Javascript ha joale e koetsoe sebatling sa hau.Likarolo tse ling tsa sebaka sena sa Marang-rang li ke ke tsa sebetsa ha javascript e koetsoe.
Ingolise ka lintlha tsa hau tse ikhethang le sethethefatsi seo u se ratang, 'me re tla tsamaisana le tlhaiso-leseling eo u fanang ka eona le lingoliloeng sebakeng sa rona sa polokelo ea litaba tse pharalletseng mme re u romelle kopi ea PDF hang hang.
Tafere Mulaw Belete Lefapha la Pharmacology, Faculty of Medicine le Health Sciences, Gondar University, Gondar, Ethiopia Lengolo le ngollanang: Tafere Mulaw Belete Tel +251 918045943Email [imeile e sirelelitsoeng] Abstract: Malaria ke bothata bo boholo ba bophelo bo botle ba lefats'e bo bakang lefu le mafu a mangata selemo le selemo Rate .Mekhoa ea phekolo ea fokola 'me e qholotsoa haholo ke ho hlaha ha likokoana-hloko tse hanyetsanang le likokoana-hloko, tse behang tšitiso e kholo taolong ea malaria.Ho thibela maemo a tšohanyetso a bophelo bo botle ba sechaba, litlhare tse thibelang malaria tse nang le tekanyo e le 'ngoe ea phekolo, phekolo e batsi, le mekhoa e mecha ea ts'ebetso. li hlokahala ka potlako.Ntšetso-pele ea meriana e thibelang malaria e ka latela mekhoa e fapaneng, ho tloha ho tokiso ea litlhare tse seng li ntse li le teng ho ea ho moralo oa litlhare tse ncha tse lebisitsoeng ho sepheo se secha.Khatelo-pele ea morao-rao ho baeloji ea likokoana-hloko le ho fumaneha ha mekhoa e fapaneng ea thekenoloji ea genomic e fana ka mefuta e mengata e fapaneng ea lipheo tse ncha. bakeng sa ntshetsopele ya dikalafo tse ntjha.Targ tse ngata tse tshepisangets bakeng sa ho kenella ha lithethefatsi ho senotsoe lilemong tsa morao tjena.Ka lebaka leo, tlhahlobo ena e tsepamisitse maikutlo tsoelo-peleng ea morao-rao ea saense le thekenoloji ho sibolloa le nts'etsopele ea litlhare tsa antimalarial.Liprotheine tse khahlang ka ho fetesisa tsa antimalarial tse ithutoang ho fihlela joale li kenyelletsa proteases, protein kinases, plasmodium sugar. transporter inhibitors, aquaporin 3 inhibitors, choline transport inhibitors, dihydroorotate dehydrogenase inhibitors, pentadiene biosynthesis inhibitor, farnesyltransferase inhibitor le li-enzyme tse amehang ho lipid metabolism le DNA replication.Tlhahlobo ena e akaretsa sepheo se secha sa limolek'hule bakeng sa mantsoe a antimalarial a hanyetsanang le lithethefatsi. , lipakane tse ncha, lithethefatsi tse thibelang malaria, mokhoa oa ho sebetsa, kokoana-hloko ea malaria
Malaria ke lefu le tšoaetsanoang le senyang la likokoana-hloko, haholo-holo Afrika e ka boroa ho Sahara, likarolong tsa Asia le Amerika Boroa.Ho sa tsotellehe boiteko bo bongata, kajeno ke e 'ngoe ea lisosa tse ka sehloohong tsa ho kula le ho shoa haholo ho basali ba bakhachane le bana.Ho latela Mokhatlo oa Lefatše oa Bophelo. Mokhatlo (WHO) tlaleho ea 2018, ho bile le linyeoe tsa malaria tse limilione tse 228 le mafu a 405,000 lefatšeng ka bophara. Hoo e ka bang halofo ea baahi ba lefats'e e kotsing ea malaria, 'me bongata ba linyeoe (93%) le lefu (94%) li etsahala Afrika.About Bakhachane ba limilione tse 125 ba kotsing ea ho tšoaroa ke malaria selemo le selemo, ’me bana ba 272 000 ba ka tlaase ho lilemo tse 5 ba bolaoa ke malaria.1 Malaria e boetse ke sesosa sa bofutsana le tšitiso e khōlō tsoelo-peleng ea moruo, haholo-holo Afrika.2 Mefuta e mehlano e khethiloeng ea malaria. Plasmodium e bakang malaria ho batho ke P. vivax, P. knowlesi, P. ovale, P. malaria le P. falciparum. Har'a tsona, Plasmodium falciparum ke mofuta o bolaeang ka ho fetisisa le o atileng haholo oa Plasmodium.3
Ha ho se na ente e sebetsang hantle, tšebeliso ea phekolo ea meriana e thibelang malaria e ntse e le eona feela tsela ea ho laola le ho thibela lefu la malaria. e 'nile ea tlalehoa hoo e batlang e le lithethefatsi tsohle tse teng tsa antimalarial, ho matlafatsa nts'etsopele ea lithethefatsi tse ncha tsa malaria khahlanong le lipakane tse teng tse tiisitsoeng le ho batla The gametophytic stage of transmission e ka boela ea sebetsa ka ho ata ha asexual ka har'a li-erythrocyte, haholo-holo mefuteng ea likokoana-hloko tse hanyetsanang.6 Li-enzyme tse ngata, ion likanale, lipalangoang, limolek'hule tse sebetsanang le tlhaselo ea lisele tse khubelu tsa mali (RBC), le limolek'hule tse ikarabellang bakeng sa khatello ea kelello ea parasite oxidative, lipid metabolism, le ho senyeha ha hemoglobin ke senotlolo sa nts'etsopele ea meriana e thibelang malaria khahlanong le malaria e fetohang ka potlako E tšepisang lipakane tse ncha tsa protozoa.7
Monyetla oa litlhare tse ncha tse thibelang malaria li ahloloa ka litlhoko tse 'maloa: mokhoa o mocha oa ts'ebetso, ha ho na khanyetso ea meriana ea hona joale ea antimalarial, phekolo ea lethal dose e le' ngoe, katleho khahlanong le sethaleng sa mali a asexual le li-gametocyte tse ikarabellang bakeng sa phetiso. lithethefatsi tse thibelang malaria li lokela ho ba le matla a ho thibela tšoaetso (chemoprotectants) le ho hloekisa sebete sa P. vivax hypnotics (anti-relapse agents).8
Ho sibolloa ha lithethefatsi tse tloaelehileng ho latela mekhoa e mengata ea ho khetholla setlhare se secha se thibelang malaria ho loantša malaria. Ena ke ho ntlafatsa mekhoa ea litlhare tse teng hona joale, ho lokisa litlhare tse thibelang malaria, ho hlahloba lihlahisoa tsa tlhaho, ho khetholla litlhare tse thibelang malaria, ho sebelisa mekhoa ea phekolo ea lik'hemik'hale le ho hlahisa meriana. bakeng sa ditshebediso tse ding.8,9
Ho phaella mekhoeng ea khale ea ho sibolla lithethefatsi e sebelisetsoang ho khetholla litlhare tse ncha tse thibelang malaria, tsebo ea baeloji ea lisele tsa Plasmodium le genome e bontšitsoe e le sesebelisoa se matla sa ho sibolla mekhoa ea ho hanyetsa lithethefatsi, 'me e na le monyetla oa ho rala lithethefatsi tse nang le ts'ebetso e phahameng ea antimalarial le antimalarial.Monyetla o moholo oa litlhare tse ncha.Ho loants'a tšitiso ea tšoaetso ea malaria hang le ka ho sa feleng.10 Tlhahlobo ea liphatsa tsa lefutso ea Plasmodium falciparum e hlokometse liphatsa tsa lefutso tse 2680 tsa bohlokoa bakeng sa kholo ea phallo ea mali, ka tsela eo ho khetholla mekhoa ea bohlokoa ea lisele tse bohlokoa bakeng sa ho hlahisa meriana e mecha.10,11 New. litlhare li lokela: (i) ho sebetsana le ho hanyetsa lithethefatsi, (ii) ho sebetsa ka potlako, (iii) ho sireletseha, haholo-holo ho bana le ho bakhachane, le (iv) ho phekola malaria ka tekanyo e le ’ngoe. Litšobotsi tsena kaofela. Sepheo sa tlhahlobo ena ke ho fana ka maikutlo a lipakane tse ncha tsa phekolo ea likokoana-hloko tsa malaria, tse ntseng li ithutoa ke lik'hamphani tse 'maloa, e le hore babali ba ka tsebisoa ka mosebetsi o fetileng.
Hona joale, boholo ba lithethefatsi tse thibelang malaria li lebisa sethaleng sa asexual sa tšoaetso ea malaria e bakang lefu la matšoao.Sethala sa pele ho erythrocytic (sebete) se ntse se sa ratehe hobane ha ho na matšoao a kliniki a hlahisoang.Lithethefatsi tse thibelang malaria li bontša khetho e kholo ea karolo (sheba setšoantšo sa 1) .Kalafo ea Malaria e thehiloeng ho eona. lihlahisoa tsa tlhaho, li-semi-synthetic le metsoako ea maiketsetso e entsoeng ho tloha lilemong tsa bo-1940. 13 Lithethefatsi tse teng tse thibelang malaria li oela likarolong tse tharo tse pharaletseng: li-quinoline derivatives, antifolates le artemisinin derivatives. Ka hona, e le hore e atlehe khahlanong le tšoaetso ea malaria, hangata metsoako ea lithethefatsi e sebelisoa ka nako e le 'ngoe.Quinoline ke moriana o thibelang malaria o sebelisoang ka ho fetisisa bakeng sa ho phekola malaria. ho phekola maloetse lekholong la bo17 la lilemo. Ho tloha bohareng ba lilemo tsa bo-1800 ho isa lilemong tsa bo-1940, quirobong e ne e le phekolo e tloaelehileng ea malaria.14 Ho phaella ho chefo, ho hlaha ha mefuta e hananang le meriana ea P. falciparum ho fokolitse tšebeliso ea quinine ea phekolo. lithethefatsi tsa bobeli ho khutsufatsa nako ea phekolo le ho fokotsa litla-morao.15,16
Setšoantšo sa 1 The life cycle of Plasmodium in people.Mehato le mefuta ea likokoana-hloko moo mefuta e fapaneng ea litlhare tse thibelang malaria e sebetsang.
Ka 1925, bafuputsi ba Majeremane ba ile ba sibolla sethethefatsi sa pele sa antimalarial, pamaquin, ka ho fetola methylene blue.Pamaquin e na le ts'ebetso e fokolang le chefo 'me e ke ke ea sebelisoa ho phekola malaria. derivative ea methylene blue e sebelisoang ho phekola malaria nakong ea Ntoa ea II ea Lefatše.17
Chloroquine e entsoe nakong ea Ntoa ea II ea Lefatše ho phekola malaria.Chloroquine ke setlhare se khethetsoeng ho phekola malaria ka lebaka la ho sebetsa ha sona, polokeho le theko e tlase.Empa tšebeliso ea eona e sa utloahaleng kapele e ile ea lebisa ho hlaheng ha mefuta ea P. falciparum e hanyetsanang le chloroquine. 18 Primaquine e sebelisoa ka mokhoa oa phekolo ho phekola ho khutlela morao Plasmodium vivax e bakoang ke hypnosis.Primaquine ke gameticidal e matla khahlanong le Plasmodium falciparum.Primaquine e baka haemolytic anemia ho bakuli ba nang le khaello ea glucose-6-phosphate dehydrogenase (G6PD). -P.Tiro ya letsatsi le letsatsi.19
Metsoako e mecha ea quinoline e ile ea etsoa, e leng se ileng sa fella ka lithethefatsi tse ncha tse kang piperaquine le amodiaquine. Kamora ho hlaha ha chloroquine resistance, amodiaquine, analoge ea chloroquine e nketsoeng sebaka ke phenyl, e ile ea bontša tšebetso e ntle haholo khahlano le mefuta e hanyetsanang le chloroquine ea Plasmoyrrm President isPlasmodium ispril setlhare sa antimalarial sa motheo se entsoeng Chaena ka 1970. Se sebetsa khahlanong le mefuta e hanyetsanang le lithethefatsi ea P. falciparum, P. vivax, P. malaria le P. ovale.Pyronadrine e se e fumaneha e le ACT le artesunate, e bontšitseng katleho e babatsehang khahlanong le bohle. likokoana-hloko tsa malaria.21 Mefloquine e ile ea hlahisoa bohareng ba lilemo tsa bo-1980 'me hona joale e buelloa bakeng sa chemoprevention ea malaria e bakoang ke mefuta eohle ea mefuta, ho akarelletsa le mefuta e hanyetsanang le chloroquine.Leha ho le joalo, tšebeliso ea eona e amahanngoa le litla-morao tse ling le ho hanyetsa lithethefatsi.22 sebetsa haholo-holo sethaleng sa mali sa likokoana-hloko, empa lithethefatsi tse ling tse thibelang malaria li sebetsa sethaleng sa sebete.Meriana ena e thibela ka ho etsa complex le heme ka li-vacuoles tsa lijo tsa likokoana-hloko.Ka hona, polymerization ea heme e koetsoe.Ka lebaka leo, heme e lokolloa nakong ea ho senyeha ha hemoglobin e bokellana ho ea maemong a chefo, e bolaea likokoana-hloko ka litšila tse chefo.
Antifolates ke lithethefatsi tse thibelang malaria tse thibelang motsoako oa folic acid, e leng ntho ea bohlokoa bakeng sa motsoako oa li-nucleotides le amino acid. (PABA), e leng karolo ea folic acid.Ba thibela dihydrofolate synthesis ka ho thibela dihydrofolate synthase, e leng enzyme ea bohlokoa ho nucleic acid biosynthesis.mashome a mabeli a metso e mene.
Pyrimethamine le proguanil ke lithethefatsi tsa schizont antimalarial tse sebetsang ka mokhoa oa asexual oa mefuta ea Plasmodium.Lithethefatsi tsena li thibela enzyme dihydrofolate reductase (DHFR), e thibelang ho fokotseha ha dihydrofolate ho tetrahydrofolate, e leng ea bohlokoa bakeng sa biosynthesis ea amino acid le nucleic acid. Proguanil is a prodrug metabolized to cyclic guanidine.Proguanil e ne e le moriana oa pele oa antifolate o sebelisoang ho phekola malaria.Lebaka ke hore e senya lisele tse khubelu tsa mali pele likokoana-hloko li li hlasela nakong ea ho kena maling.Hape, proguanil ke ntho e sireletsehileng. lithethefatsi.Pyrimethamine e sebelisoa haholo-holo le lithethefatsi tse ling tse sebetsang ka potlako.Leha ho le joalo, tšebeliso ea eona e fokotsehile ka lebaka la ho hanyetsa lithethefatsi.24,25
Atovaquone ke sethethefatsi sa pele se amohetsoeng sa malaria se lebisitseng mitochondria ea likokoana-hloko tsa Plasmodium.Atovaquone e thibela lipalangoang tsa elektronike ka ho sebetsa e le analoge ea ubiquinone ho thibela karolo ea cytochrome b ea cytochrome bc1 complex.Ha e kopantsoe le proguanil, atovaquone e bolokehile ebile e sebetsa ho bakhachane. le bana.Atovaquone e sebetsa khahlano le mokhahlelo oa thobalano oa kokoana-hloko ea kokoana-hloko le monoang.Ka hona, e thibela phetiso ea malaria ho tloha ho menoang ho ea ho batho.Motsoako o tsitsitseng le proguanil o entsoeng tlas'a lebitso la khoebo Malarone.24,26
Artemisinin e ntšitsoe ho Artemisia annua ka 1972. Artemisinin le lihlahisoa tsa eona tse kenyelletsang artemether, dihydroartemisinin, artemether le artesunate li na le ts'ebetso e pharaletseng. ea li-gametocyte ho tloha ho batho ho ea ho menoang.27 Artemisinin le lihlahisoa tsa eona li sebetsa khahlanong le mefuta e hanyetsanang le chloroquine le mefloquine. Li bolokehile, li sebetsa hantle ebile li sebetsa ka potlako khahlanong le mefuta eohle ea Plasmodium. Lithethefatsi tsena li na le bophelo bo bokhutšoane ba halofo le bioavailability e fokolang, e leng se lebisang ho hanyetsanang le lithethefatsi, ho etsa hore li se ke tsa sebetsa e le monotherapy.
Phello ea antimalarial ea artemisinin e ka 'na ea bakoa ke ho hlahisa li-radicals tsa mahala tse bakoang ke ho petsoha ha marokho a artemisinin endoperoxide ho li-vesicles tsa lijo tsa likokoana-hloko, kahoo li thibela likokoana-hloko tsa calcium ATPase le proteasome.29,30 Artemether e sebelisoa e le monotherapy.Fast oral absorption. e imena habeli ha e tsamaisoa ka pel'a lijo.Hang ha e le tsamaisong ea potoloho ea mali, artemether e kenngoa ka hydrolyzed ho dihydroartemisinin ka maleng le sebeteng.
Artesunate ke semi-synthetic derivative ka lebaka la phello ea eona e potlakileng ea ho thibela malaria, ho hloka matla a ho hanyetsa lithethefatsi le ho qhibiliha ho hoholo ha metsi.E khothalletsoa e le moriana oa pele bakeng sa malaria e matla.31
Tetracyclines le macrolides ke litlhare tse thibelang malaria tse sebetsang butle tse sebelisoang e le adjunctive therapy to quinine in falciparum malaria.Doxycycline e boetse e sebelisoa bakeng sa chemoprophylaxis libakeng tse nang le khanyetso e phahameng.32 Leano la hajoale le sebelisetsoang ho loantša ho hanana le lithethefatsi tse thibelang malaria ke tšebeliso ea phekolo ea metsoako ea meriana. leqheka le 'nile la sebelisoa nakong e fetileng ka ho sebelisa metsoako e tsitsitseng.WHO e khothaletsa artemisinin-based combination therapy (ACT) e le mokhoa oa pele oa phekolo bakeng sa malaria e sa rarahanang ea falciparum.Lebaka ke hore motsoako oa meriana o fokotsa ho hanyetsa meriana le litla-morao.33
ACT e na le karolo e matla ea artemisinin e tlosang likokoana-hloko ka potlako, le sethethefatsi sa nako e telele se felisang likokoana-hloko tse setseng le ho fokotsa ho hanyetsa ha artemisinin. LIKETSO tse khothalelitsoeng ke WHO ke artesunate/amodiaquine, artemether/ benzfluorenol, artesunate/mefloquine, artesunate/pyrroartelidine piperaquine, Artesunate/sulfadoxine/pyrimethamine, artemether/piperaquine le artemisinin/piperaquine/primaquine.Chloroquine plus primaquine e ntse e le sethethefatsi sa pele sa pheliso ea Plasmodium vivax.Quinine + tetracycline/doxycycline e na le sekhahla se phahameng sa kalafo, empa se na le litlamorao tse mpe haholo. liphello 'me e contraindicated ho bana le bakhachane34.
Mefloquine, atovaquone/proguanil, kapa doxycycline li khothaletsoa ho li-chemoprevention regimens bakeng sa baeti ba tsoang libakeng tse sa tloaelehang ho isa libakeng tse sa tloaelehang.35 Ho buelloa kalafo ea nakoana ea thibelo lihlopheng tse kotsing e kholo, ho kenyeletsoa sulfadoxine/pyrimethamine nakong ea bokhachane le amodiaquine/sulfadoxine-pyrimethamine e le nako ea selemo. .36 Halofantrine ha e tšoanelehe bakeng sa tšebeliso ea phekolo ka lebaka la cardiotoxicity.Dapsone, mepalyline, amodiaquine, le sulfonamides li ile tsa tlosoa tšebelisong ea phekolo ka lebaka la litla-morao tsa tsona.36,37 Lithethefatsi tse ling tse tsebahalang tse thibelang malaria le litla-morao tsa tsona li thathamisitsoe ho Lethathamo. 1.
Lithethefatsi tse teng hona joale tsa antimalarial li ipapisitse le phapang ea litsela tse kholo tsa metabolism lipakeng tsa mefuta ea Plasmodium le mefuta ea eona.Mekhoa e meholo ea metabolic ea kokoana-hloko, ho kenyelletsa le heme detoxification, fatty acid synthesis, nucleic acid synthesis, fatty acid synthesis, le oxidative stress, ke tse ling tsa buka. libaka tsa moralo oa lithethefatsi.38,39 Le hoja boholo ba lithethefatsi tse thibelang malaria li 'nile tsa sebelisoa ka lilemo tse' maloa, tšebeliso ea tsona hona joale e lekanyelitsoe ka lebaka la ho hanyetsa lithethefatsi. ho fapana, litlhare tse ngata tse thibelang malaria li fumanoa liphuputsong tsa mohlala oa liphoofolo tsa vivo kapa in vitro.Ka lebaka leo, mokhoa oa liketso tsa lithethefatsi tse ngata tse thibelang malaria o ntse o sa tsejoe hantle.Ho feta moo, mekhoa ea ho hanyetsa lithethefatsi tse ngata tse thibelang malaria ha e hlake.39
Taolo ea malaria e hloka mekhoa e kopanetsoeng e kang ho laola likokoana-hloko, litlhare tse thibelang malaria tse sebetsang hantle le tse sireletsehileng, le liente tse sebetsang hantle. Ha ho nahanoa ka lefu le phahameng la malaria, maemo a tšohanyetso le ho ata ha ho hanyetsa lithethefatsi, ho se sebetse ha lithethefatsi tse seng li ntse li le teng tse thibelang malaria khahlanong le mekhahlelo e seng ea erythrocyte le ea thobalano. , ho tsebahatsa meriana e mecha e thibelang malaria ka ho utloisisa mekhoa ea motheo ea metabolic ea malaria.Meriana ea malaria e bohlokoa.likokoana-hloko.Ho finyella sepheo sena, lipatlisiso tsa lithethefatsi li lokela ho shebana le lipakane tse ncha, tse netefalitsoeng ho arola metsoako e mecha ea loto.39,41
Ho na le mabaka a 'maloa a tlhokahalo ea ho khetholla lipakane tse ncha tsa metabolism.Pele, ntle le lithethefatsi tse nkiloeng ho atovaquone le artemisinin, meriana e mengata ea antimalarial ha e fapane ka lik'hemik'hale, e leng se ka lebisang ho hanyetsanang. putative chemotherapeutic targets, tse ngata ha li so netefatsoe.Haeba e netefalitsoe, e ka fana ka metsoako e meng e sebetsang hantle le e bolokehileng.Tlhahiso ea lipheo tse ncha tsa lithethefatsi le moralo oa metsoako e mecha e sebetsang ho latela lipheo tse ncha li sebelisoa haholo lefatšeng ka bophara kajeno ho sebetsana le tsona. mathata a bakoang ke ho hlaha ha ho hanyetsa lithethefatsi tse seng li ntse li le teng.40,41 Ka hona, thuto ea novel target target protein-specific inhibitors ea Plasmodium e sebelisitsoe bakeng sa ho tsebahatsa sepheo sa lithethefatsi. ho hlahile ho kenella.Lithethefatsi tsena tse ka 'nang tsa e-ba le malaria li lebisa tlhokomelo ea bohlokoa ea metabolite biosynthesis, lipalangoang tsa membrane le mekhoa ea lipontšo, le mekhoa ea ho senyeha ha hemoglobin.40,42
Plasmodium protease is a ubiquitous catalytic and regulatory enzyme e phethang karolo ea bohlokoa ho pholoheng ha likokoana-hloko tsa protozoan le mafu ao li a bakang.E etsa hore ho be le hydrolysis ea peptide bond.43 Mesebetsi ea li-protease ho lefu la malaria pathogenesis e kenyelletsa ho kenella ha lisele / lisele, ho itšireletsa mafung. ho qoba, ho kenya ts'ebetsong ea ho ruruha, tlhaselo ea erythrocyte, ho senyeha ha hemoglobin le liprotheine tse ling, autophagy, le tsoelo-pele ea likokoana-hloko.44
Malaria proteases (glutamic aspartic acid, cysteine, metal, serine le threonine) li ts'episa lipheo tsa kalafo hobane ho senyeha ha lefutso la malaria protease ho thibela ho senyeha ha hemoglobin le boemo ba erythrocyte ea kokoana-hloko.ntshetsopele.45
Ho senyeha ha li-erythrocyte le tlhaselo e latelang ea merozoite ho hloka malaria protease. Peptide ea maiketsetso (GlcA-Val-Leu-Gly-Lys-NHC2H5) e thibela Plasmodium falciparum schizont cysteine protease Pf 68. e fana ka maikutlo a hore li-protease li phetha karolo ea bohlokoa tlhaselong ea kokoana-hloko ea lisele tse khubelu tsa mali.
Ho li-vacuoles tsa lijo tsa Plasmodium falciparum, li-aspartic proteases tse 'maloa (plasma proteases I, II, III, IV) le cysteine proteases (falcipain-1, falcipain-2/, falcipain-3) li khethiloe, li sebelisoa ho theola hemoglobin, joalokaha ho bontšitsoe. ho Setšoantšo sa 2.
Ho kenyeletsoa ha likokoana-hloko tsa P. falciparum tse nang le protease inhibitors leupeptin le E-64 ho ile ha fella ka ho bokellana ha globin e sa tsitsang. ea likokoana-hloko tse nang le aspartate protease inhibitor pepstatin, globin ha ea ka ea bokellana. .49 Liphetho tsena li fana ka maikutlo a hore li-cysteine protease lia hlokahala bakeng sa mohato oa pele.Mehato ea ho senyeha ha hemoglobin ka Plasmodium falciparum.Both E-64 le pepstatin synergistically block P. falciparum development.Leha ho le joalo, ke E-64 feela e ileng ea thibela globin hydrolysis. 48,49 Li-cysteine protease inhibitors tse 'maloa, tse kang fluoromethyl ketone le vinyl sulfone, li thibela kholo ea P. falciparum le hemoglobin degra.dation.Mohlala oa liphoofolo oa malaria, fluoromethyl ketone e thibela ts'ebetso ea P. vinckei protease mme e phekola 80% ea mafu a malaria a murine. Ka hona, protease inhibitors ke batho ba tšepisang meriana e thibelang malaria. tse thibelang likokoana-hloko metabolism le tsoelo-pele.50
Li-protease tsa serine li ameha ka ho phatloha ha schizont le ho tsosolosoa ha erythrocyte nakong ea potoloho ea bophelo ea Plasmodium falciparum.E ka thibeloa ke li-serine protease inhibitors tse ngata 'me ke khetho e ntle ka ho fetisisa kaha ha ho na motho ea nang le enzyme homolog e fumanehang.The protease inhibitor LK3 e arohaneng le Streptomyces sp.degrades the malaria serine protease.51 Maslinic acid ke pentacyclic triterpenoid ea tlhaho e thibelang ho hōla ha likokoana-hloko ho tloha sethaleng sa ring ho ea sethaleng sa schizont, kahoo e felisa ho lokolloa ha merozoite le tlhaselo ea bona. -2 le falcipain-3.52 statins le inhibition ea plasma proteases ka allophenostatin-based inhibitors thibela ho senyeha ha hemoglobin le ho bolaea likokoana-hloko. Ho na le li-blockers tse ngata tsa cysteine protease tse fumanehang, ho akarelletsa Epoxomicin, lactacystin, MG132, WEHI-8416, WEHI-8416, WEHI-8416 le WEHI-9mostatin. .
Phosphoinositide lipid kinases (PIKs) ke li-enzyme tse fumanehang hohle tse phosphorylate lipids ho laola ho ata, ho phela, ho rekisa, le ho bonts'a matšoao a intracellular.Lihlopha tsa PIK tse ithutoang ka ho fetisisa ho likokoana-hloko tsa 53 ke phosphoinositide 3-kinase (PI3K) le phostophatidylididyli44KIPINOSIDIDIDIDIDIY 4. Thibelo ea li-enzyme tsena e khethiloe e le sepheo se ka 'nang sa e-ba teng bakeng sa nts'etsopele ea lithethefatsi tse thibelang malaria tse nang le litlaleho tsa ts'ebetso tse lakatsehang bakeng sa thibelo, phekolo le ho felisa malaria.54 UCT943, imidazopyrazine (KAF156) le aminopyridines ke sehlopha se secha sa metsoako ea antimalarial e lebisitseng PI. 4 litekong tsa meriana tsa Phase II.55,56 MMV048 ke motsoako o nang le ts'ebetso e ntle ea vivo prophylactic khahlanong le P. cynomolgi le e ka bang teng.MMV048 e ntse e etsa liteko tsa bongaka tsa Phase IIa Ethiopia.11
Bakeng sa khōlo e potlakileng ea lisele tse khubelu tsa mali tse nang le tšoaetso, mefuta ea Plasmodium e hloka li-substrates tse lekaneng ho tsamaisa metabolism ea tsona e matla. liprotheine tsa li-carrier le li-channel ke lipheo tse ka 'nang tsa e-ba teng ka lebaka la mesebetsi ea tsona ea bohlokoa ea ho tsamaisa metabolite, electrolyte le limatlafatsi.57 Tsena ke Plasmodium surface anion channel (PSAC) le parasitic vacuolar membrane (PVM), e fanang ka tsela e tsoelang pele ea ho jala limatlafatsi. ho kena dipharasaeteng tse intracellular.58
PSAC ke sepheo se tšepisang ka ho fetisisa hobane se fumanoa mefuteng e fapaneng ea limatlafatsi (hypoxanthine, cysteine, glutamine, glutamate, isoleucine, methionine, proline, tyrosine, pantothenic acid le choline) ho fumana likarolo tsa bohlokoa ho likokoana-hloko tsa intracellular.PSACs ha e na homology e hlakileng. ho liphatsa tsa lefutso tse tsebahalang tsa mocha.58,59 Phloridizin, dantrolene, furosemide, le niflunomide ke li-anion transporter blockers tse matla.Lithethefatsi tse kang glyburide, meglitinide, le tolbutamide li thibela ho kena ha choline liseleng tse khubelu tsa mali tse nang le likokoana-hloko.60,61
Mofuta oa mali oa Plasmodium falciparum o itšetlehile hoo e ka bang ka ho feletseng ho glycolysis bakeng sa tlhahiso ea matla, e se nang polokelo ea matla;e itšetlehile ka ho kenngoa ha glucose kamehla.Sekokoanyana se fetola pyruvate ho lactate ho hlahisa ATP, e hlokahalang bakeng sa ho ikatisa ka har'a lisele tse khubelu tsa mali. the erythrocyte membrane le 'new permeation pathway' e bakoang ke likokoana-hloko.63 Glucose e isoa likokoana-hloko ke Plasmodium falciparum hexose transporter (PFHT) .PFHT e na le litšobotsi tse tloaelehileng tsa ho tsamaisa tsoekere.GLUT1 e khetha D-glucose, ha PFHT e khona ho tsamaisa D-glucose le D-fructose. Ka hona, liphapang pakeng tsa GLUT1 le PFHT li sebelisana le li-substrates li fana ka maikutlo a hore thibelo e khethehileng ea PFHT ke sepheo se secha se tšepisang bakeng sa nts'etsopele ea litlhare tse thibelang malaria.64 Motsoako o molelele oa O-3-hexose (motsoako). 3361) e thibela ho kenngoa ha tsoekere le fructose ka PFHT, empa ha e thibele lipalangoang tsa hexose ka li-transporter tse kholo tsa mammalian le fructose (GLUT1 le 5) .361 e ile ea boela ea thibela ho kenngoa ha tsoekere ka P. vivax ea PFHT.Lithutong tse fetileng, motsoako oa 3361 o bolaile P. falciparum moetlong le ho fokotsa tlhahiso ea P. berghei mefuteng ea mouse.65
Sehlopha sa mali sa Plasmodium se itšetlehile haholo ka anaerobic glycolysis bakeng sa khōlo le tsoelo-pele. mochine oa symporter oa H+ sebakeng sa ka ntle.66 Lactate ea ho romela le ho kenngoa ha tsoekere ke tsa bohlokoa bakeng sa ho boloka litlhoko tsa matla, pH ea intracellular, le parasite osmotic stability.Lactate:H+ symporter system inhibition ke sepheo se secha se tšepisang bakeng sa nts'etsopele ea lithethefatsi tse ncha.Metsoako e mengata, joalo ka MMV007839 le MMV000972, e bolaea likokoana-hloko tsa asexual blood-stage P. falciparum ka ho thibela lactate:H+ transporter.67
Joaloka mefuta e meng ea lisele, lisele tse khubelu tsa mali li boloka maemo a tlaase a Na + ka hare. Leha ho le joalo, likokoana-hloko li eketsa ho khoneha ha lesela la erythrocyte le ho nolofatsa ho kena ha Na +, e leng se lebisang ho eketseheng ha mahloriso a erythrocyte cytoplasmic Na + ho ea boemong ba extracellular medium.Ka hona, likokoana-hloko. ba iphumana ba le mecheng ea litaba ea Na + e phahameng 'me ba tlameha ho leleka li-ion tsa Na + ho tloha lera la bona la plasma ho boloka maemo a tlaase a cytoplasmic Na + e le hore ba phele ho sa tsotellehe ho ba teng ha bona libakeng tsa intracellular. transporter (PfATP4), e sebetsang e le mokhoa oa mantlha oa pompo ea Na+ -efflux, joalo ka ha ho bonts'itsoe ho Setšoantšo sa 3.68, e thibelang sepalangoang sena E tla lebisa ho eketseha ha palo ea Na+ ka har'a likokoana-hloko, e tla qetella e lebisa lefung la parasite ea malaria.Metsoako e mengata, ho kenyeletsoa sipagamin mokhahlelong oa 2, (+)-SJ733 mohatong oa 1, le KAE609 mohatong oa 2, li na le mokhoa oa ts'ebetso o lebisitseng PfATP4.67,69
Setšoantšo sa 3. Mokhoa o hlophisitsoeng oa PfATP4 e entsoeng ke likokoana-hloko le V-mofuta oa H + -ATPase ka lefu la erythrocyte le nang le tšoaetso ka mor'a ho thibela cipargamin.
Mefuta ea Plasmodium e laola maemo a eona a Na+ ka ho sebelisa P-type ATPase transporter.E boetse e kenya H+ ka tsela e ts'oanang.Ho laola khatello e ntseng e eketseha ea H+ le ho boloka pH ea intracellular ea 7.3, parasite ea malaria e sebelisa sepalangoang sa V-type ATPase se tlatsetsang leleka H+.Ho hlahisa sethethefatsi se secha ke sepheo se tšepisang.MMV253 e thibela V-mofuta oa H+ ATPase e le mokhoa oa eona oa ts'ebetso ka khetho ea phetoho le tatellano ea liphatsa tsa lefutso.70,71
Aquaporin-3 (AQP3) ke protheine ea aquaglycerol channel e thusang ho tsamaea ha metsi le glycerol liseleng tsa mammalian.AQP3 e kenngoa ho hepatocyte ea batho ho arabela tšoaetso ea likokoana-hloko 'me e na le karolo ea bohlokoa ho ikatisang likokoana-hloko.AQP3 e fana ka phihlelo ea glycerol ho P berghei le ho thusa ho ikatisa ha kokoana-hloko sebakeng sa asexual erythrocyte.72 Ho fokotseha ha liphatsa tsa lefutso tsa AQP3 haholo ho hatelletse moroalo oa likokoana-hloko sebakeng sa sebete sa P. berghei. falciparum parasitemia in erythrocytes, e fana ka maikutlo a hore liprotheine tse amohelang li phetha karolo ea bohlokoa likarolong tse fapaneng tsa bophelo ba likokoana-hloko .73 Ho makatsang ka ho fetisisa, ho senyeha ha AQP3 ho litoeba tsa lefutso ha ho bolaee, ho fana ka maikutlo a hore protheine e amohelang e na le sepheo se secha sa phekolo. kutloisiso ea lits'ebetso tsa sebete tse anngoeng ke ts'oaetso ea Plasmodium mme e totobatsa bokhoni ba processes e le lithethefatsi tse thibelang malaria nakong e tlang.71,72
Phospholipids e phetha karolo ea bohlokoa bophelong ba intra-erythrocyte ea Plasmodium falciparum, ka bobeli e le likarolo tsa sebopeho sa lera le limolek'hule tsa taolo tse laolang mesebetsi ea li-enzyme tse fapaneng. phospholipids ea eketseha, eo phosphatidylcholine e leng eona lipid e ka sehloohong likarolong tsa tsona tsa lisele tsa lisele. Likokoana-hloko li kopanya phosphatidylcholine de novo ka ho sebelisa choline e le selelekela. ho fella ka lefu la likokoana-hloko.74 Albitiazolium, sethethefatsi se keneng litekong tsa Mokhahlelo oa II, se sebetsa haholo-holo ka ho thibela ho tsamaisoa ha choline ka har'a likokoana-hloko.Albitiazolium e bokella ho fihlela makhetlo a 1000 ka Plasmodium 'me e thibela ho hōla ha likokoana-hloko ntle le ho khutlela morao.E sebetsa ka thata ka matla. maemo.Habohlokoa, ente e le 'ngoe e ile ea phekola high pmaemo a arasitemia.75,76
Phosphocholine cytidyltransferase ke mohato o fokotsang sekhahla ho de novo biosynthesis ea phosphatidylcholine.77 The diquaternary ammonium compound G25 le dicationic compound T3 inhibit phosphatidylcholine synthesis in parasites.G25 ke 1000-folds less toxic drug lead the mammalian cell line. metsoako ea ho sibolla le ntshetsopele ea lithethefatsi tse thibelang malaria.78,79
Mohato o ka sehloohong oa ho ata ha mefuta ea Plasmodium ho batho ba bangata ke karohano e pharaletseng le e potlakileng ea DNA ea likokoana-hloko, e itšetlehileng ka ho fumaneha ha metabolite ea bohlokoa e kang pyrimidines. glycoproteins.Nucleotide synthesis e latela litsela tse peli tse ka sehloohong: tsela ea salvage le tsela ea de novo.Dihydroorotate dehydrogenase (DHODH) ke enzyme ea bohlokoa e etsang hore oxidation ea dihydroorotate e orotate, mohato oa ho fokotsa lebelo ho de novo pyrimidine synthesis, DHODH ka lebaka leo. e emela sepheo se ka 'nang sa tšepisa bakeng sa nts'etsopele ea lithethefatsi tse thibelang malaria.80 Lisele tsa batho li fumana pyrimidines ka ho pholosa li-pyrimidine tse seng li ntse li entsoe kapa ka de novo synthesis.Haeba tsela ea de novo biosynthetic e thibetsoe, sele e tla itšetleha ka tsela ea pholoso 'me sele e ke ke ea shoa. Leha ho le joalo, ho thibela de novo pyrimidine biosynthesis ho likokoana-hloko ho fella ka lefu la lisele tsena hobaneparasite ea malaria e haelloa ke tsela ea pyrimidine salvage, e etsang hore likokoana-hloko li be kotsing ea ho thibeloa ke DHODH.81 DSM190 le DSM265 ke li-inhibitors tse khethang tsa enzyme ea DHODH, eo hajoale e leng litekong tsa bongaka tsa Mokhahlelo oa 2. P218 ke inhibitor ea DHODH e sebetsang khahlanong le pyrimethamine- kaofela. mefuta e hanyetsanang hona joale e Mokhahlelong oa 1.KAF156 (Ganaplacide) hajoale e tekong ea bongaka ea Phase 2b ka phenylfluorenol.82
Li-Isoprenoids lia hlokahala bakeng sa phetoho ea lipid ea morao-rao ea liprotheine le ho pheta-pheta ha asexual ea Plasmodium falciparum.Isoprenoids li entsoe ho tloha ho tse hlano tsa carbon precursor isopentyl diphosphate (IPP) kapa li-isomer tsa eona, dimethylallyl diphosphate (DMAPP), ka e 'ngoe ea litsela tse peli tse ikemetseng.Mevalonate. pathway le 2C-methyl-D-erythritol 4-phosphate (MEP) pathway.Likokoana-hloko tse ngata, litsela tsena tse peli li kopane.Bacteria le Plasmodium falciparum li itšetlehile ka ho feletseng tseleng ea MEP, athe batho ha ba joalo.Ka hona, li-enzyme tse teng Tsela ea MEP e hlahlojoa e le sepheo se secha sa phekolo.Plasmodium falciparum 1-deoxy-xylulose-5-phosphate reductoisomerase (pfDxr) e thusa ho fokotsa sekhahla tseleng ea MEP, ho etsa hore enzyme ena ea likokoana-hloko e be sepheo se tšepisang bakeng sa nts'etsopele ea litlhare tse thibelang malaria. .83,84 PfDXR inhibitors inhibit Plasmodium falciparum.Plasmodium falciparum e hola ebile ha e na chefo liseleng tsa batho.PfDXR ke sepheo se secha se ka bang teng hontshetsopele ya dithethefatsi tse thibelang malaria.83 Fosmidomycin, MMV019313 le MMV008138 thibela DOXP reductoisomerase, enzyme e ka sehloohong ya tsela ya DOXP e sieo bathong.Hobane ho thibela protheine prenylation ho Plasmodium ho sitisa kgolo ya targeted target as a-asexual parasites, antimalari5.
Liprotheine tsa prenylated li phetha karolo ea bohlokoa mekhoeng e fapa-fapaneng ea lisele tse kenyeletsang ho rekisoa ha vesicle, transduction ea lipontšo, taolo ea DNA replication, le karohano ea lisele. ho fetisoa ha sehlopha sa farnesyl, 15-carbon isoprenoid lipid unit, ho tloha farnesyl pyrophosphate ho ea C-terminus ea liprotheine tse nang le CaaX motif.Farnesyltransferase ke sepheo se secha se tšepisang bakeng sa nts'etsopele ea lithethefatsi tse thibelang malaria hobane thibelo ea eona e bolaea likokoana-hloko.86
Nakong e fetileng, phetoho ea ho hanyetsa likokoana-hloko ka farnesyltransferase inhibitor BMS-388,891 tetrahydroquinoline e bontšitse liphetoho protheine ea peptide substrate-binding domain.Ha ho khethoa tetrahydroquinoline e 'ngoe e nang le BMS-339,941, phetoho e ile ea fumanoa ho farnesyl binding pyrophosphate. Phuputsong e 'ngoe, liphetoho li ile tsa fumanoa karolong ea beta ea farnesyltransferase ea MMV019066 e hanyetsanang le P. falciparum. .87
E 'ngoe ea lipakane tse tšepisang bakeng sa ho hlahisa meriana e mecha ke ho thibela P. falciparum ribosome, hammoho le likarolo tse ling tsa mechine ea phetolelo e ikarabellang bakeng sa protheine synthesis.Mefuta ea Plasmodium e na le liphatsa tsa lefutso tse tharo: nucleus, mitochondria, le acroplasts (ho tloha ho residual chloroplasts). Liphatsa tsa lefutso tsohle li hloka mochini oa ho fetolela hore li sebetse.Li-protein synthesis inhibitors li na le katleho e kholo ea bongaka joalo ka lithibela-mafu tse sebetsang hantle.Doxycycline, clindamycin, le azithromycin li na le thuso ea kalafo ea malaria hobane li thibela li-ribosomes ho likokoana-hloko tsa mitochondria le li-aplastoplast, li etsa hore li-organelle tsena li se ke tsa sebetsa.88 P. falciparum ribosome e nka sebaka se bohareng sa ho iphetola ha lintho pakeng tsa prokaryote le eukaryote, e e khethollang ka mokhoa o hlakileng ho ribosome ea motho 'me kahoo e fana ka sepheo sa bohlokoa se tšepisang se secha.Plasmodium falciparum elongation factor 2 (pfEF2) ke karolo ea ribosome e susumetsang translocation ea GTP- ea ribosomes hammoho le moferefereenger RNA mme e bohlokoa bakeng sa motsoako oa protheine ho eukaryotes.PfEF2 e ile ea aroloa e le sepheo se secha sa nts'etsopele ea lithethefatsi tse thibelang malaria.87,89
Thibelo ea protheine synthesis Nka ho sibolloa ha sordarin, sehlahisoa sa tlhaho se thibelang motsoako oa protheine ea fungal ka ho thibela tomoso ea eukaryotic elongation factor 2. Ka ho tšoanang, M5717 (eo pele e neng e le DDD107498), inhibitor e khethiloeng ea 80S ribosome-interacting phase, P hona joale Lithuto tsa 1, tse netefatsang bokhoni ba PfEF2 e le sepheo se sebetsang sa lithethefatsi tse thibelang malaria.88,90
Likarolo tse ka sehloohong tsa malaria e matla ke ho tlosoa ha li-erythrocyte tse tšoaelitsoeng ke likokoana-hloko, ho ruruha, le ho thibela microvasculature.Plasmodium falciparum e sebelisa heparan sulfate ha e ntse e khomarela endothelium le lisele tse ling tsa mali, ho baka tšitiso ea ho phalla ha mali.Ho thibela lisele tsena tse sa tloaelehang le pathogen -ho sebelisana le lithethefatsi ho khutlisa phallo ea mali e koetsoeng le ho ama kholo ea likokoana-hloko.91
Liphuputso tse 'maloa li bontšitse hore sevuparin, e leng anti-adhesion polysaccharide e entsoeng ho tloha heparin, e na le liphello tsa antithrombin-eliminating.Sevuparin e thibela ho hlaseloa ha merozoite ho erythrocyte, ho tlama li-erythrocyte tse nang le tšoaetso ho li-erythrocyte tse sa tšoaetsanoang le tse nang le tšoaetso, le ho tlama ho vascular endotherinds endothelinds lisele. ho ea ho N-terminal extracellular heparan sulfate-binding structure of Plasmodium falciparum erythrocyte membrane protein 1, Duffy-binding-like domain 1α (DBL1α), 'me ho nahanoa hore ke ntho ea bohlokoa ho sequering erythrocyte e nang le tšoaetso.92,93 Lethathamo le leng la 2 le akaretsa liteko tsa tleliniki ka mekhahlelo e fapaneng.
Nako ea poso: Mar-24-2022