Iterambere rishya mubushakashatsi no guteza imbere imiti mishya

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Ishami rya Tafere Mulaw Belete ishami rya farumasi, ishami ryubuvuzi nubumenyi bwubuzima, kaminuza ya Gondar, Gondar, muri Etiyopiya Abandikirana: Tafere Mulaw Belete Tel +251 918045943Email .Uburyo bwo kuvura ni buke kandi burahangayikishijwe cyane no kuvuka kwa parasite irwanya indwara, bitera imbogamizi ikomeye mu kurwanya malariya. Kugira ngo hirindwe ibibazo byihutirwa by’ubuzima rusange, imiti igabanya ubukana bwa virusi hamwe nubuvuzi bumwe, ubushobozi bwo kuvura, hamwe nuburyo bushya bwo gukora birakenewe byihutirwa. Iterambere ryibiyobyabwenge rishobora gukurikiza inzira zitandukanye, uhereye ku guhindura imiti iriho kugeza ku gishushanyo mbonera cy’ibiyobyabwenge bigamije intego nshya. kubwiterambere ryimiti mishya.Byose bitanga ikizereets yo kwivanga mu biyobyabwenge byagaragaye mu myaka yashize. Kubera iyo mpamvu, iri suzuma ryibanda ku iterambere rya siyansi n’ikoranabuhanga rigezweho mu kuvumbura no guteza imbere imiti igabanya ubukana bwa poroteyine. Inhibitori ya transport, inhibitor ya aquaporin 3, inhibitori ya choline, inhibitor ya dihydroorotate dehydrogenase, inhibitor ya pentadiene biosynthesis, inhibitori ya farnesyltransferase na enzymes zigira uruhare muri metabolisme ya lipide no kwigana ADN. , intego nshya, imiti igabanya ubukana, uburyo bwo gukora, malariya parasite
Malariya ni indwara yanduza parasitike yanduye, cyane cyane muri Afurika yo munsi y'Ubutayu bwa Sahara, mu bice bya Aziya no muri Amerika y'Epfo. Nubwo hashyizweho ingufu nyinshi, uyu munsi ni imwe mu mpamvu zitera indwara n'impfu cyane cyane ku bagore batwite ndetse no ku bana. Dukurikije ubuzima bw'isi Raporo y’umuryango (OMS) 2018, ku isi hose habaruwe miliyoni 228 n’abapfa 405.000. Hafi ya kimwe cya kabiri cy’abatuye isi bafite ibyago byo kurwara malariya, aho usanga umubare munini w’abantu (93%) n’impfu (94%) bibera muri Afurika. Hafi Miliyoni 125 z'abagore batwite bafite ibyago byo kurwara malariya buri mwaka, kandi abana 272.000 bari munsi yimyaka 5 bapfa bazize malariya.1 Malariya nayo itera ubukene n'inzitizi ikomeye mu iterambere ry'ubukungu, cyane cyane muri Afrika.2 Ubwoko butanu bwamenyekanye bwa Plasmodium itera malariya mubantu ni P. vivax, P. knowlesi, P. ovale, P. malariya na P. falciparum.Muri ibi, Plasmodium falciparum nubwoko bwica kandi bwiganje bwa Plasmodium.3.
Mugihe hatabayeho urukingo rukora neza, gukoresha imiti igabanya ubukana bikomeza kuba inzira yonyine yo gucunga no gukumira indwara ya malariya. Ubushakashatsi bwakozwe bwerekanye ko imikorere y’imiti myinshi yanduza ibiza byihutirwa byangiza imiti ya Plasmodium spp.4 Kurwanya ibiyobyabwenge byavuzwe hamwe nibiyobyabwenge hafi ya byose biboneka, bishimangira iterambere ryimiti mishya igabanya ubukana hamwe no gushakisha icyiciro cya gametophytique yo kwanduza gishobora no gukwirakwizwa no kudahuza ibitsina muri erythrocytes, cyane cyane mubwoko bwa parasite irwanya.6 Enzymes nyinshi, ion imiyoboro, abatwara abantu, imikoranire ya molekile Igitero cya selile itukura (RBC), hamwe na molekile zitera guhagarika umutima wa parasite, metabolisme ya lipide, hamwe no kwangirika kwa hemoglobine ni urufunguzo rwo guteza imbere imiti mishya irwanya malariya ihindura vuba Isezeranya intego nshya kuri protozoa.7.
Ubushobozi bwimiti mishya igabanya ubukana busuzumwa nibisabwa byinshi: uburyo bushya bwibikorwa, nta kurwanya imiti igabanya ubukana bwa none, kuvura inshuro imwe, gukora neza haba mu maraso adahuje igitsina ndetse na gametocytes ishinzwe kwanduza. Byongeye kandi, shyashya imiti igabanya ubukana igomba kugira ingaruka mukurinda kwandura (chemoprotectants) no gukuraho umwijima wa hypnotics ya P. vivax (anti-relaps agents) .8
Ubuvumbuzi bwa gakondo bukurikiza uburyo butandukanye bwo kumenya imiti mishya igabanya ubukana bwa malariya.Ibyo ni uguhindura uburyo bwo gufata imiti igezweho, guhindura imiti isanzwe, gusuzuma ibicuruzwa bisanzwe, gutandukanya imiti igabanya ubukana, gukoresha imiti ivura imiti, no guteza imbere imiti kubindi bikoreshwa.8,9
Usibye uburyo gakondo bwo kuvumbura ibiyobyabwenge bikoreshwa mukumenya imiti igabanya ubukana bwa virusi, ubumenyi bwibinyabuzima bya selile ya Plasmodium na genome byagaragaye ko ari igikoresho gikomeye cyo kuvumbura uburyo bwo kurwanya ibiyobyabwenge, kandi bufite ubushobozi bwo gukora ibiyobyabwenge bifite ibikorwa byinshi bya antimalariya na antimalariya.Ubushobozi bukomeye kumiti mishya.Kurwanya malariya ishobora kwanduza rimwe na rimwe.10 Kwipimisha genetike ya Plasmodium falciparum byagaragaje genes 2680 zingirakamaro mu mikurire y’amaraso adahuje igitsina, bityo bikagaragaza inzira zingenzi zingirakamaro mu guteza imbere imiti mishya.10,11 Gishya ibiyobyabwenge bigomba: (i) gukemura ikibazo cyo kurwanya ibiyobyabwenge, (ii) gukora byihuse, (iii) kugira umutekano, cyane cyane ku bana no ku bagore batwite, na (iv) gukiza malariya mu kigero kimwe.12 Ikibazo ni ugushaka imiti ikemura ibyo byose biranga. Intego y'iri suzuma ni ugutanga igitekerezo cyintego nshya zo kuvura malariya ya malariya, irimo kwigwa namasosiyete menshi, kugirango abasomyi bamenyeshejwe ibikorwa byabanje.
Kugeza ubu, imiti myinshi igabanya ubukana yibasira icyiciro cya mbere cyo kwandura malariya itera indwara yibimenyetso. Icyiciro kibanziriza erythrocytike (umwijima) ntigikurura kuko nta bimenyetso by’amavuriro bitangwa. ibicuruzwa karemano, igice cya sintetike hamwe nubukorikori byakozwe kuva 1940.13 Imiti iriho ya antimalarial iri mubice bitatu bigari: ibikomoka kuri cinoline, antifolates hamwe na artemisinin.Nta muti numwe wigeze uvumburwa cyangwa ngo ukorwe ushobora kurandura amoko yose ya parasite. Kubwibyo rero, kugirango bigire ingaruka nziza yo kwandura malariya, guhuza ibiyobyabwenge bikunze gutangwa icyarimwe.Quinoline niwo muti ukoreshwa cyane mu kuvura malariya. kuvura indwara mu kinyejana cya 17. Kuva hagati ya 1800 kugeza 1940, quiicyenda ni bwo buryo busanzwe bwo kuvura malariya.14 Usibye uburozi, kuvuka kw'imiti irwanya imiti ya P. falciparum byagabanije gukoresha imiti ya quinine.Nyamara, quinine iracyakoreshwa mu kuvura malariya ikabije, akenshi ikaba ifatanije na a imiti ya kabiri kugabanya igihe cyo kuvura no kugabanya ingaruka.15,16
Igishushanyo 1 Inzira yubuzima bwa Plasmodium mubantu.Imiterere nuburyo bwa parasite aho ubwoko butandukanye bwimiti igabanya ubukana.
Mu 1925, abashakashatsi b'Abadage bavumbuye imiti yambere ya sintetike ya antimalarial, pamaquin, bahindura methylene ubururu.Pamaquin ifite ubushobozi buke nuburozi kandi ntishobora gukoreshwa mu kuvura malariya.Ariko pamaquin itanga imiti igabanya ubukana bwa mitiweli.Mepacrine (quinacrine) nubundi ibikomoka kuri methylene ubururu bwakoreshejwe mu kuvura malariya mu Ntambara ya Kabiri y'Isi Yose.17
Chloroquine yakozwe mu gihe cy'Intambara ya Kabiri y'Isi Yose kugira ngo ivure malariya.Chloroquine niwo muti wo guhitamo kuvura malariya bitewe n'ingaruka zayo, umutekano ndetse n'igiciro gito.Ariko gukoresha bidahwitse byatumye havuka amoko ya P. falciparum irwanya chloroquine. 18 Primaquine ikoreshwa mu kuvura vivax yongeye kwisubiramo iterwa na hypnose.Primaquine ni gameticidal ikomeye irwanya Plasmodium falciparum. -P.Ibikorwa bya buri munsi.19
Ibikomoka kuri Quinoline bishya byahujwe, bivamo imiti mishya nka piperaquine na amodiaquine.Nyuma yo kugaragara kwa chloroquine irwanya chloroquine, amodiaquine, igereranya na fenil igereranya chloroquine, yerekanye imbaraga nziza zirwanya chloroquine irwanya Plasmodium falciparum.20 Pyrronadrine. ibiyobyabwenge bya antimalarial byatejwe imbere mubushinwa mumwaka wa 1970.Ni byiza kurwanya imiti irwanya ibiyobyabwenge bya P. falciparum, P. vivax, P. malariya na P. ovale.Pyronadrine ubu iraboneka nka ACT hamwe na artesunate, yerekanye ingaruka nziza kuri bose. malariya parasite.21 Mefloquine yakozwe hagati yimyaka ya za 1980 kandi kuri ubu irasabwa kwirinda imiti ya malariya iterwa nubwoko bwose, harimo nubwoko bwa chloroquine.Nyamara, ikoreshwa ryayo rifitanye isano ningaruka zimwe na zimwe no kurwanya ibiyobyabwenge.22 Imiti ikomoka kuri Quinoline. kora cyane cyane kumaraso ya parasite, ariko imiti imwe n'imwe ya antimalariya ikora kurwego rwumwijima.Iyi miti irabuza gukora complex hamwe na heme mubiribwa bya parasite.Niyo mpamvu, polymerisime ya heme irahagarikwa.Nkigisubizo, heme yarekuwe mugihe cyo kumeneka kwa hemoglobine irundanya kugeza kurwego rwuburozi, ikica parasite hamwe nuburozi bwuburozi. makumyabiri na batatu
Antifolates ni imiti igabanya ubukana bwa aside folike, ikaba ari ngombwa mu gusanisha nucleotide na aside amine. .
Pyrimethamine na proguanil ni imiti igabanya ubukana bwa schizont ikora ku buryo budasanzwe bwubwoko bwa Plasmodium.Iyi miti ibuza enzyme dihydrofolate reductase (DHFR), ibuza kugabanya dihydrofolate kuri tetrahydrofolate, ari ngombwa kuri biosynthesis ya aminide acide na nucleic. Proguanil ni prodrug metabolised to cyclic guanidine.Proguanil niwo muti wa mbere wa antifolate wakoreshejwe mu kuvura malariya. Impamvu ni uko isenya uturemangingo tw'amaraso atukura mbere yuko parasite ibatera mu gihe cyo kwinjira mu maraso.Ikindi kandi, proguanil ni umutekano. ibiyobyabwenge.Pyrimethamine ikoreshwa cyane cyane nibindi biyobyabwenge byihuta.Nyamara, imikoreshereze yayo yagabanutse kubera kurwanya ibiyobyabwenge.24,25
Atovaquone niwo muti wa mbere wemejwe na antimalarial yibasira mitochondriya ya parasite ya Plasmodium.Atovaquone ibuza gutwara electron ikora nk'ikigereranyo cya ubiquinone kugirango ibuze cytochrome b igice cya cytochrome bc1. Iyo ihujwe na proguanil, atovaquone iba ifite umutekano kandi ikora neza kubagore batwite. hamwe nabana.
Artemisinin yakuwe muri Artemisia annua mumwaka wa 1972.Artemisinin nibiyikomokaho harimo artemether, dihydroartemisinin, artemether na artesunate bifite ibikorwa byinshi bya spasitori. ya gametocytes kuva ku bantu kugeza ku mibu.27 Artemisinin n'ibiyikomokaho bigira umumaro mukurwanya chloroquine- na mefloquine birwanya amoko.Birafite umutekano, bikora neza kandi byihuta byihuta byubwoko bwose bwa Plasmodium.Nyamara, artemisinin ntiyakuyeho ubukererwe bwumwijima. parasite.Iyi miti ifite ubuzima bucye bwigihe gito na bioavailable nke, biganisha ku kurwanya ibiyobyabwenge, bigatuma bitagira ingaruka nka monotherapy. Kubwibyo rero, ibikomoka kuri artemisinin birasabwa hamwe nindi miti igabanya ubukana.28
Ingaruka ya antimalarial ya artemisinin irashobora guterwa no kubyara radicals yubusa ituruka kumiraro ya artemisinin endoperoxide yibiraro bya parasite, bityo bikabuza parasite calcium ATPase na proteasome.29,30 Artemether ikoreshwa nka monotherapy. Kwinjira mumanwa byihuse.Bioavailability gukuba kabiri iyo bikozwe imbere yibyo kurya.Igihe cyo kuzenguruka kwa sisitemu, byose hamwe ni hydrolyzed to dihydroartemisinin munda numwijima.
Artesunate ikomoka kuri kimwe cya kabiri cyogukora bitewe ningaruka zihuse za antimalarial, kutagira imiti igabanya ubukana hamwe n’amazi menshi.
Tetracyclines na macrolide ni imiti igabanya ubukana bwa mitiweli ikoreshwa nkubuvuzi bufatika bwo kwineza muri malariya ya falciparum.Doxycycline ikoreshwa kandi muri chemoprophylaxis mu turere turwanya cyane.32 Ubu buryo bukoreshwa mukurwanya imiti igabanya ubukana ni ubu buryo bwo kuvura imiti. ingamba zakoreshejwe kera ukoresheje guhuza neza. Ninde usaba ko artemisinin ishingiye ku buvuzi (ACT) nk'umurongo wa mbere wo kuvura malariya idakomeye.Impamvu ni uko guhuza ibiyobyabwenge bigabanya kurwanya ibiyobyabwenge n'ingaruka.33
ACT irimo ibintu bya artemisinin ikomeye ikuraho parasite byihuse, hamwe nibiyobyabwenge bimaze igihe bikuraho parasite zisigaye kandi bikagabanya ubukana bwa artemisinin. ACTs yasabwe na OMS ni artesunate / amodiaquine, artemether / benzfluorenol, artesunate / mefloquine, artesunate / pyrrolidine piperaquine, Artesunate / sulfadoxine / pyrimethamine, artemether / piperaquine na artemisinin / piperaquine / primaquine.Chloroquine wongeyeho primaquine ikomeza kuba imiti yambere yo kurandura vivax ya Plasmodium.Quinine + ifite tetracycline / ifite igipimo kinini ingaruka kandi zandujwe mubana nabagore batwite34.
Mefloquine, atovaque । 1.
Kugeza ubu imiti igabanya ubukana ishingiye ku itandukaniro riri hagati yinzira nyabagendwa iri hagati yubwoko bwa Plasmodium nubwoko bwayo. Inzira nyamukuru ya parasite ya metabolike, harimo kwangiza heme, synthesis ya fatty, synthesis nucleic, synthesis ya fatty aside, hamwe na stress ya okiside, ni bimwe mubitabo bishya imbuga zo gushushanya ibiyobyabwenge.38,39 Nubwo imiti myinshi igabanya ubukana imaze imyaka itari mike ikoreshwa, kuri ubu ikoreshwa ryayo ni mike kubera kurwanya ibiyobyabwenge. Dukurikije ibitabo, nta miti igabanya ubukana yabonetse ibuza ibiyobyabwenge bizwi.7,40 Muri Ibinyuranye, imiti myinshi ya antimalariya ivumburwa mubikoko muri vivo cyangwa mubushakashatsi bwikitegererezo cya vitro.Niyo mpamvu, uburyo bwo gukora imiti myinshi ya antimalariya ntiburamenyekana.Ikindi kandi, uburyo bwo kurwanya imiti myinshi ya malariya ntibusobanutse.39
Kurwanya Malariya bisaba ingamba zihamye nko kurwanya inzitizi, imiti igabanya ubukana bwa virusi itera virusi, hamwe ninkingo zifatika. Urebye impfu nyinshi n’uburwayi bwa malariya, ibyihutirwa no gukwirakwiza ibiyobyabwenge, kutagira imiti igabanya ubukana bwa virusi itera erythrocyte ndetse n’imibonano mpuzabitsina. , kumenyekanisha imiti mishya igabanya ubukana bwa malariya.Imiti ya Malariya ni ingenzi.parasite.Kugera kuri iyi ntego, ubushakashatsi bwibiyobyabwenge bugomba kwibasira intego nshya, zemewe zo gutandukanya ibibyimba bishya.39,41
Hariho impamvu nyinshi zituma dukenera kumenya intego nshya za metabolike.Bwa mbere, usibye imiti ikomoka kuri atovaquone na artemisinin, imiti myinshi ya antimalariya ntabwo itandukanye na chimique, ishobora gutera kwambukiranya.Icyiciro cya kabiri, bitewe nubwinshi butandukanye. intego za chimiotherapeutic intego, benshi ntibaremezwa.Niba byemejwe, birashobora gutanga ibintu bimwe na bimwe bifite akamaro kandi bifite umutekano.Kumenyekanisha intego nshya zibiyobyabwenge no gushushanya ibice bishya bikora kuri intego nshya birakoreshwa henshi kwisi kugirango bikemuke ibibazo bituruka kukigaragara cyo kurwanya ibiyobyabwenge bihari.40,41 Kubwibyo rero, ubushakashatsi bwibintu bishya bya poroteyine yihariye ya Plasmodium yakoreshejwe mu kumenyekanisha ibiyobyabwenge. Kuva hamenyekana genome ya P. falciparum, intego nyinshi zerekeye ibiyobyabwenge. intervention yagaragaye.Iyi miti ishobora kurwanya antimalarial yibanda kuri metabolite biosynthesis, transport ya membrane na sisitemu yerekana ibimenyetso, hamwe na degogation ya hemoglobine.40,42
Poroteyine yitwa Plasmodium ni enzyme ya catalitiki kandi igenga hose igira uruhare runini mu kubaho kwa parasite ya protozoan n'indwara zitera.Bitera hydrolysis ya peptide.43 Uruhare rwa protease mu gutera indwara ya malariya harimo kwanduza selile / tissue, immunite guhunga, gukora ibikorwa byo gutwika, gutera erythrocyte, gusenya hemoglobine nizindi poroteyine, autophagy, hamwe niterambere rya parasite.44
Indwara ya Malariya (glutamic aspartic aside, cysteine, icyuma, serine na threonine) isezeranya intego yo kuvura kuko ihungabana rya protease gene irinda iyangirika rya hemoglobine hamwe na erythrocyte ya parasite.iterambere.45
Isenyuka rya erythrocytes hamwe nigitero cya merozoite bisaba protease ya malariya. Peptide ya syntetique (GlcA-Val-Leu-Gly-Lys-NHC2H5) ibuza Plasmodium falciparum schizont cysteine ​​protease Pf 68.Bibuza gutera erythrocyte. yerekana ko poroteyine zigira uruhare runini mugutera parasite gutera selile zitukura.Niyo mpamvu, protease ari intego itanga intego yo guteza imbere imiti igabanya ubukana.46
Muri Plasmodium falciparum ibiryo bya vacuole, protease nyinshi za aspartic (plasma protease I, II, III, IV) hamwe na protease ya sisitemu (falcipain-1, falcipain-2 /, falcipain-3) byashyizwe mu bwigunge, Byakoreshejwe mu gutesha agaciro hemoglobine, nkuko bigaragara mu gishushanyo cya 2.
Kwiyongera kwa parasite yumuco P. falciparum hamwe na protease inhibitor leupeptin na E-64 byatumye habaho kwirundanya kwa globine itemewe.Leupeptin ibuza sisitemu na proteine ​​zimwe na zimwe za serine, ariko E-64 irabuza cyane protease za sisitemu.47,48 Nyuma yubushakashatsi. ya parasite hamwe na aspartate protease inhibitor pepstatine, globin ntabwo yegeranije.Ubushakashatsi bwakozwe bwerekanye ko inzitizi ya cystatine itabuza kwangirika kwa globine gusa, ahubwo ikanabuza intambwe yambere yo gusenyuka kwa hemoglobine, nka hemoglobine, gusohora heme kuva globin, no gutanga umusaruro wa heme. .. 48,49 Inzitizi nyinshi za poroteyine ya sisitemu, nka fluoromethyl ketone na vinyl sulfone, ibuza gukura kwa P. falciparum na degra ya hemoglobine.Dation.Mu nyamaswa y’inyamanswa ya malariya, fluoromethyl ketone ibuza ibikorwa bya protease ya P. vinckei kandi ikiza 80% by’indwara ya malariya. ibuza parasite metabolism niterambere.50
Poroteyine za serine zigira uruhare mu guturika kwa schizont hamwe na erythrocyte mu gihe cyubuzima bwa Plasmodium falciparum.Bishobora guhagarikwa na poroteyine nyinshi za serine kandi ni amahitamo meza kuko nta enzyme ya homologique yabantu ihari. Protease inhibitor LK3 yitandukanije na Streptomyces sp.itesha agaciro poroteyine ya malariya.51 Acide ya Maslinic ni pentacyclic triterpenoid isanzwe ibuza gukura kwa parasite kuva murwego rwimpeta kugeza kuri schizont, bityo bikarangiza irekurwa rya merozoite no kubatera.Uruhererekane rukomeye rwa 2-pyrimidine nitrile ya falcipain. 2 .
Fosifinositide ya lipide kinase (PIKs) ni enzymes ziboneka hose za fosifori ya lipide kugirango igabanye ikwirakwizwa, kubaho, gucuruza, hamwe n’ibimenyetso byerekana ibimenyetso. Ibyiciro bya PIK byizwe cyane muri parasite 53 ni fosifinositide 3-kinase (PI3K) na phosphatidylinositol 4-kinase (PI4K). Kubuza iyi misemburo byagaragaye ko ari intego ishobora guteza imbere imiti igabanya ubukana hamwe n’ibikorwa byifuzwa byo gukumira, kuvura no kurandura malariya.54 UCT943, imidazopyrazine (KAF156) na aminopyridine ni icyiciro gishya cy’imiti igabanya ubukana bwa PI. . mu cyiciro cya II cyamavuriro.55,56 MMV048 ni uruhurirane hamwe nibyiza mubikorwa bya vivo byo kurwanya P. cynomolgi kandi birashoboka as kwanduza ibiyobyabwenge.MMV048 kuri ubu arimo gukorerwa ibizamini byo kwa Phase IIa muri Etiyopiya.11
Kugirango imikurire yihuse mumaraso atukura yanduye, ubwoko bwa Plasmodium busaba insimburangingo ihagije kugirango byorohereze metabolisme ikomeye.Niyo mpamvu, parasite itegura erythrocytes yakira itwara abayitwara kabuhariwe itandukanye cyane nabatwara ingirabuzimafatizo mu gufata no gukuraho metabolite.Noneho rero, abatwara nka poroteyine zitwara imiyoboro hamwe ninzira zishobora kwibasirwa kubera uruhare runini mugutwara metabolite, electrolytite nintungamubiri.57 Izi ni umuyoboro wa anion wa Plasmodium (PSAC) hamwe na parasitike vacuolar membrane (PVM), itanga inzira ikwirakwiza yintungamubiri. muri parasite idasanzwe.58
PSAC niyo ntego itanga icyizere cyane kuko iboneka muburyo butandukanye bwintungamubiri (hypoxanthine, cysteine, glutamine, glutamate, isoleucine, methionine, proline, tyrosine, aside pantothenique na choline) kugirango ibone uruhare runini muri parasite yo mu nda.PSACs nta homologiya isobanutse neza. kumenyekanisha imiyoboro ya gen.
Imiterere yamaraso ya Plasmodium falciparum yishingikiriza hafi ya glycolysis kugirango itange ingufu, idafite ububiko bwingufu;ishingiye ku gufata glucose ihoraho. Parasite ihindura pyruvate kugirango yonsa kugirango ikore ATP, isabwa kwigana imbere mumaraso atukura.62 Glucose ijyanwa bwa mbere muri erythrocytes ya parasitike ikomatanyirijwe hamwe na transport ya glucose yakira, GLUT1, muri membrane ya erythrocyte hamwe na parasite iterwa na 'inzira nshya ya permeation' .63 Glucose ijyanwa muri parasite na transport ya Plasmodium falciparum hexose itwara abantu (PFHT) .PFHT ifite ibintu bisanzwe biranga abatwara isukari. GLUT1 ihitamo D-glucose, mugihe PFHT ishobora gutwara D. 3361) ibuza gufata glucose na fructose na PFHT, ariko ntibibuza gutwara hexose na glucose nini y’inyamabere n’abatwara fructose (GLUT1 na 5) .Ikomatanya 3361 yanabujije gufata glucose na P. vivax ya PFHT.Mu bushakashatsi bwabanje, compound 3361 yishe P. falciparum mu muco kandi bigabanya imyororokere ya P. berghei muburyo bwimbeba.65
Guteranya amaraso ya Plasmodium ahanini biterwa na anaerobic glycolysis kugirango ikure kandi ikure.60 Uturemangingo twamaraso dutukura twanduye parasite twinjiza glucose inshuro 100 kurenza uturemangingo tw'amaraso dutukura. uburyo bwa H + butera inkunga mubidukikije.66 Kwohereza ibicuruzwa hanze no gufata glucose nibyingenzi mukubungabunga ingufu, pH idasanzwe, hamwe na parasite osmotic itekanye.Lactate: Kubuza sisitemu ya H + ni intego nshya itanga icyizere cyo guteza imbere imiti mishya.Ibintu bimwe na bimwe, nka MMV007839 na MMV000972, byica amaraso adahuje igitsina P. falciparum parasite mukubuza lactate: H + transport.67
Kimwe nubundi bwoko bwimikorere, selile yamaraso itukura igumana imbere ya Na + imbere.Nyamara, parasite yongerera ubushobozi bwa erythrocyte membrane kandi ikorohereza Na + kwinjira, bigatuma habaho kwiyongera kwa erythrocyte cytoplasmic Na + kurwego rwurwego rudasanzwe.Ibyo, parasite. kwisanga mu bitangazamakuru byo hejuru bya Na + kandi bagomba kwirukana Na + ion muri plasma membrane kugirango bagumane urwego rwa cytoplasme Na + kugirango babeho nubwo bahari mumyanya ndangagitsina.Muri iki gihe, Na + kwinjira muri parasite bigengwa no gukoresha ATPase ya P. abatwara ibintu (PfATP4), ikora nka parasite yambere ya pompe ya Na + -efflux, nkuko bigaragara ku gishushanyo cya 3.68, kubuza uyu mutwara Bizatuma ubwiyongere bwa Na + imbere muri parasite, amaherezo bikazaviramo urupfu malariya parasite. Ibintu byinshi, harimo sipagamine mugice cya 2, (+) - SJ733 mugice cya 1, na KAE609 mugice cya 2, bifite uburyo bwibikorwa byibasira PfATP4.67,69
Igicapo 3. Uburyo bwateganijwe bwa parasite iterwa na PfATP4 na V-V ya H + -PPase mu rupfu rwa erythrocyte yanduye nyuma yo kubuza cipargamin.
Ubwoko bwa plasmodium bugenzura urwego rwa Na + ukoresheje ubwikorezi bwa P bwo mu bwoko bwa P.Butumiza kandi H + binyuze munzira isa.Kugenzura ubwiyongere bwa H + no gukomeza pH idasanzwe ya 7.3, parasite ya malariya ikoresha ubwuzuzanye bwa V-bwoko bwa ATPase kuri kwirukana H + .Gutegura ibiyobyabwenge bishya nintego itanga icyizere.MM2525 ibuza ubwoko bwa V-H + ATPase nkuburyo bwayo bwo gukora muguhitamo mutation hamwe na genome ikurikirana.70,71
Aquaporin-3 (AQP3) ni poroteyine ya aquaglycerol yorohereza urujya n'uruza rw'amazi na glycerol mu ngirangingo z’inyamabere.AQP3 iterwa na hepatocytes y’abantu mu rwego rwo kwandura parasite kandi ifite uruhare runini mu kwigana parasite.AQP3 itanga uburyo bwa glycerol muri P . berghei kandi yoroshya kwigana parasite mugice cya erythrocyte idasanzwe.72 Kugabanuka kwa genetike ya AQP3 byagabanije cyane umutwaro wa parasite mugice cyumwijima wa P. berghei.Ikindi kandi, kuvura hamwe na AQP3 inhibitor auphen byagabanije P. berghei parasitemia muri hepatocytes na P. falciparum parasitemia muri erythrocytes, byerekana ko poroteyine zakira zigira uruhare runini mubuzima butandukanye bwa parasite .73 Igishimishije cyane, ihungabana rya AQP3 mu mbeba za genetique ntabwo ryica, byerekana ko poroteyine yakira ifite intego nshya yo kuvura.Iyi mirimo itwongerera imbaraga. gusobanukirwa imikorere yumwijima yakira kwandura Plasmodium kandi ikagaragaza ubushobozi bwiyi processes nk'imiti igabanya ubukana.71,72
Fosifolipide igira uruhare runini mubuzima bwimbere ya erythrocyte yubuzima bwa Plasmodium falciparum, haba mubice bigize imiterere ya membrane ndetse na molekile igenga imikorere yimisemburo itandukanye. Izi molekile ningirakamaro mukubyara parasite imbere mumasemburo yamaraso atukura. Nyuma yigitero cya erythrocyte, urwego rwa fosifolipide rwiyongera, murirwo fosifatiidiloline ni lipide nini mubice bigize selile ya membrane.Parasite ikomatanya phosphatidylcholine de novo ikoresheje choline nkibibanziriza.Iyi nzira ya de novo ningirakamaro mukuzamuka kwa parasite no kubuza fosifatique. bikaviramo urupfu rwa parasite. imiterere.Ntabwo bivuze ko inshinge imwe yakize purwego rwa arasitemiya.75,76
Fosifokoline cytidyltransferase nintambwe igabanya igipimo muri de novo biosynthesis ya phosphatidylcholine. ibice mu kuvumbura imiti igabanya ubukana hamwe niterambere.78,79
Intambwe yingenzi mu gukwirakwiza amoko ya Plasmodium mubantu bakira ni igabana ryinshi kandi ryihuse rya ADN ya parasite, biterwa no kuboneka kwa metabolite ya ngombwa nka pyrimidine. Muri Plasmodium, nucleotide ya pyrimidine igira uruhare runini muguhuza ADN, fosifolipide na glycoproteine. Sintezike ya nucleotide ikurikira inzira ebyiri nyamukuru: inzira ya salvage n'inzira ya de novo. Yerekana intego ishobora gutanga intego yo guteza imbere imiti igabanya ubukana.80 Ingirabuzimafatizo zabantu zibona pyrimidine mugukiza pyrimidine zimaze gushingwa cyangwa na de novo synthesis.Niba inzira ya de novo biosynthetic ihagaritswe, selile izashingira kumuhanda wa salvage kandi selile ntizipfa. Ariko, kubuza de novo pyrimidine biosynthesis muri parasite bivamo urupfu rwingirabuzimafatizo kuko themalariya parasite ibura inzira ya salvage ya pyrimidine, ituma parasite yibasirwa no kubuzwa na DHODH.81 DSM190 na DSM265 ni inzitizi zangiza za parasite DHODH enzyme, ubu iri mubigeragezo byamavuriro.P218 ni DHODH inhibitor ikora kuri pyrimethamine- imiti irwanya ubu iri mu cyiciro cya 1.KAF156 (Ganaplacide) kuri ubu iri mu cyiciro cya 2b cyamavuriro hamwe na fenylfluorenol.82
Isoprenoide irakenewe kugirango lipide ihindurwe nyuma yo guhinduranya poroteyine no kwigana ibitsina bya Plasmodium falciparum. inzira na 2C-methyl-D-erythritol 4-fosifate (MEP) inzira.Mu binyabuzima byinshi, iyi nzira yombi iratandukanye. Bagiteri na Plasmodium falciparum biterwa rwose ninzira ya MEP, mugihe abantu atari bo.Noneho rero, enzymes muri. Inzira ya MEP irashakishwa nkintego nshya zo kuvura.Plasmodium falciparum 1-deoxy-xylulose-5-fosifate reductoisomerase (pfDxr) itera intambwe igabanya umuvuduko munzira ya MEP, bigatuma iyi misemburo ya parasite iba intego yo guteza imbere imiti igabanya ubukana bwa virusi. .83,84 inhibitori ya PfDXR ibuza Plasmodium falciparum.Plasmodium falciparum ikura kandi ntabwo yangiza umubiri wa selile.PfDXR nintego nshya muriiterambere ryimiti igabanya ubukana.83 Fosmidomycin, MMV019313 na MMV008138 ibuza DOXP reductoisomerase, enzyme yingenzi yinzira ya DOXP idahari mubantu.Kuko kubuza poroteyine kwangiza muri Plasmodium bihagarika imikurire ya parasite idasanzwe.85.
Intungamubiri za poroteyine zigira uruhare runini mubikorwa bitandukanye bya selile harimo gucuruza imitsi, kwanduza ibimenyetso, kugenzura iyerekanwa rya ADN, no kugabana ingirabuzimafatizo.Iyi mpinduka nyuma yubusobanuro yorohereza guhuza poroteyine zo mu nda ibyara kandi byorohereza imikoranire ya poroteyine na poroteyine.Farnesyltransferase itera catalizike. kwimura itsinda rya farnesyl, 15-karubone isoprenoid lipid, kuva kuri farnesyl pyrophosphate kuri C-terminus ya proteyine zirimo motif ya CaaX.Farnesyltransferase nintego nshya itanga icyizere cyo guteza imbere imiti igabanya ubukana kuko kubuza kwica parasite.86
Mbere, ubwihindurize bwo kurwanya parasite na farnesyltransferase inhibitor BMS-388.891 tetrahydroquinoline yerekanaga ihinduka ryimiterere ya poroteyine ya peptide substrate-binding domaine.Mu gutoranya indi tetrahydroquinoline hamwe na BMS-339,941, habonetse ihinduka rya parnesyl pyrophosphate. .Muyindi nyigo, mutation yabonetse muri farnesyltransferase beta subunit ya MMV019066 irwanya P. falciparum. Ubushakashatsi bwakozwe bwerekana ko ihinduka ryimiterere ihindura urufunguzo rwimikorere ya molekile nto hamwe na site ikora ya farnesylation, bikaviramo kurwanya ibiyobyabwenge .87
Imwe mu ntego zitanga ikizere cyo guteza imbere imiti mishya ni uguhagarika P. falciparum ribosome, kimwe nibindi bice byimashini zubuhinduzi zishinzwe sintezamubiri ya poroteyine. Ubwoko bwa plasmodium bufite genome eshatu: nucleus, mitochondria, na acroplasts (biva kuri chloroplasts isigaye). Genome zose zisaba imashini zubuhinduzi gukora.Ibikoresho bya sintezike ya poroteyine bigira uruhare runini mubuvuzi nka antibiyotike nziza.Doxycycline, clindamycin, na azithromycine ifite imiti igabanya ubukana kuko ibuza ribosomes muri parasite mitochondria na aplastoplasts, bigatuma izo ngirabuzimafatizo zidakora.88 Igishimishije, the. P. falciparum ribosome ifata hagati yubwihindurize hagati ya prokaryote na eukaryote, itandukanya cyane na ribosome yumuntu bityo igatanga intego nshya itanga icyizere.Plasmodium falciparum onongation factor 2 (pfEF2) nikintu cya ribosome itera guhinduranya GTP. ya ribosomes hamwe n'akajagarienger RNA kandi ni ngombwa muri synthesis ya protein muri eukaryote.PfEF2 yitaruye nkintego nshya yo guteza imbere imiti igabanya ubukana.87.89
Kubuza intungamubiri za poroteyine Fata ivumburwa rya sordarine, igicuruzwa gisanzwe kibuza guhitamo intungamubiri za poroteyine zo mu bwoko bwa fungal muguhagarika umusemburo wa eukaryotic urambuye 2.Nkuko bimeze, M5717 (yahoze ari DDD107498), ihitamo 80S ribosome ikorana na PfEF2, kuri ubu iri mu cyiciro. Ubushakashatsi 1, kwemeza ubushobozi bwa PfEF2 nkintego nziza kumiti igabanya ubukana.88,90
Ibintu nyamukuru biranga malariya ikabije ni ugukurikirana kwa erythrocytes yanduye parasite, gutwika, no guhagarika microcasculature.Plasmodium falciparum ikoresha heparan sulfate kuko ifata endotelium nizindi selile zamaraso. -Imikoreshereze yibiyobyabwenge igarura umuvuduko wamaraso kandi ikagira ingaruka kumikurire ya parasite.91
Ubushakashatsi bwinshi bwerekanye ko sevuparin, anti-adhesion polysaccharide ikozwe muri heparin, igira ingaruka zo gukuraho antithrombine. kuri N-terminal idasanzwe ya heparan sulfate-ihuza imiterere ya Plasmodium falciparum erythrocyte membrane protein 1, Duffy-binding-nka domaine 1α (DBL1α), kandi ikekwa ko ari ikintu cyingenzi mugukurikirana erythrocytes yanduye.92,93 Imbonerahamwe 2 ibizamini bya kliniki mubyiciro bitandukanye.