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Tafere Mulaw Belete Department of Pharmacology, Faculty of Medicine and Health Sciences, Gondar University, Gondar, Ethiopia Tsamba: Tafere Mulaw Belete Tel +251 918045943Email [email protected] Abstract: Malaria idambudziko guru rehutano pasi rose rinokonzera kufa kukuru uye kurwara gore rega rega Rate .Marapirwo angashomeka uye anopikiswa zvikuru nekumuka kwezvipembenene zvinoshingirira, izvo zvinopa chipingamupinyi chikuru pakurwisa marariya.Kudzivirira njodzi dzinongoitika dzeutano hweveruzhinji, mishonga inorwisa marariya ine dozi rimwe chete, kurapa kwakawanda, uye nzira itsva dzekuita. dzinodiwa nokukurumidza.Kugadzirwa kwemishonga yeAntimalarial inogona kutevera nzira dzakasiyana-siyana, kubva pakugadziriswa kwemishonga iripo kusvika pakugadzirwa kwemishonga itsva inotarisa zvinangwa zvitsva.Kufambira mberi kwemazuva ano mubiology yeparasite uye kuvapo kwemichina yakasiyana-siyana yegenomic inopa huwandu hwezvinangwa zvitsva. yekuvandudzwa kwemishonga mitsva.Several promising targets yekupindira kwemishonga yakaratidzwa mumakore achangopfuura.Naizvozvo, kuongorora uku kunotarisa kufambira mberi kwesayenzi uye teknolojia mukutsvaga nekuvandudzwa kwemishonga inorwisa marariya.Inonyanya kufadza antimalarial target proteins yakadzidzwa kusvika ikozvino inosanganisira proteases, protein kinases, plasmodium shuga. transporter inhibitors, aquaporin 3 inhibitors, choline transport inhibitors, dihydroorotate dehydrogenase inhibitors, pentadiene biosynthesis inhibitor, farnesyltransferase inhibitor uye ma enzymes anobatanidzwa mu lipid metabolism uye DNA replication.Kuongorora uku kunopfupisa zvinangwa zvitsva zvema molecular mumashoko e-antimalarial drug: Ke yavo yemishonga yekurwisa zvinodhaka. , zvinangwa zvitsva, mishonga yekudzivirira marariya, maitiro ekuita, chirwere chemalaria
Malaria chirwere chinotapukira cheparasitic chinoparadza, kunyanya kunyika dziri kumaodzanyemba kweSahara muAfrica, dzimwe nzvimbo dzeAsia neSouth America.Pasinei nekuedza kwakawanda, nhasi ndicho chimwe chezvikonzero zvikuru zvekurwara nendufu zvikuru mumadzimai ane pamuviri nevana.Maererano neWorld Health Sangano (WHO) 2018 rakashuma, kune 228 miriyoni yechirwere chemalaria uye 405 000 vakafa pasi rose. Inenge hafu yevanhu pasi rose vari panjodzi yemarariya, uye ruzhinji rwevanhu (93%) uye ndufu (94%) dziri kuitika muAfrica. About Vakadzi vane pamuviri vanosvika mamiriyoni 125 vari panjodzi yemarariya gore negore, uye vana 272 000 vari pasi pemakore mashanu vanofa nemarariya.1 Malaria inokonzerawo urombo uye chipingamupinyi chikuru mukusimukira kweupfumi, zvikuru muAfrica. Plasmodium inokonzera marariya muvanhu iP. vivax, P. knowlesi, P. ovale, P. malaria neP. falciparum.Pane idzi, Plasmodium falciparum ndiyo inouraya uye inopararira zvikuru muPlasmodium.3
Kana pasina mushonga unoshanda, kushandiswa kwekurapa kwemishonga inorwisa marariya inoramba iri nzira chete yekugadzirisa nekudzivirira chirwere chemalaria.Ongororo dzinoverengeka dzakaratidza kuti kushanda kwemishonga yakawanda yemarariya kunokanganiswa nekukurumidzira muPlasmodium spp.4 Kuramba kwezvinodhaka. yakashumwa pamwe nemishonga inenge iripo yemishonga inorwisa marariya, kusimbisa kukurudzirwa kwemishonga mitsva yekudzivirira marariya kune zvinangwa zviripo zvakasimbiswa uye kutsvaga The gametophytic stage of transmission inogonawo kuita seasexual proliferation mukati me erythrocytes, kunyanya mukurwisana kweparasite marudzi.6 Several enzymes, ion nzira, vatakuri, mamorekuru anodyidzana kupinda kweRed blood cell (RBC), uye mamorekuru ane chekuita neparasite oxidative stress, lipid metabolism, uye hemoglobin degradation ndiwo akakosha pakugadzirwa kwemishonga mitsva yekudzivirira marariya inorwisa marariya inokurumidza kuchinja.
Kugona kwemishonga mitsva yekudzivirira marariya kunotongwa nezvakawanda zvinodiwa: nzira itsva yekuita, hapana kupesana nemishonga yemazuva ano antimalarial, kurapa kwedosi rimwe chete, kushanda zvakanaka padanho reropa reasexual uye gametocytes inotarisirwa kutapurirana. mishonga inorwisa marariya inofanira kuva nesimba mukudzivirira utachiona (chemoprotectants) uye kuchenesa chiropa cheP. vivax hypnotics (anti-relapse agents).8
Kuwanikwa kwemishonga yechinyakare kunotevera nzira dzakati wandei dzekutsvaga mushonga mutsva wekudzivirira marariya kurwisa marariya. Izvi kuvandudza marongero azvino emishonga uye magadzirirwo, kugadzirisa zvinodhaka zvinodzivirira marariya, kuongorora zvigadzirwa zvechisikigo, kupatsanura mishonga inodzivirira kurwisa marariya, kushandisa nzira dzekubatanidza chemotherapy, nekugadzira mishonga. kune mamwe mashandisirwo.8,9
Pamusoro penzira dzechinyakare dzekuwana zvinodhaka dzinoshandiswa kuona zvinodhaka zvinorwisa marariya, ruzivo rwePlasmodium cell biology uye genome rwakaratidzwa sechishandiso chine simba chekufumura nzira dzekudzivisa zvinodhaka, uye ine mukana wekugadzira mishonga ine yakanyanya antimalarial uye antimalarial chiitiko.Kugona kukuru kwemishonga mitsva.Kurwisa kuvhiringa kutapurirana kwemarariya zvachose.10 Genetic screening yePlasmodium falciparum yakaratidza 2680 majini akakosha pakukura kweropa-asexual, nokudaro zvichiratidza nzira dzinokosha dzemasero dzinokosha pakugadzira mishonga mitsva.10,11 New mishonga inofanira: (i) kugadzirisa kusabatwa nemishonga, (ii) kukurumidza kushanda, (iii) ive yakachengeteka, kunyanya muvana nevakadzi vane pamuviri, uye (iv) kurapa marariya nedoro rimwe chete.12 Dambudziko nderekutsvaga mushonga unobatsira. Zvose izvi maitiro.Chinangwa chekuongorora uku ndechekupa pfungwa yezvinangwa zvitsva zvekurapa zvirwere zvemalaria, izvo zviri kuongororwa nemakambani akawanda, kuitira kuti vaverengi vazive nezvebasa rapfuura.
Parizvino, mishonga yakawanda inorwisa marariya inonangana nechikamu chechirwere chemalaria icho chinokonzera zviratidzo zvechirwere. The pre-erythrocytic (chiropa) danho rinoramba risingataridzike nokuti hapana zviratidzo zvechipatara zvinogadzirwa. Mishonga yeAntimalarial inoratidzira kusarudzwa kwechikamu (ona Mufananidzo 1). zvigadzirwa zvechisikigo, semi-synthetic uye mishonga yekugadzira yakagadzirwa kubva kumakore ekuma1940.13 Mishonga yekudzivirira marariya iripo inowira mumapoka matatu akafara: quinoline derivatives, antifolates uye artemisinin derivatives.Hapana mushonga mumwe chete wati wawanikwa kana kugadzirwa unogona kupedza marudzi ese emalaria. Nokudaro, kuti ibudirire pakurwisa utachiona hwemarariya, misanganiswa yemishonga inowanzopiwa panguva imwe cheteyo.Quinoline mushonga unorwisa marariya unonyanya kushandiswa pakurapa marariya.Quinine, alkaloid iri yoga kubva pamakwati emuti wecinchona, ndiwo wakatanga kushandiswa mushonga wekudzivirira marariya. kurapa zvirwere muzana remakore rechi17. Kubva pakati pema1800 kusvika kuma1940, quimapfumbamwe ndiwo aishandiswa pakurapa marariya.14 Pamusoro pehuturu, kubuda kwemhando dzisingaurayiwi nemishonga dzeP. falciparum kwakaganhurira kushandiswa kwequinine mukurapa.Zvisinei, quinine ichiri kushandiswa kurapa marariya yakakomba, kazhinji kazhinji pamwe chete ne mushonga wechipiri kupfupisa nguva yekurapa uye kuderedza mhedzisiro.15,16
Mufananidzo 1 Hupenyu hwePlasmodium muvanhu.Matanho uye mafomu emaparasite umo marudzi akasiyana emishonga inorwisa marariya inoshanda.
Muna 1925, vatsvakurudzi veGermany vakawana mushonga wekutanga wemishonga yemarariya, pamaquin, nekugadzirisa methylene blue.Pamaquin ine simba shoma uye huturu uye haigoni kushandiswa kurapa marariya. yakabva kune methylene blue yakashandiswa kurapa marariya munguva yeHondo Yenyika II.17
Chloroquine yakagadzirwa munguva yeHondo Yenyika II kurapa marariya.Chloroquine mushonga unonyanya kushandiswa pakurapa marariya nekuda kwekushanda kwayo, kuchengeteka uye kudhura kwayo.Asi kushandiswa kwayo kusina musoro kwakazoita kuti pave nemhando yeP. falciparum isingagadziriswi nechloroquine. 18 Primaquine inoshandiswa mukurapa kurapa relapsing Plasmodium vivax inokonzerwa nehypnosis.Primaquine ine simba gameticidal against Plasmodium falciparum.Primaquine inokonzeresa hemolytic anemia muvarwere vaneglucose-6-phosphate dehydrogenase (G6PD). -P.Kuitwa kweDiurnal.19
Mishonga mitsva yequinoline yakagadzirwa, izvo zvakaita kuti pave nemishonga mitsva yakaita sepiperaquine neamodiaquine.Mushure mekubuda kwechloroquine resistance, amodiaquine, phenyl-substituted analogi yechloroquine, yakaratidza kushanda kwakanakisa pakurwisa chloroquine-resistant strains ePlasmoyrrum20faldrik base antimalarial drug yakagadzirwa muChina muna 1970.Inoshanda pakurwisa zvinodhaka zvisingaite zveP. falciparum, P. vivax, P. malaria uye P. ovale.Pyronadrine yava kuwanikwa seACT ine artesunate, iyo yakaratidza kushanda kwakanakisa kune vese. marariya parasites.21 Mefloquine yakagadzirwa pakati pemakore ekuma1980 uye ikozvino inokurudzirwa kuti iite chemoprevention yemarariya inokonzerwa nemarudzi ose, kusanganisira chloroquine-resistant strains.Zvisinei, kushandiswa kwayo kunobatanidza nemimwe migumisiro yechirwere uye kusagadzikana kwemishonga.22 Mishonga inobva kuQuinoline inoshanda zvakanyanya padanho reropa reparasite, asi mimwe mishonga inorwisa marariya inoshanda pachiropa. Mishonga iyi inodzivisa nekuita complex neheme muzvokudya zveparasite.Nekudaro, heme polymerization yakavharwa.Nekuda kweizvozvo, iyo heme inoburitswa panguva yekuparara kwehemoglobin inoungana kusvika kune chepfu, ichiuraya hutachiona nemarara ane chepfu.makumi maviri nenhatu
Antifolates mishonga inorwisa marariya inodzivisa kuumbwa kwe folic acid, iyo inokosha pakugadzirwa kwe nucleotides uye amino acids.Antifolates inovhara kupatsanurwa kwenyukireya yePlasmodium marudzi panguva ye schizont chikamu mu erythrocytes uye hepatocytes.Sulfadoxine ine chimiro chakafanana nepara-aminobenzoic acid. (PABA), chikamu che folic acid.Vanodzivisa dihydrofolate synthesis nekudzivisa dihydrofolate synthase, enzyme inokosha mu nucleic acid biosynthesis.makumi maviri nemana
Pyrimethamine uye proguanil schizont antimalarial zvinodhaka zvinoshanda pamhando yeasexual yePlasmodium mhando.Mishonga iyi inodzivisa enzyme dihydrofolate reductase (DHFR), iyo inodzivisa kuderedzwa kwe dihydrofolate kune tetrahydrofolate, iyo inokosha kune biosynthesis yeamino acids uye nucleic acids. Proguanil is a prodrug metabolized to cyclic guanidine.Proguanil ndiyo yekutanga antifolate mushonga wakashandiswa mukurapa marariya.Chikonzero ndechekuti inoparadza masero matsvuku eropa risati rapinda muropa.Uyezve, proguanil inochengetedza. mushonga.Pyrimethamine inonyanya kushandiswa nemamwe madhiragi anokurumidza kuita.Zvisinei, kushandiswa kwayo kwadzikira nekuda kwekuramba zvinodhaka.24,25
Atovaquone ndiwo mushonga wekutanga unobvumidzwa wekudzivirira marariya wakanangana nemitochondria yePlasmodium parasite.Atovaquone inovharisa kutakura maelectron kuburikidza nekuita seubiquinone analogi kuvhara cytochrome b chikamu checytochrome bc1 complex.Kana yasanganiswa neproguanil, atovaquone haina njodzi uye inoshanda kumadzimai akazvitakura uye vana.Atovaquone inoshanda padanho repabonde reparasite yemuridzi uye mosquito.Nekudaro, inodzivirira kutapurirana kwemarariya kubva kuumhutu kuenda kuvanhu.Musanganiswa wakagadziriswa neproguanil wakagadzirwa pasi pezita rekutengesa Malarone.24,26
Artemisinin yakatorwa kubva muArtemisia annua muna 1972.Artemisinin nezvimwe zvinobva mairi zvinosanganisira artemether, dihydroartemisinin, artemether uye artesunate vane wide spectrum activity.Artemisinin inhibits all parasite stages in red blood cells, especially in the first stages of their growth.Inotadzisawo kutapurirana kweutachiona. zvemagametocyte kubva kuvanhu kuenda kuumhutu.27 Artemisinin nezvinobva pairi inoshanda pakurwisa chloroquine- uye mefloquine-resistant strains.Idzo dzakachengeteka, dzinoshanda uye dzinokurumidza kuita ropa schizonts kumarudzi ese ePlasmodium.Zvisinei, artemisinin haina kubvisa hepatic latency yeropa re parasite.Mishonga iyi ine hafu yeupenyu hupfupi uye kushaikwa kwehupenyu, zvichiita kuti zvinodhaka zvisingarambiki, zvichiita kuti zvisashanda se monotherapy.Naizvozvo, zvigadzirwa zveartemisinin zvinokurudzirwa pamwe chete nemamwe mishonga inorwisa marariya.28
Iyo antimalarial effect ye artemisinin inogona kunge yakakonzerwa nechizvarwa chemahara radicals anokonzerwa nekutsemuka kweartemisinin endoperoxide mabhiriji mune zvipembenene zvekudya vesicles, nokudaro inhibiting parasite calcium ATPase uye proteasome.29,30 Artemether inoshandiswa se monotherapy.Fast oral absorption.Bioavavailability. yakapetwa kaviri kana ichishandiswa pamberi pezvokudya.Kamwe mu systemic circulation, artemether is hydrolyzed to dihydroartemisinin muhutu uye chiropa.
Artesunate is a semi-synthetic derivative nekuda kwekukurumidza kwayo antimalarial effect, kushayikwa kwekukosha kwemishonga yemishonga uye kunyanya kunyungudika kwemvura.Inokurudzirwa semushonga wekutanga wemarariya akanyanya.31
Tetracyclines uye macrolides mishonga inorwisa marariya inononoka inoshandiswa seadjunctive therapy to quinine in falciparum malaria.Doxycycline inoshandiswawo kurapa chemoprophylaxis munzvimbo dzine utachiona hwakanyanya.32 Nzira yemazuva ano inoshandiswa kurwisa antimalarial drug resistance ndiyo kurapa kushandiswa kwemisanganiswa yemishonga. nzira yakashandiswa kare nekushandisa misanganiswa yakagadziriswa.WHO inokurudzira artemisinin-based combination therapy (ACT) senzira yekutanga yekurapa kwefalciparum malaria isina kuoma.Chikonzero ndechokuti kusanganiswa kwemishonga kunoderedza kusagadzikana kwezvinodhaka nemigumisiro.33
ACT ine chikamu chine simba cheartemisinin chinokurumidza kubvisa zvipembenene, uye mushonga wenguva refu unobvisa zvipembenene zvakasara uye kuderedza artemisinin kushorwa.Mitemo inokurudzirwa neWHO ndeye artesunate/amodiaquine, artemether/ benzfluorenol, artesunate/mefloquine, artesunate/dihydroartelidine piperaquine, Artesunate/sulfadoxine/pyrimethamine, artemether/piperaquine uye artemisinin/piperaquine/primaquine.Chloroquine plus primaquine inoramba iri mushonga wekutanga wekupedza Plasmodium vivax.Quinine + tetracycline/doxycycline ine mushonga mukuru wepadivi, migumisiro uye inopikiswa muvana nevakadzi vane pamuviri34.
Mefloquine, atovaquone/proguanil, kana doxycycline inokurudzirwa mune chemoprevention regimens kune vanofamba kubva kunzvimbo dzisina kupera kusvika kune dzimwe nzvimbo.35 Kurapa kwekudzivirira kwepakati mumapoka ane ngozi inokurudzirwa, kusanganisira sulfadoxine/pyrimethamine panguva yekuzvitakura uye amodiaquine/sulfadoxine-pyrimethamine semwaka .36 Halofantrine haikodzeri kushandiswa kwekurapa nekuda kwe cardiotoxicity.Dapsone, mepalyline, amodiaquine, uye sulfonamides zvakabviswa kubva pakushandiswa kwekurapa nekuda kwemigumisiro yavo.36,37 Mimwe mishonga inonyanyozivikanwa ye antimalarial nemigumisiro yaro yakanyorwa muTebhu. 1.
Parizvino mishonga yekudzivirira marariya inowanikwa pamisiyano yenzira huru dzemetabolism pakati pemhando dzePlasmodium nedzinodzigamuchira.Nzvimbo huru yeparasite, kusanganisira heme detoxification, fatty acid synthesis, nucleic acid synthesis, fatty acid synthesis, uye oxidative stress, ndezvimwe zvezvinyorwa. nzvimbo dzekugadzira zvinodhaka.38,39 Kunyange zvazvo mishonga yakawanda yemarariya yakashandiswa kwemakore anoverengeka, kushandiswa kwavo ikozvino kwakaderera nekuda kwekusagadzikana kwezvinodhaka.Maererano nemabhuku, hapana mishonga inorwisa marariya yakawanikwa inodzivisa zvinozivikanwa zvinodhaka zvinangwa.7,40 In kusiyana, mishonga yakawanda inorwisa marariya inowanikwa mumhuka in vivo kana in vitro model zvidzidzo.Saka, maitiro ekuita kwemishonga yakawanda yemarariya inoramba isingazivikanwi.Uyezve, nzira dzekudzivisa mishonga yakawanda yemarariya hadzina kujeka.39
Kudzora marariya kunoda nzira dzakarongeka dzakadai sevector control, inoshanda uye yakachengeteka mishonga yekudzivirira marariya, uye majekiseni anobudirira.Tichifunga nezvehuwandu hwekufa uye hurwere hwemarariya, njodzi uye kupararira kwekurwisa zvinodhaka, kusashanda kwemishonga iripo yekudzivirira marariya kurwisa asiri erythrocyte uye matanho epabonde. , kuzivikanwa kwemishonga mitsva yekudzivirira marariya kuburikidza nekunzwisisa nzira dzekutanga dzemetabolism dzemarariya.Mishonga yemarariya yakakosha.zvipembenene.Kuzadzisa chinangwa ichi, tsvakurudzo yezvinodhaka inofanira kunangana nezvinangwa zvitsva, zvakatenderwa kuti zviparadzanise mishonga mitsva yemutobvu.39,41
Pane zvikonzero zvakawanda zvekuda kuziva zvinangwa zvitsva zvemetabolism. Chekutanga, kunze kwemishonga inotorwa neatovaquone uye artemisinin, mishonga yakawanda inorwisa marariya haina makemikari akasiyana-siyana, izvo zvinogona kutungamirira kune-cross-resistance. putative chemotherapeutic targets, mazhinji haasati asimbiswa.Kana akasimbiswa, anogona kupa mamwe makomisheni anoshanda uye akachengeteka.Kuzivikanwa kwezvinangwa zvemishonga mitsva uye kugadzirwa kwemishonga mitsva inoshanda pazvinangwa zvitsva zvinoshandiswa zvakanyanya pasi rose nhasi kugadzirisa. matambudziko anokonzerwa nekubuda kwekusagadzikana kwemishonga iripo.40,41 Nokudaro, chidzidzo chetsvairo yeprotein-specific inhibitors yePlasmodium yakashandiswa pakuzivikanwa kwechinangwa chemishonga.Kubva pakubudiswa kweP. falciparum genome, zvinangwa zvitsva zvakawanda zvezvinodhaka zvinodhaka. kupindira kwakabuda.Izvi zvingaita mishonga yekudzivirira marariya inotarisa key metabolite biosynthesis, membrane transport uye zviratidzo zvezviratidzo, uye hemoglobin degradation process.40,42
Plasmodium protease is a ubiquitous catalytic and regulatory enzyme inoita basa rinokosha mukupona kweprotozoan parasites nezvirwere zvavanokonzera.Inokonzeresa hydrolysis yepeptide bonds.43 Mabasa emaprotease muchirwere chemalaria anosanganisira kupinda kwesero/tishu, immune evasion, activation of inflammation, erythrocyte invasion, kuputsika kwehemoglobin nemamwe mapuroteni, autophagy, uye kukura kweparasite.44
Malaria proteases (glutamic aspartic acid, cysteine, simbi, serine uye threonine) vari kuvimbisa kurapa kwavanonangana nekuti kukanganisika kwechirwere chemalaria protease gene kunotadzisa kudzikira kwehemoglobin uye danho reparasite erythrocyte.budiriro.45
Kuparara kwe erythrocytes uye kupindira kunotevera kwemerozoites kunoda marariya proteases.A synthetic peptide (GlcA-Val-Leu-Gly-Lys-NHC2H5) inhibits Plasmodium falciparum schizont cysteine protease Pf 68This and paracyte-protease inhibit. inoratidza kuti ma<em>protease anoita basa guru mukupinda kweparasite mumasero matsvuku eropa.Naizvozvo, ma<em>protease ivavariro inovimbisa yekugadzirwa kwemishonga inorwisa marariya.46
MuPlasmodium falciparum food vacuoles, akati wandei aspartic proteases (plasma proteases I, II, III, IV) uye cysteine proteases (falcipain-1, falcipain-2/, falcipain-3) akaparadzaniswa, Anoshandiswa kuderedza hemoglobin, sezvakaratidzwa muMufananidzo 2.
Kuvharirwa kweprotease inhibitors leupeptin neE-64 zvakakonzera kuunganidzwa kweglobin isina kusimba. Leupeptin inhibits cysteine uye mamwe serine proteases, asi E-64 inodzivisa zvakananga cysteine , 7 proteases mushure me484. yezvipembenene zvine aspartate protease inhibitor pepstatin, globin haina kuunganidza.Ongororo dzinoverengeka dzakaratidza kuti cystatin inhibitors haingodziviri kuparara kweglobin chete, asiwo inodzivirira matanho ekutanga ekuparara kwehemoglobin, senge hemoglobin denaturation, heme kubuda kubva kuglobin, uye kugadzirwa kweheme. .49 Migumisiro iyi inoratidza kuti cysteine proteases inodiwa padanho rekutanga.Matanho ekuparara kwehemoglobin nePlasmodium falciparum.Zvose E-64 uye pepstatin synergistically block P. falciparum development.Zvisinei, E-64 chete yakavhara globin hydrolysis. 48,49 Several cysteine protease inhibitors, senge fluoromethyl ketone uye vinyl sulfone, inhibit P. falciparum kukura uye hemoglobin degra.dation.Mumuenzaniso wemhuka wemarariya, fluoromethyl ketone inhibits P. vinckei protease basa uye inorapa 80% yemurine marariya zvirwere.Naizvozvo, protease inhibitors vari kuvimbisa vashandi vemishonga inorwisa marariya.Basa rakatevera rakaonekwa biologically active falcipain inhibitors, kusanganisira chalcone, phenothiazine uye phenothiazine izvo zvinovhara utachiona hwemetabolism uye kukura.50
Serine proteases inobatanidzwa mu schizont rupture uye erythrocyte reinvasion panguva yePlasmodium falciparum life cycle.Inogona kuvharwa nemaserine protease inhibitors akawanda uye ndiyo yakanakisisa sarudzo sezvo pasina munhu enzyme homolog inowanikwa.Iyo protease inhibitor LK3 yakaparadzaniswa neStreptomyces sp.inokanganisa marariya serine protease.51 Maslinic acid is a natural pentacyclic triterpenoid inodzivisa kukura kwezvipembenene kubva pachikamu chemhete kusvika kune schizont stage, nokudaro kugumisa kusunungurwa kwemerozoite uye kupinda kwavo.Mutsara we2-pyrimidine nitrile inhibition yakasimba ye falcipain. -2 uye falcipain-3.52 statins uye inhibition yeplasma proteases neallophenostatin-based inhibitors inodzivirira kuparara kwehemoglobin uye kuuraya zvipembenene.Several cysteine protease blockers iripo, kusanganisira Epoxomicin, lactacystin, MG132, WEHI-8416, WEHI-8416, WEHI-8416, WEHI-8916 .
Phosphoinositide lipid kinases (PIKs) ma enzymes anowanikwa kwose kwose ayo phosphorylate lipids kuti agadzirise kupararira, kurarama, kutengesa, uye kuisa zviratidzo zvemukati.Makirasi ePIK akadzidzwa zvakanyanya mu 53 parasites phosphoinositide 3-kinase (PI3K) uye phosphatolseselseprose (4K) uye phosphatoselseprose (4K) PIC4. Kudzivirirwa kwema enzymes aya kwakaonekwa sechinhu chingave chinangwa chekugadzirwa kwemishonga inorwisa marariya ine maitiro anodiwa emabasa ekudzivirira, kurapwa uye kubvisa marariya.54 UCT943, imidazopyrazine (KAF156) uye aminopyridines ikirasi itsva yemishonga inorwisa marariya inotarisa PI. (4)K uye inhibit intracellular development of multiple Plasmodium species at every stage of host infection.Nokudaro, kunanga (PI3K) nePI(4)K kunogona kuvhura nzira itsva dzinobva pakuwanikwa kwemishonga yekuona novel antimalarial drugs.KAF156 parizvino iriko muChikamu chechipiri chekiriniki miedzo.55,56 MMV048 musanganiswa une good in vivo prophylactic activity against P. cynomolgi uye zvinogona as mushonga unovharira kutapurira.MMV048 parizvino irikuitwa Phase IIa kiriniki yekuedza muEthiopia.11
Nokuda kwekukura nokukurumidza mumasero matsvuku eropa ane utachiona, mhando dzePlasmodium dzinoda huwandu hwakakwana hwema substrates kuti dzifambise simba radzo remetabolism.Saka, zvipembenene zvinogadzirira mauto erythrocytes kuburikidza nekuita vatakuri vane ruzivo rwakasiyana zvakanyanya kubva kune vatakuri vemasero mukutora uye kubvisa metabolites. mapuroteni anotakura uye migero ndiyo inogona kutariswa nekuda kwemabasa avo anokosha mukutakura kwematabolites, electrolytes uye zvokudya zvinovaka muviri.57 Iyi ndiyo Plasmodium surface anion channel (PSAC) uye parasitic vacuolar membrane (PVM), iyo inopa nzira inoramba ichipararira kune zvinovaka muviri. kupinda intracellular parasite.58
PSAC ndiyo inonyanya kuvimbiswa nokuti inowanikwa mumhando dzakasiyana-siyana dzezvokudya (hypoxanthine, cysteine, glutamine, glutamate, isoleucine, methionine, proline, tyrosine, pantothenic acid uye choline) kuwana mabasa anokosha mu intracellular parasites.PSACs haina homology yakajeka. kune inozivikanwa host channel genes.58,59 Phloridizin, dantrolene, furosemide, uye niflunomide ane simba anion transporter blockers.Mishonga yakadai seglyburide, meglitinide, uye tolbutamide inodzivisa kupinda kwecholine mumasero matsvuku eropa ane utachiona.60,61
Chimiro cheropa chePlasmodium falciparum chinotsamira zvachose pa glycolysis yekugadzira simba, pasina kuchengetedza simba;inovimba nekugara kweglucose.Chirwere ichi chinoshandura pyruvate kuti iite lactate kuti ibudise ATP, iyo inodiwa pakudzokorora mukati memasero matsvuku eropa.62 Glucose inotanga kuendeswa muparasitize erythrocytes nekubatanidzwa kwehost cell's glucose transporter, GLUT1, mu iyo erythrocyte membrane uye parasite-induced 'new permeation pathway'.63 Glucose inotakurwa kuita zvipembenene nePlasmodium falciparum hexose transporter (PFHT).PFHT ine mamwe maitiro ekutakura shuga.GLUT1 inosarudza D-glucose, nepo PFHT inogona kutakura D-glucose uye D-fructose. Nokudaro, kusiyana kweGLUT1 uye PFHT kuwirirana ne substrates kunoratidza kuti kusarudzwa kuvharidzirwa kwePFHT ndiyo chinangwa chitsva chinovimbisa chekugadzirwa kwemishonga inorwisa marariya.64 A long-chain O-3-hexose derivative (compound) 3361) inhibisa glucose uye fructose kutorwa nePFHT, asi haidziviriri kutakura hexose nehukuru hwemammalian glucose uye fructose transporters (GLUT1 uye 5) .361 yakavharawo glucose kutorwa neP. vivax yePFHT.Muzvidzidzo zvekare, komputa 3361 yakauraya P. falciparum mutsika uye yakaderedza kubereka kweP. berghei mumakonzo.65
Plasmodium blood grouping inonyanya kuenderana neanaerobic glycolysis yekukura nekukura.60 Parasite-infected red blood cells inotora glucose 100 times faster than uninfected blood cells.The parasite metabolizes glucose through glycolysis to lactate, which is exported from the parasite via lactate: an H + symporter mechanism mumhepo yekunze.66 Lactate export uye glucose uptake inokosha pakuchengetedza simba rinodiwa, intracellular pH, uye parasite osmotic kugadzikana.Lactate:H+ symporter system inhibition chinhu chitsva chinovimbisa chinangwa chekugadzirwa kwemishonga mitsva.Makomboni akawanda, akadai seMMV007839 neMMV000972, anouraya asexual blood-stage P. falciparum parasites nekudzivisa lactate:H+ transporter.67
Kufanana nemamwe marudzi emasero, masero matsvuku eropa anoramba akadzikama mukati meNa + mazinga.Zvisinei, zvipembenene zvinowedzera kupera kwe erythrocyte membrane uye kufambisa Na + kupinda, zvichiita kuti kuwedzerwa kwe erythrocyte cytoplasmic Na + concentration kusvika pamwero we extracellular medium.Saka, zvipembenene. vanozviwana vari mupamusoro weNa + media uye vanofanira kudzinga Na + ions kubva mu membrane yavo ye plasma kuti vachengetedze pasi cytoplasmic Na + mazinga kuti vararame pasinei nekuvapo kwavo munzvimbo dze intracellular. transporter (PfATP4), iyo inoshanda separasite's primary Na+-efflux pump mechanism, sezvinoratidzwa mumufananidzo 3.68, inhibiting mutakuri uyu Zvichaita kuti kuwedzerwa kwehuwandu hweNa + mukati meparasite, iyo inozopedzisira yatungamirira kurufu rwe Malaria parasite.Makomponi akawanda, kusanganisira sipagamin muchikamu chechipiri, (+)-SJ733 muchikamu chekutanga, uye KAE609 muchikamu chechipiri, ine nzira yekuita iyo inotarisa PfATP4.67,69
Mufananidzo 3. Yakarongwa nzira yeparasite-induced PfATP4 uye V-mhando H + -ATPase muhutachiona hwe erythrocyte rufu runotevera cipargamin inhibition.
Plasmodium marudzi anodzora mazinga eNa+ nekushandisa P-type ATPase transporter.Inopinzawo H+ kuburikidza nenzira yakafanana.Kugadzirisa kuwedzera kweH + concentration uye kuchengetedza intracellular pH ye7.3, chirwere chemalaria chinoshandisa imwe yeV-type ATPase transporter kusvika dzinga H+.Kugadzira mushonga mutsva chinangwa chinovimbisa.MMV253 inhibits V-type H+ ATPase senzira yayo yekuita nekusarudzwa kwekuchinja uye kutevedzana kwegenome yose.70,71
Aquaporin-3 (AQP3) inonzi aquaglycerol channel protein inobatsira kufamba kwemvura uye glycerol mumasero emammalian.AQP3 inokonzerwa nehepatocytes yevanhu mukutarisana nehutachiona hwehutachiona uye ine basa rinokosha mukudzokorora kweparasite.AQP3 inopa ruzivo rweglycerol muP .berghei uye inofambisa kudzokorora kweparasite mu asexual erythrocyte stage.72 Genetic depletion of AQP3 yakanyanya kudzvinyirira mutoro weparasite muchikamu chechiropa cheP. falciparum parasitemia mu erythrocytes, zvichiratidza kuti mapuroteni anotambira anoita mabasa akakosha mumatanho akasiyana ehupenyu hweparasite .73 Zvinonyanya kushamisa, kukanganiswa kweAQP3 mumakonzo emajini hakusi kuuraya, zvichiratidza kuti mapuroteni ane simba anogona kuve matsva ekurapa chinangwa.Iri basa rinowedzera kunzwisisa kwemaitiro echiropa anobatwa nehutachiona hwePlasmodium uye inosimbisa kugona kweiyi processes semishonga yemangwana antimalarial.71,72
Phospholipids inobata basa rinokosha mu intra-erythrocyte life cycle yePlasmodium falciparum, zvose sezvikamu zvemukati memembrane uye semamorekuru anotonga anodzora mabasa ema enzymes akasiyana-siyana.Mamorekuru aya akakosha pakuberekana kweparasite mukati memasero matsvuku eropa.Mushure mekupinda kwe erythrocyte, Phospholipid levels inowedzera, of which phosphatidylcholine is the main lipid in their cell membrane components.Parasites synthesize phosphatidylcholine de novo using choline as a precursor.This de novo pathway yakakosha pakukura kweparasite uye kurarama.Inhibits choline transport into parasites and inhibits phosphatidylcholine, zvichikonzera kufa kweparasite.74 Albitiazolium, mushonga wakapinda muChikamu chechipiri chekuedza, unoshanda zvakanyanya nekudzivisa kutakurwa kwecholine muparasite.Albitiazolium inounganidza kusvika ku1000 muPlasmodium uye inodzivisa kukura kweparasite pasina kudzoka zvakare.Inoshanda muhasha. mamiriro.Notably, jekiseni rimwe chete rakapora high parasitemia levels.75,76
Phosphocholine cytidyltransferase inhanho-yekuderedza nhanho mu de novo biosynthesis ye phosphatidylcholine.77 Diquaternary ammonium compound G25 uye dhizaini T3 inhibit phosphatidylcholine synthesis in parasites.G25 ndeye 1000-fold zvishoma zvishoma zvinodhaka zvinodhaka zvinotungamirira mammalian mishonga. zvinosanganiswa mukuwanikwa kwemishonga inorwisa marariya uye kukura.78,79
Nhanho inokosha mukupararira kwemarudzi ePlasmodium muvanhu mauto ndiyo yakakura uye yakakurumidza kupatsanurwa kweparasite DNA, iyo inoenderana nekuwanikwa kwematabolites anokosha akadai se pyrimidines.Mu Plasmodium, pyrimidine nucleotides inoita basa rinokosha mukubatanidzwa kweDNA, phospholipids uye glycoproteins.Nucleotide synthesis inotevera nzira mbiri huru: nzira yekuponesa uye de novo nzira.Dihydroorotate dehydrogenase (DHODH) insamesheni inokosha inokonzera oxidation ye dihydroorotate kuti iite orotate, chiyero-chinogadzirisa danho mu de novo pyrimidine synthesis, DHODH saka. inomiririra chinangwa chinogona kuvimbiswa chekugadzirwa kwemishonga inorwisa marariya.80 Masero evanhu anowana pyrimidines kuburikidza nekununura kare yakaumbwa pyrimidines kana ne de novo synthesis.Kana de novo biosynthetic nzira yakavharwa, sero richavimba nenzira yekuponesa uye sero haizofi. Zvisinei, kudziviswa kwe de novo pyrimidine biosynthesis mumaparasite kunoguma nekufa kwemasero aya nokutiMalaria parasite haina pyrimidine salvage pathway, izvo zvinoita kuti utachiona huve pangozi yekuvhariswa neDHODH.81 DSM190 uye DSM265 inosarudza inhibitors yeparasite DHODH enzyme, iyo parizvino iri muChikamu chechipiri chekiriniki miedzo.P218 inhibitor yeDHODH inoshanda kune ese pyrimethamine- kusagadzikana kwemaitiro ikozvino muChikamu 1.KAF156 (Ganaplacide) ikozvino muChikamu che2b chekliniki yekuedza ne phenylfluorenol.82
Isoprenoids inodiwa kuti post-translational lipid modification yemapuroteni uye asexual replication yePlasmodium falciparum.Isoprenoids inogadzirwa kubva kune mashanu-carbon precursor isopentyl diphosphate (IPP) kana isomeri yayo, dimethylallyl diphosphate (DMAPP), neimwe yenzira mbiri dzakazvimiririra.Mevalonate. nzira uye 2C-methyl-D-erythritol 4-phosphate (MEP) nzira.Muzhinji microorganisms, nzira mbiri idzi dzinopindirana.Bacteria nePlasmodium falciparum zvinoenderana zvachose neMEP nzira, asi vanhu havasi.Naizvozvo, ma enzymes mu MEP nzira inoongororwa sezvingangove zvitsva zvinonangwa pakurapa.Plasmodium falciparum 1-deoxy-xylulose-5-phosphate reductoisomerase (pfDxr) inokonzeresa nhanho-yekumisikidza nhanho munzira yeMEP, ichiita iyi enzyme yeparasite chinangwa chinovimbisa chekugadzirwa kwenovel mishonga yekurwisa marariya. .83,84 PfDXR inhibitors inhibit Plasmodium falciparum.Plasmodium falciparum inokura uye haina chepfu kumasero evanhu.antimalarial drug development.83 Fosmidomycin, MMV019313 uye MMV008138 inhibit DOXP reductoisomerase, enzyme inokosha yeDOXP nzira iyo isipo muvanhu.Nekuda kwekuti inhibition yeprotein prenylation muPlasmodium inokanganisa kukura kweasexual target is anti8ri5 parasites.
Prenylated mapuroteni anoita basa rinokosha mumhando dzakasiyana-siyana dzemaserura dzinosanganisira kutengesa vesicle, kushandura kwechiratidzo, mutemo weDNA replication, uye kupatsanurwa kwesero.Iyi post-translational modification inobatsira kusungirirwa kweprotein intracellular kune membranes uye inofambisa mapuroteni-protein interactions.Farnesyltransferase inogadzirisa kuendeswa kweboka refarnesyl, 15-carbon isoprenoid lipid unit, kubva farnesyl pyrophosphate kusvika kuC-terminus yemapuroteni ane CaaX motif.Farnesyltransferase chinangwa chitsva chinovimbisa chekugadzirwa kwemishonga inorwisa marariya nokuti inhibition yayo inouraya parasite.86
Kare, kushanduka kwekurwisana nemaparasites ne farnesyltransferase inhibitor BMS-388,891 tetrahydroquinoline yakaratidza kuchinja kweprotein ye peptide substrate-binding domain.Pakusarudzwa kweimwe tetrahydroquinoline neBMS-339,941, kuchinja kwakawanikwa mufarnesyl binding pyrophosphate. .Mune imwe tsvakurudzo, kuchinja kwakawanikwa mufarnesyltransferase beta subunit yeMMV019066-resistant strain yeP. falciparum. Zvidzidzo zvekuenzanisira zvakaratidza kuti kuchinja kunokanganisa nzvimbo yakakosha yekubatana kweiyo molecule duku nefarnesylation inoshanda nzvimbo, zvichiita kuti zvinodhaka zvinodhaka. .87
Chimwe chezvinangwa zvinovimbisa zvekugadzira mishonga mitsva ndeyekuvhara P. falciparum ribosome, pamwe chete nezvimwe zvikamu zvemichina yekushandura inotarisira mapuroteni synthesis.Plasmodium marudzi ane majenome matatu: nucleus, mitochondria, uye acroplasts (kubva kune masara chloroplasts). Magenome ese anoda michina yekushandura kuti ishande.Maprotein synthesis inhibitors ane budiriro huru yekiriniki semishonga inorwisa mabhakitiriya.Doxycycline, clindamycin, neazithromycin zvine mushonga wemarariya wekurapa nekuti anodzivirira ribosomes muparasite mitochondria nemaaplastoplast, zvichiita kuti organelles idzi dzisashande.88 P. falciparum ribosome inotora nzvimbo yepakati yekushanduka-shanduka pakati peprokaryotes neeukaryotes, ichiisiyanisa zvakanyanya kubva kune ribosome yemunhu nekudaro ichipa chinhu chakakosha chinovimbisa chinangwa chitsva. ye ribosomes pamwe nekusagadzikanaenger RNA uye yakakosha kuprotein synthesis mueukaryotes.PfEF2 yakaparadzaniswa sechinangwa chitsva chekugadzirwa kwemishonga inorwisa marariya.87,89
Inhibition yeprotein synthesis Tora kuwanikwa kwe sordarin, chigadzirwa chechisikigo chinosarudza kuvhara fungal protein synthesis nekudzivisa mbiriso eukaryotic elongation factor 2.Saizvozvo, M5717 (yaimbova DDD107498), inosarudza inhibitor ye80S ribosome-interacting, P parizvino iri infF. 1 zvidzidzo, kusimbisa kukwanisa kwePfEF2 sechinangwa chinoshanda chemishonga inorwisa marariya.88,90
Chinhu chikuru chemalaria yakakomba kutorwa kwe erythrocyte ine utachiona, kuzvimba, nekuvharika kwe microvasculature.Plasmodium falciparum inoshandisa heparan sulfate painonamira paendothelium nemamwe masero eropa, zvichikonzera kuvharika kwekuyerera kweropa.Kudzivirira aya abnormal cells and pathogen -kupindirana kwezvinodhaka kunodzorera ropa rakavharika uye kunokanganisa kukura kweparasite.91
Ongororo dzakawanda dzakaratidza kuti sevuparin, anti-adhesion polysaccharide yakagadzirwa kubva kuheparin, ine antithrombin-eliminating madhara. kuN-terminal extracellular heparan sulfate-binding structure yePlasmodium falciparum erythrocyte membrane protein protein 1, Duffy-binding-like domain 1α (DBL1α), uye inofungidzirwa kuti chinhu chinokosha pakutsvaga erythrocytes ine utachiona.92,93 Imwe Tafura 2 inopfupisa miedzo yekiriniki pamatanho akasiyana.
Nguva yekutumira: Mar-24-2022