Skip to content
2000
Volume 32, Issue 29
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X

Abstract

The malaria parasite expresses four related papain-family cysteine proteases. Targeting these different cysteine proteases can elucidate their roles and potential as therapeutic targets, thereby expanding the pool of antimalarial targets. During gametogenesis, cysteine proteases like SERA-5, SERA-3, DPAP-1, DPAP-2, DPAP-3, and Falcipain-1 are required for parasitophorous vacuole membrane (PVM) rupture. In the liver stage, cysteine proteases such as Falcipain-1 and SERA-3, SERA-4, SERA-5, and SERA-6 are essential. Additionally, cysteine proteases like DPAP-3, Falcipain-1, Falcipain-2, Falcipain-3, and SERA-5, SERA-6 play crucial roles in merozoite invasion into red blood cells (RBCs), hemoglobin degradation, and merozoite release from RBCs. This review summarizes the available literature describing the key roles of various cysteine proteases in the life cycle of the malaria parasite and their potential targets for antimalarial therapy. Understanding these proteases could aid in developing novel antimalarial treatments and overcoming drug resistance.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cmc/10.2174/0109298673308069240815072244
2024-08-23
2025-09-10

  • From This Site

    /content/journals/cmc/10.2174/0109298673308069240815072244
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. UddinA. SinghV. IrfanI. MohammadT. Singh HadaR. Imtaiyaz HassanM. AbidM. SinghS. Identification and structure–activity relationship (SAR) studies of carvacrol derivatives as potential anti-malarial against Plasmodium falciparum falcipain-2 protease.Bioorg. Chem.202010310414210.1016/j.bioorg.2020.10414232763521
     [Google Scholar]
  2. UddinA. ChawlaM. IrfanI. MahajanS. SinghS. AbidM. Medicinal chemistry updates on quinoline- and endoperoxide-based hybrids with potent antimalarial activity.RSC Med. Chem.2021121244210.1039/D0MD00244E34046596
     [Google Scholar]
  3. KumarB. MohammadT. Amaduddin HussainA. IslamA. AhmadF. AlajmiM.F. SinghS. PandeyK.C. HassanM.I. AbidM. Targeting metacaspase-3 from Plasmodium falciparum towards antimalarial therapy: A combined approach of in silico and in vitro investigation.J. Biomol. Struct. Dyn.202139242143010.1080/07391102.2019.171119431900062
     [Google Scholar]
  4. World malaria report.2021Avialble from: https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2021
  5. AlamA. GoyalM. IqbalM.S. PalC. DeyS. BinduS. MaityP. BandyopadhyayU. Novel antimalarial drug targets: Hope for new antimalarial drugs.Expert Rev. Clin. Pharmacol.20092546948910.1586/ecp.09.2822112223
     [Google Scholar]
  6. WoldemichaelD. TufaT. New targets in malaria parasite chemotherapy: A review.Malar. Control Elimin.2015s1
     [Google Scholar]
  7. TseE.G. KorsikM. ToddM.H. The past, present and future of anti-malarial medicines.Malar. J.20191819310.1186/s12936‑019‑2724‑z30902052
     [Google Scholar]
  8. KannanR. KumarK. SahalD. KukretiS. ChauhanV.S. Reaction of artemisinin with haemoglobin: Implications for antimalarial activity.Biochem. J.2005385240941810.1042/BJ2004117015361062
     [Google Scholar]
  9. NsanzabanaC. Resistance to artemisinin combination therapies (ACTs): Do not forget the partner drug!Trop. Med. Infect. Dis.2019412610.3390/tropicalmed401002630717149
     [Google Scholar]
  10. EjigiriI. SinnisP. Plasmodium sporozoite–host interactions from the dermis to the hepatocyte.Curr. Opin. Microbiol.200912440140710.1016/j.mib.2009.06.00619608456
     [Google Scholar]
  11. KrotoskiW.A. Killick-KendrickR. KoontzL.C. GarnhamP.C.C. BrayR.S. GwadzR.W. WolfR. StanfillP.S. CogswellF.B. SindenR. CollinsW.E. Demonstration of hypnozoites in sporozoite-transmitted Plasmodium vivax infection.Am. J. Trop. Med. Hyg.19823161291129310.4269/ajtmh.1982.31.12916816080
     [Google Scholar]
  12. SturmA. GraeweS. Franke-FayardB. RetzlaffS. BolteS. RoppenserB. AepfelbacherM. JanseC. HeusslerV. Alteration of the parasite plasma membrane and the parasitophorous vacuole membrane during exo-erythrocytic development of malaria parasites.Protist20091601516310.1016/j.protis.2008.08.00219026596
     [Google Scholar]
  13. GrüringC. HeiberA. KruseF. UngefehrJ. GilbergerT.W. SpielmannT. Development and host cell modifications of Plasmodium falciparum blood stages in four dimensions.Nat. Commun.20112116510.1038/ncomms116921266965
     [Google Scholar]
  14. WunderlichJ. RohrbachP. DaltonJ.P. The malaria digestive vacuole.Front. Biosci.2012441424144822652884
     [Google Scholar]
  15. SilvestriniF. AlanoP. WilliamsJ.L. Commitment to the production of male and female gametocytes in the human malaria parasite Plasmodium falciparum.Parasitology2000121546547110.1017/S003118209900669111128797
     [Google Scholar]
  16. BillkerO. LindoV. PanicoM. EtienneA.E. PaxtonT. DellA. RogersM. SindenR.E. MorrisH.R. Identification of xanthurenic acid as the putative inducer of malaria development in the mosquito.Nature1998392667328929210.1038/326679521324
     [Google Scholar]
  17. LimvirojW. YanoK. YudaM. AndoK. ChinzeiY. Immuno-electron microscopic observation of Plasmodium berghei CTRP localization in the midgut of the vector mosquito Anopheles stephensi.J. Parasitol.200288466467210.1645/0022‑3395(2002)088[0664:IEMOOP]2.0.CO;212197111
     [Google Scholar]
  18. KadotaK. IshinoT. MatsuyamaT. ChinzeiY. YudaM. LawJ.H. Essential role of membrane-attack protein in malarial transmission to mosquito host.Proc. Natl. Acad. Sci. USA200410146163101631510.1073/pnas.040618710115520375
     [Google Scholar]
  19. IshinoT. OritoY. ChinzeiY. YudaM. A calcium-dependent protein kinase regulates Plasmodium ookinete access to the midgut epithelial cell.Mol. Microbiol.20065941175118410.1111/j.1365‑2958.2005.05014.x16430692
     [Google Scholar]
  20. VanderbergJ. RhodinJ. Differentiation of nuclear and cytoplasmic fine structure during sporogonic development of Plasmodium berghei.J. Cell Biol.1967323C7C1010.1083/jcb.32.3.C76034491
     [Google Scholar]
  21. SindenR.E. GarnhamP.C.C. A comparative study on the ultrastructure of plasmodium sporozoites within the oocyst and salivary glands, with particular reference to the incidence of the micropore.Trans. R. Soc. Trop. Med. Hyg.197367563163710.1016/0035‑9203(73)90031‑X4591782
     [Google Scholar]
  22. SindenR.E. Excystment by sporozoites of malaria parasites.Nature1974252548131410.1038/252314a04431453
     [Google Scholar]
  23. MénardR. SultanA.A. CortesC. AltszulerR. van DijkM.R. JanseC.J. WatersA.P. NussenzweigR.S. NussenzweigV. Circumsporozoite protein is required for development of malaria sporozoites in mosquitoes.Nature1997385661433634010.1038/385336a09002517
     [Google Scholar]
  24. ThathyV. FujiokaH. GanttS. NussenzweigR. NussenzweigV. MénardR. Levels of circumsporozoite protein in the Plasmodium oocyst determine sporozoite morphology.EMBO J.20022171586159610.1093/emboj/21.7.158611927543
     [Google Scholar]
  25. LingelbachK. KirkK. RogersonS. LanghorneJ. CarucciD.J. WatersA. Molecular approaches to malaria.Mol. Microbiol.200454357558710.1111/j.1365‑2958.2004.04362.x15491351
     [Google Scholar]
  26. TanM.S.Y. DavisonD. SanchezM.I. AndersonB.M. HowellS. SnijdersA. Edgington-MitchellL.E. DeuE. Novel broad-spectrum activity-based probes to profile malarial cysteine proteases.PLoS One2020151e022734110.1371/journal.pone.022734131923258
     [Google Scholar]
  27. RosenthalP.J. Cysteine proteases of malaria parasites.Int. J. Parasitol.20043413-141489149910.1016/j.ijpara.2004.10.00315582526
     [Google Scholar]
  28. BarrettA.J. RawlingsN.D. Evolutionary lines of cysteine peptidases.Biol. Chem.2001382572773410.1515/bchm.2001.382.5.72711517925
     [Google Scholar]
  29. WuY. WangX. LiuX. WangY. Data-mining approaches reveal hidden families of proteases in the genome of malaria parasite.Genome Res.200313460161610.1101/gr.91340312671001
     [Google Scholar]
  30. SologubL. KuehnA. KernS. PrzyborskiJ. SchilligR. PradelG. Malaria proteases mediate inside-out egress of gametocytes from red blood cells following parasite transmission to the mosquito.Cell. Microbiol.201113689791210.1111/j.1462‑5822.2011.01588.x21501358
     [Google Scholar]
  31. EdwardsG. Antimalarial chemotherapy: Mechanisms of action, resistance and new directions in drug discover.Br. J. Clin. Pharmacol.2001524464464
     [Google Scholar]
  32. SturmA. AminoR. van de SandC. RegenT. RetzlaffS. RennenbergA. KruegerA. PollokJ.M. MenardR. HeusslerV.T. Manipulation of host hepatocytes by the malaria parasite for delivery into liver sinusoids.Science200631357911287129010.1126/science.112972016888102
     [Google Scholar]
  33. HoppC.S. BennettB.L. MishraS. LehmannC. HansonK.K. LinJ. RousseauK. CarvalhoF.A. van der LindenW.A. SantosN.C. BogyoM. KhanS.M. HeusslerV. SinnisP. Deletion of the rodent malaria ortholog for falcipain-1 highlights differences between hepatic and blood stage merozoites.PLoS Pathog.2017139e100658610.1371/journal.ppat.100658628922424
     [Google Scholar]
  34. MishraM. SinghV. SinghS. Structural insights into key Plasmodium proteases as therapeutic drug targets.Front. Microbiol.20191039410.3389/fmicb.2019.0039430891019
     [Google Scholar]
  35. PutriantiE.D. Schmidt-ChristensenA. HeusslerV. MatuschewskiK. IngmundsonA. A Plasmodium cysteine protease required for efficient transition from the liver infection stage.PLoS Pathog.2020169e100889110.1371/journal.ppat.100889132956401
     [Google Scholar]
  36. BhanotP. SchauerK. CoppensI. NussenzweigV. A surface phospholipase is involved in the migration of plasmodium sporozoites through cells.J. Biol. Chem.200528086752676010.1074/jbc.M41146520015590623
     [Google Scholar]
  37. BurdaP.C. RoelliM.A. SchaffnerM. KhanS.M. JanseC.J. HeusslerV.T. A Plasmodium phospholipase is involved in disruption of the liver stage parasitophorous vacuole membrane.PLoS Pathog.2015113e100476010.1371/journal.ppat.100476025786000
     [Google Scholar]
  38. RueckerA. SheaM. HackettF. SuarezC. HirstE.M.A. MilutinovicK. Withers-MartinezC. BlackmanM.J. Proteolytic activation of the essential parasitophorous vacuole cysteine protease SERA6 accompanies malaria parasite egress from its host erythrocyte.J. Biol. Chem.201228745379493796310.1074/jbc.M112.40082022984267
     [Google Scholar]
  39. StallmachR. KavishwarM. Withers-MartinezC. HackettF. CollinsC.R. HowellS.A. YeohS. KnuepferE. AtidA.J. HolderA.A. BlackmanM.J. Plasmodium falciparum SERA5 plays a non-enzymatic role in the malarial asexual blood-stage lifecycle.Mol. Microbiol.201596236838710.1111/mmi.1294125599609
     [Google Scholar]
  40. Schmidt-ChristensenA. SturmA. HorstmannS. HeusslerV.T. Expression and processing of Plasmodium berghei SERA3 during liver stages.Cell. Microbiol.20081081723173410.1111/j.1462‑5822.2008.01162.x18419771
     [Google Scholar]
  41. OttoH.H. SchirmeisterT. Cysteine proteases and their inhibitors.Chem. Rev.199797113317210.1021/cr950025u11848867
     [Google Scholar]
  42. VaughanJ.A. SchellerL.F. WirtzR.A. AzadA.F. Infectivity of Plasmodium berghei sporozoites delivered by intravenous inoculation versus mosquito bite: Implications for sporozoite vaccine trials.Infect. Immun.19996784285428910.1128/IAI.67.8.4285‑4289.199910417207
     [Google Scholar]
  43. PrudêncioM. RodriguezA. MotaM.M. The silent path to thousands of merozoites: The Plasmodium liver stage.Nat. Rev. Microbiol.200641184985610.1038/nrmicro152917041632
     [Google Scholar]
  44. CoppiA. Pinzon-OrtizC. HutterC. SinnisP. The Plasmodium circumsporozoite protein is proteolytically processed during cell invasion.J. Exp. Med.20052011273310.1084/jem.2004098915630135
     [Google Scholar]
  45. RennenbergA. LehmannC. HeitmannA. WittT. HansenG. NagarajanK. DeschermeierC. TurkV. HilgenfeldR. HeusslerV.T. Exoerythrocytic Plasmodium parasites secrete a cysteine protease inhibitor involved in sporozoite invasion and capable of blocking cell death of host hepatocytes.PLoS Pathog.201063e100082510.1371/journal.ppat.100082520361051
     [Google Scholar]
  46. LehmannC. HeitmannA. MishraS. BurdaP.C. SingerM. PradoM. NiklausL. LacroixC. MénardR. FrischknechtF. StanwayR. SinnisP. HeusslerV. A cysteine protease inhibitor of Plasmodium berghei is essential for exo-erythrocytic development.PLoS Pathog.2014108e100433610.1371/journal.ppat.100433625166051
     [Google Scholar]
  47. RosenthalP.J. Falcipains and other cysteine proteases of malaria parasites.Adv. Exp. Med. Biol.2011712304810.1007/978‑1‑4419‑8414‑2_321660657
     [Google Scholar]
  48. Siqueira-NetoJ.L. DebnathA. McCallL.I. BernatchezJ.A. NdaoM. ReedS.L. RosenthalP.J. Cysteine proteases in protozoan parasites.PLoS Negl. Trop. Dis.2018128e000651210.1371/journal.pntd.000651230138453
     [Google Scholar]
  49. BekonoB.D. Ntie-KangF. Owono OwonoL.C. MegnassanE. Targeting cysteine proteases from plasmodium falciparum: a general overview, rational drug design and computational approaches for drug discovery.Curr. Drug Targets201819550152610.2174/138945011766616122112243228003005
     [Google Scholar]
  50. AbugriJ. Targeting the Plasmodium falciparum proteome and organelles for potential antimalarial drug candidates.Heliyon202288e1039010.20944/preprints202111.0190.v1
     [Google Scholar]
  51. McKerrowJ.H. SunE. RosenthalP.J. BouvierJ. The proteases and pathogenicity of parasitic protozoa.Annu. Rev. Microbiol.199347182185310.1146/annurev.mi.47.100193.0041338257117
     [Google Scholar]
  52. GluzmanI.Y. FrancisS.E. OksmanA. SmithC.E. DuffinK.L. GoldbergD.E. Order and specificity of the Plasmodium falciparum hemoglobin degradation pathway.J. Clin. Invest.19949341602160810.1172/JCI1171408163662
     [Google Scholar]
  53. BlackmanM. Proteases involved in erythrocyte invasion by the malaria parasite: Function and potential as chemotherapeutic targets.Curr. Drug Targets200011598310.2174/138945000334946111475536
     [Google Scholar]
  54. KlembaM. GoldbergD.E. Biological roles of proteases in parasitic protozoa.Annu. Rev. Biochem.200271127530510.1146/annurev.biochem.71.090501.14545312045098
     [Google Scholar]
  55. TilleyL. DixonM.W.A. KirkK. The Plasmodium falciparum-infected red blood cell.Int. J. Biochem. Cell Biol.201143683984210.1016/j.biocel.2011.03.01221458590
     [Google Scholar]
  56. SemenovA. OlsonJ.E. RosenthalP.J. Antimalarial synergy of cysteine and aspartic protease inhibitors.Antimicrob. Agents Chemother.19984292254225810.1128/AAC.42.9.22549736544
     [Google Scholar]
  57. OlsonJ. LeeG.K. SemenovA. RosenthalP.J. Antimalarial effects in mice of orally administered peptidyl cysteine protease inhibitors.Bioorg. Med. Chem.19997463363810.1016/S0968‑0896(99)00004‑810353642
     [Google Scholar]
  58. LeeB.J. SinghA. ChiangP. KempS.J. GoldmanE.A. WeinhouseM.I. VlasukG.P. RosenthalP.J. Antimalarial activities of novel synthetic cysteine protease inhibitors.Antimicrob. Agents Chemother.200347123810381410.1128/AAC.47.12.3810‑3814.200314638488
     [Google Scholar]
  59. EttariR. BovaF. ZappalàM. GrassoS. MicaleN. Falcipain-2 inhibitors.Med. Res. Rev.201030113616710.1002/med.2016319526594
     [Google Scholar]
  60. EttariR. PrevitiS. Di ChioC. ZappalàM. Falcipain-2 and Falcipain-3 inhibitors as promising antimalarial agents.Curr. Med. Chem.202128153010303110.2174/1875533XMTA4nNzUc332744954
     [Google Scholar]
  61. DahlE.L. RosenthalP.J. Biosynthesis, localization, and processing of falcipain cysteine proteases of Plasmodium falciparum.Mol. Biochem. Parasitol.2005139220521210.1016/j.molbiopara.2004.11.00915664655
     [Google Scholar]
  62. PasupureddyR. VermaS. PantA. SharmaR. SeshadriS. PandeV. SaxenaA.K. DixitR. PandeyK.C. Crucial residues in falcipains that mediate hemoglobin hydrolysis.Exp. Parasitol.2019197435010.1016/j.exppara.2019.01.00530648557
     [Google Scholar]
  63. GreenbaumD.C. BaruchA. GraingerM. BozdechZ. MedzihradszkyK.F. EngelJ. DeRisiJ. HolderA.A. BogyoM. A role for the protease falcipain 1 in host cell invasion by the human malaria parasite.Science200229856002002200610.1126/science.107742612471262
     [Google Scholar]
  64. HanspalM. DuaM. TakakuwaY. ChishtiA.H. MizunoA. Plasmodium falciparum cysteine protease falcipain-2 cleaves erythrocyte membrane skeletal proteins at late stages of parasite development: Presented in part in abstract form at the 43rd annual meeting of the american society of Hematology, Orlando, FL, 2001.Blood200210031048105410.1182/blood‑2002‑01‑010112130521
     [Google Scholar]
  65. MeloP.M.S. El Chamy MalufS. AzevedoM.F. PaschoalinT. BuduA. BagnaresiP. Henrique-SilvaF. Soares-CostaA. GazariniM.L. CarmonaA.K. Inhibition of Plasmodium falciparum cysteine proteases by the sugarcane cystatin CaneCPI-4.Parasitol. Int.201867223323610.1016/j.parint.2017.12.00529288140
     [Google Scholar]
  66. SinghV. HadaR.S. UddinA. AnejaB. AbidM. PandeyK.C. SinghS. Inhibition of hemoglobin degrading protease falcipain-2 as a mechanism for anti-malarial activity of triazole-amino acid hybrids.Curr. Top. Med. Chem.202020537738910.2174/156802662066620013016234732000644
     [Google Scholar]
  67. SinghA. KalamuddinM. MaqboolM. MohmmedA. MalhotraP. HodaN. Quinoline carboxamide core moiety-based compounds inhibit P. falciparum falcipain-2: Design, synthesis and antimalarial efficacy studies.Bioorg. Chem.202110810451410.1016/j.bioorg.2020.10451433280833
     [Google Scholar]
  68. RosenthalPJ. Falcipain cysteine proteases of malaria parasites: An update.Biochim. Biophys. Acta BBA - Proteins Proteomics202018683140362
     [Google Scholar]
  69. Arastu-KapurS. PonderE.L. FonovićU.P. YeohS. YuanF. FonovićM. GraingerM. PhillipsC.I. PowersJ.C. BogyoM. Identification of proteases that regulate erythrocyte rupture by the malaria parasite Plasmodium falciparum.Nat. Chem. Biol.20084320321310.1038/nchembio.7018246061
     [Google Scholar]
  70. DeuE. LeyvaM.J. AlbrowV.E. RiceM.J. EllmanJ.A. BogyoM. Functional studies of Plasmodium falciparum dipeptidyl aminopeptidase I using small molecule inhibitors and active site probes.Chem. Biol.201017880881910.1016/j.chembiol.2010.06.00720797610
     [Google Scholar]
  71. TanakaT.Q. DeuE. Molina-CruzA. AshburneM.J. AliO. SuriA. KortagereS. BogyoM. WilliamsonK.C. Plasmodium dipeptidyl aminopeptidases as malaria transmission-blocking drug targets.Antimicrob. Agents Chemother.201357104645465210.1128/AAC.02495‑1223836185
     [Google Scholar]
  72. GhoshS. ChisholmS.A. DansM. LakkavaramA. KennedyK. RalphS.A. CounihanN.A. de Koning-WardT.F. The cysteine protease dipeptidyl aminopeptidase 3 does not contribute to egress of Plasmodium falciparum from host red blood cells.PLoS One2018133e019353810.1371/journal.pone.019353829509772
     [Google Scholar]
  73. MillerS.K. GoodR.T. DrewD.R. DelorenziM. SandersP.R. HodderA.N. SpeedT.P. CowmanA.F. de Koning-WardT.F. CrabbB.S. A subset of Plasmodium falciparum SERA genes are expressed and appear to play an important role in the erythrocytic cycle.J. Biol. Chem.200227749475244753210.1074/jbc.M20697420012228245
     [Google Scholar]
  74. YeohS. O’DonnellR.A. KoussisK. DluzewskiA.R. AnsellK.H. OsborneS.A. HackettF. Withers- MartinezC. MitchellG.H. BannisterL.H. BryansJ.S. KettleboroughC.A. BlackmanM.J. Subcellular discharge of a serine protease mediates release of invasive malaria parasites from host erythrocytes.Cell200713161072108310.1016/j.cell.2007.10.04918083098
     [Google Scholar]
  75. Withers-MartinezC. StrathM. HackettF. HaireL.F. HowellS.A. WalkerP.A. ChristodoulouE. DodsonG.G. BlackmanM.J. The malaria parasite egress protease SUB1 is a calcium-dependent redox switch subtilisin.Nat. Commun.201451372610.1038/ncomms472624785947
     [Google Scholar]
  76. CollinsC.R. HackettF. AtidJ. TanM.S.Y. BlackmanM.J. The Plasmodium falciparum pseudoprotease SERA5 regulates the kinetics and efficiency of malaria parasite egress from host erythrocytes.PLoS Pathog.2017137e100645310.1371/journal.ppat.100645328683142
     [Google Scholar]
  77. ThomasJ.A. TanM.S.Y. BissonC. BorgA. UmrekarT.R. HackettF. HaleV.L. Vizcay-BarrenaG. FleckR.A. SnijdersA.P. SaibilH.R. BlackmanM.J. A protease cascade regulates release of the human malaria parasite Plasmodium falciparum from host red blood cells.Nat. Microbiol.20183444745510.1038/s41564‑018‑0111‑029459732
     [Google Scholar]
  78. BanerjeeR. LiuJ. BeattyW. PelosofL. KlembaM. GoldbergD.E. Four plasmepsins are active in the Plasmodium falciparum food vacuole, including a protease with an active-site histidine.Proc. Natl. Acad. Sci. USA200299299099510.1073/pnas.02263009911782538
     [Google Scholar]
  79. NasamuA.S. GlushakovaS. RussoI. VaupelB. OksmanA. KimA.S. FremontD.H. ToliaN. BeckJ.R. MeyersM.J. NilesJ.C. ZimmerbergJ. GoldbergD.E. Plasmepsins IX and X are essential and druggable mediators of malaria parasite egress and invasion.Science2017358636251852210.1126/science.aan147829074774
     [Google Scholar]
  80. PinoP. CaldelariR. MukherjeeB. VahokoskiJ. KlagesN. MacoB. CollinsC.R. BlackmanM.J. KursulaI. HeusslerV. BrochetM. Soldati-FavreD. A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress.Science2017358636252252810.1126/science.aaf867529074775
     [Google Scholar]
  81. TeixeiraC. GomesJ.R. GomesP. Falcipains, Plasmodium falciparum cysteine proteases as key drug targets against malaria.Curr. Med. Chem.201118101555157210.2174/09298671179532832821428877
     [Google Scholar]
  82. ArisueN. PalacpacN.M.Q. TouganT. HoriiT. Characteristic features of the SERA multigene family in the malaria parasite.Parasit. Vectors202013117010.1186/s13071‑020‑04044‑y32252804
     [Google Scholar]
  83. RuppI. BosseR. SchirmeisterT. PradelG. Effect of protease inhibitors on exflagellation in Plasmodium falciparum.Mol. Biochem. Parasitol.2008158220821210.1016/j.molbiopara.2007.12.00918243365
     [Google Scholar]
  84. KuehnA. PradelG. The coming-out of malaria gametocytes.J. Biomed. Biotechnol.2010201011110.1155/2010/97682720111746
     [Google Scholar]
  85. BrooksS.R. WilliamsonK.C. Proteolysis of Plasmodium falciparum surface antigen, Pfs230, during gametogenesis.Mol. Biochem. Parasitol.20001061778210.1016/S0166‑6851(99)00201‑710743612
     [Google Scholar]
  86. EksiS. CzesnyB. Van GemertG.J. SauerweinR.W. ElingW. WilliamsonK.C. Malaria transmission-blocking antigen, Pfs230, mediates human red blood cell binding to exflagellating male parasites and oocyst production.Mol. Microbiol.200661499199810.1111/j.1365‑2958.2006.05284.x16879650
     [Google Scholar]
  87. ArisueN. HiraiM. AraiM. MatsuokaH. HoriiT. Phylogeny and evolution of the SERA multigene family in the genus Plasmodium.J. Mol. Evol.2007651829110.1007/s00239‑006‑0253‑117609844
     [Google Scholar]
  88. AlyA.S.I. MatuschewskiK. A malarial cysteine protease is necessary for Plasmodium sporozoite egress from oocysts.J. Exp. Med.2005202222523010.1084/jem.2005054516027235
     [Google Scholar]
  89. EksiS. CzesnyB. GreenbaumD.C. BogyoM. WilliamsonK.C. Targeted disruption of Plasmodium falciparum cysteine protease, falcipain 1, reduces oocyst production, not erythrocytic stage growth.Mol. Microbiol.200453124325010.1111/j.1365‑2958.2004.04108.x15225318
     [Google Scholar]
  90. TorresJ.A. RodriguezM.H. RodriguezM.C. de la Cruz Hernandez-HernandezF. Plasmodium berghei: Effect of protease inhibitors during gametogenesis and early zygote development.Exp. Parasitol.2005111425525910.1016/j.exppara.2005.08.00316198343
     [Google Scholar]
  91. EksiS. CzesnyB. van GemertG.J. SauerweinR.W. ElingW. WilliamsonK.C. Inhibition of Plasmodium falciparum oocyst production by membrane-permeant cysteine protease inhibitor E64d.Antimicrob. Agents Chemother.20075131064107010.1128/AAC.01012‑0617178799
     [Google Scholar]
  92. SinnisP. NardinE. Sporozoite antigens: Biology and immunology of the circumsporozoite protein and thrombospondin-related anonymous protein.Chem. Immunol.200280709610.1159/00005884012058652
     [Google Scholar]
  93. CoppiA. NatarajanR. PradelG. BennettB.L. JamesE.R. RoggeroM.A. CorradinG. PerssonC. TewariR. SinnisP. The malaria circumsporozoite protein has two functional domains, each with distinct roles as sporozoites journey from mosquito to mammalian host.J. Exp. Med.2011208234135610.1084/jem.2010148821262960
     [Google Scholar]
  94. SultanA.A. ThathyV. FrevertU. RobsonK.J.H. CrisantiA. NussenzweigV. NussenzweigR.S. MénardR. TRAP is necessary for gliding motility and infectivity of plasmodium sporozoites.Cell199790351152210.1016/S0092‑8674(00)80511‑59267031
     [Google Scholar]
  95. EjigiriI. RaghebD.R.T. PinoP. CoppiA. BennettB.L. Soldati-FavreD. SinnisP. Shedding of TRAP by a rhomboid protease from the malaria sporozoite surface is essential for gliding motility and sporozoite infectivity.PLoS Pathog.201287e100272510.1371/journal.ppat.100272522911675
     [Google Scholar]
  96. BoysenK.E. MatuschewskiK. Inhibitor of cysteine proteases is critical for motility and infectivity of Plasmodium sporozoites.MBio201346e00874-1310.1128/mBio.00874‑1324281719
     [Google Scholar]
  97. AlyA.S.I. VaughanA.M. KappeS.H.I. Malaria parasite development in the mosquito and infection of the mammalian host.Annu. Rev. Microbiol.200963119522110.1146/annurev.micro.091208.07340319575563
     [Google Scholar]
  98. BurdaP.C. CaldelariR. HeusslerV.T. Manipulating the Plasmodium life cycle to study pathogen-host interactions.Trends Parasitol.2020361085085932891493
     [Google Scholar]
  99. KafsackB.F.C. Rovira-GraellsN. ClarkT.G. BancellsC. CrowleyV.M. CampinoS.G. WilliamsA.E. DroughtL.G. KwiatkowskiD.P. BakerD.A. CortésA. LlinásM. A transcriptional switch underlies commitment to sexual development in malaria parasites.Nature2014507749124825210.1038/nature1292024572369
     [Google Scholar]
  100. SoniS. DhawanS. RosenK.M. ChafelM. ChishtiA.H. HanspalM. Characterization of events preceding the release of malaria parasite from the host red blood cell.Blood Cells Mol. Dis.200535220121110.1016/j.bcmd.2005.05.00616087367
     [Google Scholar]
  101. DameJ.B. ReddyG.R. YowellC.A. Plasmodium falciparum histo-aspartic protease (HAP): Molecular cloning, expression, and characterization of an aspartic hemoglobinase implicated in trophozoite hemoglobin degradation.Mol. Biochem. Parasitol.200313215970
     [Google Scholar]
  102. TragerW. JensenJ.B. Human malaria parasites in continuous culture.Science1976193425467367510.1126/science.781840781840
     [Google Scholar]
  103. GlushakovaS. YinD. LiT. ZimmerbergJ. Membrane transformation during malaria parasite release from human red blood cells.Curr. Biol.200515181645165010.1016/j.cub.2005.07.06716169486
     [Google Scholar]
  104. Salazar-CalderónM. de MonbrisonF. MuraI. VendevilleC. ChauvièreG. ViscogliosiE. Plasmodium falciparum: Altered expression of major food vacuole proteases in parasites subjected to a mixture of protease inhibitors.Exp. Parasitol.20071164481489
     [Google Scholar]
  105. DahlE.L. RosenthalP.J. Apicoplast translation, transcription and genome replication: Targets for antimalarial antibiotics.Trends Parasitol.200824627928410.1016/j.pt.2008.03.00718450512
     [Google Scholar]
  106. BoyleM.J. WilsonD.W. RichardsJ.S. RiglarD.T. TettehK.K.A. ConwayD.J. RalphS.A. BaumJ. BeesonJ.G. Isolation of viable Plasmodium falciparum merozoites to define erythrocyte invasion events and advance vaccine and drug development.Proc. Natl. Acad. Sci. USA201010732143781438310.1073/pnas.100919810720660744
     [Google Scholar]
  107. KhalilovR.K. BakishzadeA. NasibovaA. Future prospects of biomaterials in nanomedicine.Adv. Biol. Earth Sci.2024951010.62476/abes.9s5
     [Google Scholar]
  108. RosicG. SelakovicD. OmarovaS. Cancer signaling, cell/gene therapy, diagnosis and role of nanobiomaterials.Adv. Biol. Earth Sci.20249113410.62476/abes9s11
     [Google Scholar]
  109. HuseynovE. KhalilovR. MohamedA.J. Novel nanomaterials for hepatobiliary diseases treatment and future perspectives.Adv. Biol. Earth Sci.20249819110.62476/abes9s81
     [Google Scholar]
/content/journals/cmc/10.2174/0109298673308069240815072244
Loading
Therapeutic Targeting and Role of Cysteine Proteases in the Life Cycle of Malaria Parasite
Curr. Med. Chem. 32, 6198 (2025); https://doi.org/10.2174/0109298673308069240815072244
/content/journals/cmc/10.2174/0109298673308069240815072244
/content/journals/cmc/10.2174/0109298673308069240815072244
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): chemotherapeutic target; Cysteine proteases; drug development; falcipain; inhibitors; malaria

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test