994,170(4):971-977.
[11]Hastings IM,Watkins WM,White NJ.The evolution of drug-resistant malaria:the role of drug elimination half-life[J].Philos Trans R Soc Lond B Biol Sci,2002,357(1420):505-519.
[12]Yeung S,Pongtavornpinyo W,Hastings IM,et al.Antimalarial drug resistance,artemisinin-based combination therapy,and the contribution of modeling to elucidating policy choices[J].Am J Trop Med Hyg,2004,71(2 Suppl):179-186.
[13]Noedl H,Se Y,Schaecher K,et al.Evidence of artemisinin-resistant malaria in western Cambodia[J].N Engl J Med,2008,359(24):2619-2620.
[14]Ferreira PE,Culleton R,Gil JP,et al.Artemisinin resistance in Plasmodium falciparum:what is it really?[J].Trends Parasitol,2013,29(7):318-320.
[15]Tun KM,Imwong M,Lwin KM,et al.Spread of artemisinin-resistant Plasmodium falciparum in Myanmar:a crosssectional survey of the K13 molecular marker[J].Lancet Infect Dis,2015,15(4):415-421.
[16]Das S,Saha B,Hati AK,et al.Evidence of artemisinin-resistant Plasmodium falciparum malaria in eastern India[J].N Engl JMed,2018,379(20):1962-1964.
[17]Grist EP,Flegg JA,Humphreys G,et al.Optimal health and disease management using spatial uncertainty:a geographic characterization of emergent artemisinin-resistant Plasmodium falciparum distributions in Southeast Asia[J].Int J Health Geogr,2016,15(1):37.
[18]Huang F,Takala-Harrison S,Jacob CG,et al.A single mutation in K13 predominates in Southern China and is associated with delayed clearance of Plasmodium falciparum following artemisinin treatment[J].J Infect Dis,2015,212(10):1629-1635.
[19]Lu F,Culleton R,Zhang M,et al.Emergence of Indigenous Artemisinin-Resistant Plasmodium falciparum in Africa[J].NEngl J Med,2017,376(10):991-993.
[20]Ikeda M,Kaneko M,Tachibana SI,et al.Artemisinin-resistant Plasmodium falciparum with high survival rates,Uganda,2014-2016[J].Emerg Infect Dis,2018,24(4):718-726.
[21]WHO.World Malaria Report 2014[R].2014.
[22]Marsh K.Malaria disaster in Africa[J].Lancet,1998,352(9132):924.
[23]Eastman RT,Fidock DA.Artemisinin-based combination therapies:a vital tool in efforts to eliminate malaria[J].Nat Rev Microbiol,2009,7(12):864-874.
[24]Meunier B,Robert A.Heme as trigger and target for trioxane-containing antimalarial drugs[J].Acc Chem Res,2010,43(11):1444-1451.
[25]Egan TJ.Haemozoin formation[J].Mol Biochem Parasitol,2008,157(2):127-136.
[26]Combrinck JM,Mabotha TE,Ncokazi KK,et al.Insights into the role of heme in the mechanism of action of antimalarials[J]ACS Chem Biol,2013,8(1):133-137.
[27]Clark M,Fisher NC,Kasthuri R,et al.Parasite maturation and host serum iron influence the labile iron pool of erythrocyte stage Plasmodium falciparum[J].Br J Haematol,2013,161(2):262-269.
[28]Wang J,Zhang CJ,Chia WN,et al.Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum[J].Nat Commun,2015,6:10111.
[29]Ke H,Sigala PA,Miura K,et al.The heme biosynthesis pathway is essential for Plasmodium falciparum development in mosquito stage but not in blood stages[J].J Biol Chem,2014,289(50):34827-34837.
[30]Klonis N,Xie SC,McCaw JM,et al.Altered temporal response of malaria parasites determines differential sensitivity to artemisinin[J].Proc Natl Acad Sci USA,2013,110(13):5157-5162.
[31]Adjalley SH,Johnston GL,Li T,et al.Quantitative assessment of Plasmodium falciparum sexual development reveals potent transmission-blocking activity by methylene blue[J].Proc Natl Acad Sci USA,2011,108(47):E1214-1223.
[32]Meister S,Plouffe DM,Kuhen KL,et al.Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery[J].Science,2011,334(6061):1372-1377.
[33]Ismail HM,Barton VE,Panchana M,et al.A click chemistrybased proteomic approach reveals that 1,2,4-trioxolane and artemisinin antimalarials share a common protein alkylation profile[J].Angew Chem Weinheim Bergstr Ger,2016,128(22):6511-6515.
[34]Bridgford JL,Xie SC,Cobbold SA,et al.Artemisinin kills malaria parasites by damaging proteins and inhibiting the proteasome[J].Nat Commun,2018,9(1):3801.
[35]Mbengue A,Bhattacharjee S,Pandharkar T,et al.A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria[J].Nature,2015,520(7549):683-687.
[36]Straimer J,Gnadig NF,Witkowski B,et al.Drug resistance.K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates[J].Science,2015,347(6220):428-431.
[37]WHO:Artemisinin Resistance and Artemisinin-based Combination Therapy Efficacy[R].http://apps.who.int/iris/bitstream/handle/10665/274362/WHO-CDS-GMP-2018.18-eng.pdf?ua=1,Status report August 2018.
[38]Bhattacharjee S,Coppens I,Mbengue A,et al.Remodeling of the malaria parasite and host human red cell by vesicle amplification that induces artemisinin resistance[J].Blood,2018,131(11):1234-1247.
[39]Nascimbeni AC,Codogno P,Morel E.Phosphatidylinositol-3-phosphate in the regulation of autophagy membrane dynamics[J].FEBS J,2017,284(9):1267-1278.
[40]Mok S,Ashley EA,Ferreira PE,et al.Drug resistance.Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance[J].Science,2015347(6220):431-435.
[41]Suresh N,Haldar K.Mechanisms of artemisinin resistance in Plasmodium falciparum malaria[J].Curr Opin Pharmacol,2018,42:46-54.
[42]Rocamora F,Zhu L,Liong KY,et al.Oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites[J].PLoS Pathog,2018,14(3):e1006930.
[43]Cowell AN,Istvan ES,Lukens AK,et al.Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics[J].Science,2018,359(6372):191-199.
[44]Hanscheid T,Hardisty DW.How"resistant"is artemisinin resistant malaria?-The risks of ambiguity using the term"resistant"malaria[J].Travel Med Infect Dis,2018,24:23-24.
[45]Rosenthal PJ.Artefenomel:a promising new antimalarial drug[J].Lancet Infect Dis,2016,16(1):6-8.
[46]Cao J,Sturrock HJ,Cotter C,et al.Communicating and monitoring surveillance and response activities for malaria elimination:China's"1-3-7"strategy[J].PLoS Med,2014,11(5):e1001642.