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Tafere Mulaw Belete Department of Pharmacology, Kws Qhia Ntawv ntawm Tshuaj thiab Kev Noj Qab Haus Huv Sciences, Gondar University, Gondar, Ethiopia Kev Sau Ntawv: Tafere Mulaw Belete Tel +251 918045943Email [email tiv thaiv] Abstract: Malaria yog ib qho teeb meem kev noj qab haus huv thoob ntiaj teb ua rau muaj kev tuag thiab mob hnyav txhua xyoo. .Txoj kev kho mob tsis tshua muaj thiab nyuaj heev los ntawm qhov tshwm sim ntawm cov kab mob resistant kab mob, uas ua rau muaj kev cuam tshuam loj rau kev tswj tus kab mob malaria.Txawm li cas los xij, txhawm rau tiv thaiv cov xwm txheej kev noj qab haus huv rau pej xeem, cov tshuaj tiv thaiv kab mob tshiab tshiab nrog kev kho ib zaug, kev kho dav dav, thiab cov txheej txheem tshiab ntawm kev ua. yog qhov xav tau sai sai.Kev txhim kho tshuaj tiv thaiv kab mob tuaj yeem ua raws ntau txoj hauv kev, txij li kev hloov kho cov tshuaj uas twb muaj lawm mus rau kev tsim cov tshuaj tshiab tsom rau cov hom phiaj tshiab.Tam sim no kev nce qib hauv cov kab mob parasite biology thiab muaj cov genomic technologies sib txawv muab ntau lub hom phiaj tshiab. rau txoj kev loj hlob ntawm cov kev kho mob tshiab.Ob lub cog lus targets rau kev cuam tshuam tshuaj tau raug nthuav tawm nyob rau hauv xyoo tas los no.Yog li ntawd, qhov kev tshuaj xyuas no tsom mus rau qhov kev tshawb fawb thiab thev naus laus zis tshiab tshaj plaws hauv kev tshawb pom thiab kev txhim kho cov tshuaj tiv thaiv kab mob tshiab.Qhov kev nthuav dav tshaj plaws antimalarial phiaj cov proteins kawm txog tam sim no suav nrog proteases, protein kinases, plasmodium qab zib. transporter inhibitors, aquaporin 3 inhibitors, choline thauj inhibitors, dihydroorotate dehydrogenase inhibitors, pentadiene biosynthesis inhibitor, farnesyltransferase inhibitor thiab enzymes koom nrog hauv lipid metabolism thiab DNA replication.Qhov kev tshuaj xyuas no nthuav tawm cov hom phiaj tshiab rau kev txhim kho tshuaj tiv thaiv kab mob thiab lawv cov tshuaj tiv thaiv. , cov hom phiaj tshiab, tshuaj tiv thaiv kab mob, hom kev ua, malaria parasite
Malaria yog ib qho kab mob sib kis loj heev, tshwj xeeb tshaj yog nyob rau hauv sub-Saharan Africa, thaj chaw ntawm Asia thiab South America.Txawm hais tias muaj ntau qhov kev siv zog, niaj hnub no nws yog ib qho ntawm cov ua rau mob thiab tuag feem ntau hauv cov poj niam cev xeeb tub thiab menyuam yaus.Raws li World Health Lub koom haum (WHO) 2018 tsab ntawv ceeb toom, muaj 228 lab tus neeg mob malaria thiab 405,000 tus neeg tuag thoob ntiaj teb. Yuav luag ib nrab ntawm lub ntiaj teb cov pej xeem muaj kev pheej hmoo ntawm malaria, feem ntau ntawm cov neeg mob (93%) thiab tuag (94%) tshwm sim hauv Africa.Hais txog 125 lab tus poj niam cev xeeb tub muaj kev pheej hmoo ntawm tus kab mob npaws txhua xyoo, thiab 272,000 tus menyuam yaus hnub nyoog qis dua 5 xyoos tuag los ntawm malaria.1 Malaria kuj yog qhov ua rau muaj kev txom nyem thiab yog ib qho teeb meem loj rau kev loj hlob ntawm kev lag luam, feem ntau hauv Africa.2 tsib hom kev txheeb xyuas ntawm Plasmodium uas ua rau mob malaria hauv tib neeg yog P. vivax, P. knowlesi, P. ovale, P. malaria thiab P. falciparum.Ntawm no, Plasmodium falciparum yog hom kab mob tuag taus tshaj plaws thiab nthuav dav ntawm Plasmodium.3.
Thaum tsis muaj cov tshuaj tiv thaiv zoo, kev siv tshuaj tiv thaiv kab mob npaws tseem yog tib txoj hauv kev los tswj thiab tiv thaiv kab mob malaria. Ntau qhov kev tshawb fawb tau pom tias qhov ua tau zoo ntawm cov tshuaj tiv thaiv kab mob feem ntau cuam tshuam los ntawm xwm txheej kub ntxhov ntawm cov tshuaj tiv thaiv Plasmodium spp.4 Cov tshuaj tiv thaiv. tau tshaj tawm nrog yuav luag tag nrho cov tshuaj muaj antimalarial, txhawb kev txhim kho cov tshuaj tiv thaiv kab mob tshiab tiv thaiv cov hom phiaj uas twb muaj lawm thiab kev tshawb fawb rau The gametophytic theem ntawm kev sib kis kuj tuaj yeem ua rau kev loj hlob ntawm kev sib deev hauv erythrocytes, tshwj xeeb tshaj yog nyob rau hauv cov kab mob resistant.6 Ob peb enzymes, ion. cov kab, kev thauj mus los, kev cuam tshuam cov molecules Red blood cell (RBC) ntxeem tau, thiab cov molecules lub luag haujlwm rau cov kab mob oxidative kev nyuaj siab, lipid metabolism, thiab hemoglobin degradation yog qhov tseem ceeb rau kev txhim kho cov tshuaj tiv thaiv kab mob tshiab tiv thaiv kab mob npaws sai sai Cov phiaj xwm tshiab rau protozoa.7
Lub peev xwm ntawm cov tshuaj tiv thaiv kab mob tshiab tau txiav txim los ntawm ntau qhov yuav tsum tau ua: hom tshiab ntawm kev ua, tsis muaj qhov cuam tshuam rau cov tshuaj tiv thaiv kab mob tam sim no, kev kho ib zaug, kev ua tau zoo ntawm ob theem ntshav asexual thiab gametocytes lub luag haujlwm rau kev sib kis. Cov tshuaj tiv thaiv kab mob malarial yuav tsum muaj kev tiv thaiv kab mob (chemoprotectants) thiab tshem tawm daim siab ntawm P. vivax hypnotics (cov tshuaj tiv thaiv rov qab).8
Kev tshawb nrhiav tshuaj niaj hnub ua raws li ntau txoj hauv kev los txheeb xyuas cov tshuaj tiv thaiv kab mob tshiab los tiv thaiv malaria.Cov no yog kev ua kom zoo dua cov tshuaj tiv thaiv tam sim no thiab cov qauv tsim, hloov kho cov tshuaj tiv thaiv kab mob uas twb muaj lawm, tshuaj xyuas cov khoom ntuj tsim, cais cov tshuaj tiv thaiv rov qab, siv cov tshuaj sib xyaw ua ke, thiab tsim cov tshuaj. rau lwm yam siv.8,9
Ntxiv nrog rau cov kev tshawb pom tshuaj ib txwm siv los txheeb xyuas cov tshuaj tiv thaiv kab mob tshiab tshiab, kev paub txog Plasmodium cell biology thiab genome tau pom tias yog ib qho cuab yeej muaj zog rau kev nthuav tawm cov tshuaj tiv thaiv kab mob, thiab muaj peev xwm tsim cov tshuaj nrog cov tshuaj tiv thaiv kab mob siab thiab tiv thaiv kab mob.Muaj peev xwm zoo rau cov tshuaj tshiab.Tshuaj tiv thaiv kab mob malaria cuam tshuam kev cuam tshuam ib zaug thiab rau tag nrho.10 Kev tshuaj ntsuam caj ces ntawm Plasmodium falciparum txheeb xyuas 2680 cov noob tseem ceeb rau kev loj hlob ntawm cov ntshav asexual, yog li txheeb xyuas cov txheej txheem tseem ceeb ntawm tes uas tseem ceeb rau kev tsim tshuaj tshiab.10,11 Tshiab Cov tshuaj yuav tsum: (i) daws cov tshuaj tiv thaiv, (ii) ua sai sai, (iii) muaj kev nyab xeeb, tshwj xeeb tshaj yog nyob rau hauv cov menyuam yaus thiab cov poj niam cev xeeb tub, thiab (iv) kho malaria hauv ib koob.12 Qhov kev sib tw yog nrhiav cov tshuaj uas hais txog tag nrho cov yam ntxwv no.Lub hom phiaj ntawm qhov kev tshuaj xyuas no yog muab lub tswv yim ntawm lub hom phiaj tshiab rau kev kho mob malaria parasites, uas tau kawm los ntawm ntau lub tuam txhab, kom cov neeg nyeem tuaj yeem paub txog kev ua haujlwm yav dhau los.
Tam sim no, feem ntau cov tshuaj tiv thaiv kab mob malaria tsom rau theem asexual ntawm tus kab mob malaria uas ua rau cov tsos mob tshwm sim.The pre-erythrocytic (lub siab) theem tseem tsis txaus ntseeg vim tias tsis muaj cov tsos mob tshwm sim. Cov tshuaj tua kab mob muaj ntau theem xaiv (saib daim duab 1). Kev kho mob malaria raws li. natural products, semi-synthetic and synthetic compounds tsim los ntawm xyoo 1940s.13 Cov tshuaj tiv thaiv kab mob malarial uas twb muaj lawm poob rau hauv peb pawg dav: quinoline derivatives, antifolates thiab artemisinin derivatives.Tam sim no tsis tau tshawb pom lossis tsim cov tshuaj uas muaj peev xwm tshem tawm tag nrho cov kab mob malaria parasites. Yog li ntawd, kom ua tau zoo tiv thaiv kab mob malaria, kev sib xyaw ntawm cov tshuaj feem ntau yog siv ib txhij.Quinoline yog cov tshuaj tua kab mob uas siv ntau tshaj plaws rau kev kho mob malaria.Quinine, ib qho alkaloid cais tawm ntawm cov tawv ntoo ntawm tsob ntoo cinchona, yog thawj cov tshuaj tiv thaiv kab mob malaria siv. los kho tus kab mob nyob rau hauv lub xyoo pua 17th.Los ntawm nruab nrab-1800s mus rau 1940s, quicuaj yog tus qauv kev kho mob rau malaria.14 Ntxiv rau qhov muaj toxicity, qhov tshwm sim ntawm cov tshuaj tiv thaiv kab mob P. falciparum tau txwv txoj kev siv tshuaj quinine.Txawm li cas los xij, quinine tseem siv los kho tus mob malaria, feem ntau yog ua ke nrog cov tshuaj quinine. thib ob tshuaj kom txo lub sij hawm kho thiab txo cov kev mob tshwm sim.15,16
Daim duab 1 Lub neej voj voog ntawm Plasmodium nyob rau hauv tib neeg. Cov theem thiab cov ntaub ntawv ntawm parasites nyob rau hauv ntau hom tshuaj tiv thaiv kab mob ua.
Xyoo 1925, cov kws tshawb fawb German tau tshawb pom thawj cov tshuaj tiv thaiv kab mob malarial, pamaquin, los ntawm kev hloov kho methylene blue.Pamaquin muaj kev ua tau zoo thiab toxicity thiab tsis tuaj yeem siv los kho tus mob malaria.Tab sis pamaquin muab cov hmoov txhuas los tsim cov tshuaj tiv thaiv kab mob zoo dua. Mepacrine (quinacrine) yog lwm qhov. derivative ntawm methylene xiav siv los kho malaria thaum Ntiaj Teb Tsov Rog II.17
Chloroquine tau tsim tawm thaum Tsov Rog Ntiaj Teb Zaum II los kho malaria.Chloroquine yog cov tshuaj xaiv rau kev kho mob malaria vim nws cov txiaj ntsig zoo, kev nyab xeeb thiab tus nqi qis.Tab sis nws cov kev siv irrational tsis ntev tau coj mus rau qhov tshwm sim ntawm chloroquine-resistant P. falciparum hom. 18 Primaquine yog siv los kho tus mob ntshav qab zib Plasmodium vivax los ntawm hypnosis.Primaquine muaj zog gameticidal tiv thaiv Plasmodium falciparum.Primaquine ua rau hemolytic anemia hauv cov neeg mob uas muaj cov piam thaj-6-phosphate dehydrogenase (G6PD) deficiency. -P.Diurnal activity.19
Cov quinoline derivatives tshiab tau tsim los, ua rau cov tshuaj tshiab xws li piperaquine thiab amodiaquine.Tom qab qhov tshwm sim ntawm chloroquine tsis kam, amodiaquine, phenyl-hloov analogue ntawm chloroquine, pom tau tias muaj txiaj ntsig zoo tiv thaiv chloroquine-resistant strains ntawm Plasmodium falci. Base antimalarial tshuaj tsim nyob rau hauv Tuam Tshoj nyob rau hauv 1970.Nws yog zoo tiv thaiv tshuaj tiv thaiv kab mob ntawm P. falciparum, P. vivax, P. malaria thiab P. ovale.Pyronadrine yog tam sim no muaj nyob rau hauv ACT nrog artesunate, uas tau qhia tau zoo heev tiv thaiv tag nrho cov. malaria parasites.21 Mefloquine tau tsim nyob rau hauv nruab nrab-1980s thiab tam sim no tau pom zoo rau kev tiv thaiv kab mob malaria los ntawm txhua hom, nrog rau cov kab mob chloroquine-resistant.Txawm li cas los xij, nws siv yog txuam nrog qee yam kev phiv thiab tshuaj tiv thaiv.22 Quinoline-derived tshuaj ua feem ntau ntawm cov ntshav theem ntawm cov kab mob parasite, tab sis qee cov tshuaj tiv thaiv kab mob ua rau ntawm daim siab theem.Cov tshuaj no inhibit los ntawm kev tsim cov tshuaj tiv thaiv kab mob.ex nrog heme nyob rau hauv parasite cov zaub mov vacuoles.Yog li ntawd, heme polymerization yog blocked.Vim li ntawd, lub heme tso tawm thaum lub sij hawm tawg ntawm hemoglobin accumulates mus rau cov tshuaj lom, tua cov cab nrog tshuaj lom pov tseg.nees nkaum peb.
Antifolates yog cov tshuaj tiv thaiv kab mob uas cuam tshuam cov synthesis ntawm folic acid, uas yog qhov tseem ceeb rau kev sib txuas ntawm nucleotides thiab amino acids.Antifolates thaiv nuclear kev faib tawm ntawm Plasmodium hom thaum lub sij hawm schizont theem hauv erythrocytes thiab hepatocytes.Sulfadoxine muaj cov qauv zoo sib xws rau para-aminobenzoic acid. (PABA), ib feem ntawm folic acid.Lawv inhibit dihydrofolate synthesis los ntawm inhibiting dihydrofolate synthase, ib tug tseem ceeb enzyme nyob rau hauv nucleic acid biosynthesis.nees nkaum plaub.
Pyrimethamine thiab proguanil yog schizont antimalarial tshuaj uas ua rau cov asexual daim ntawv ntawm Plasmodium hom.Cov tshuaj no inhibit lub enzyme dihydrofolate reductase (DHFR), uas inhibits qhov txo ntawm dihydrofolate rau tetrahydrofolate, uas yog ib qho tseem ceeb rau biosynthesis ntawm amino acids thiab nucleic acids. Proguanil yog ib qho prodrug metabolized rau cyclic guanidine.Proguanil yog thawj cov tshuaj antifolate siv rau kev kho mob malaria.Qhov laj thawj yog vim li cas nws rhuav tshem cov qe ntshav liab ua ntej cov kab mob invades lawv thaum lawv nkag mus rau hauv cov hlab ntsha.Kuj, proguanil yog ib qho kev nyab xeeb. tshuaj.Pyrimethamine feem ntau yog siv nrog rau lwm yam tshuaj uas ua kom ceev ceev.Txawm li cas los xij, nws siv tau txo qis vim kev siv tshuaj tiv thaiv.24,25
Atovaquone yog thawj zaug pom zoo tshuaj tiv thaiv kab mob uas tsom mus rau mitochondria ntawm Plasmodium parasite.Atovaquone inhibits electron thauj los ntawm kev ua raws li ubiquinone analog los thaiv cov cytochrome b feem ntawm cytochrome bc1 complex.Thaum ua ke nrog proguanil, atovaquone muaj kev nyab xeeb thiab zoo rau cov poj niam cev xeeb tub. thiab cov menyuam yaus.Atovaquone muaj txiaj ntsig zoo rau kev sib deev theem ntawm cov cab cab ntawm tus tswv tsev thiab yoov tshaj cum.Yog li ntawd, nws inhibits kev sib kis ntawm malaria los ntawm yoov tshaj cum rau tib neeg.A tsau ua ke nrog proguanil tsim nyob rau hauv lub npe lag luam Malarone.24,26
Artemisinin tau muab rho tawm los ntawm Artemisia annua xyoo 1972.Artemisinin thiab nws cov derivatives suav nrog artemether, dihydroartemisinin, artemether thiab artesunate muaj cov haujlwm dav dav. ntawm gametocytes los ntawm tib neeg mus rau yoov tshaj cum.27 Artemisinin thiab nws cov derivatives muaj txiaj ntsig zoo tiv thaiv kab mob chloroquine- thiab mefloquine-resistant.Lawv muaj kev nyab xeeb, muaj txiaj ntsig zoo thiab ua kom ceev cov ntshav schizonts tawm tsam tag nrho cov hom Plasmodium.Txawm li cas los xij, artemisinin tsis tau tshem tawm cov kab mob siab ntawm lub siab. Parasite.Cov tshuaj no muaj lub neej luv luv thiab tsis muaj bioavailability, ua rau cov tshuaj tiv thaiv, ua rau lawv tsis zoo li monotherapy.Yog li ntawd, artemisinin derivatives raug pom zoo ua ke nrog lwm cov tshuaj tiv thaiv kab mob.28
Cov nyhuv antimalarial ntawm artemisinin tej zaum yuav yog vim cov tiam ntawm dawb radicals uas tshwm sim los ntawm lub cleavage ntawm artemisinin endoperoxide txuas hniav nyob rau hauv parasite zaub mov vesicles, yog li inhibiting parasite calcium ATPase thiab proteasome.29,30 Artemether yog siv raws li monotherapy.Fast qhov ncauj absorption.Bioavailability doubled thaum noj nyob rau hauv lub xub ntiag ntawm zaub mov.Ib zaug nyob rau hauv lub systemic ncig, artemether yog hydrolyzed rau dihydroartemisinin nyob rau hauv lub plab thiab daim siab.
Artesunate yog ib tug semi-synthetic derivative vim nws cov nyhuv antimalarial sai, tsis muaj cov tshuaj tiv thaiv tseem ceeb thiab ntau dua solubility.Rau pom zoo raws li ib tug thawj kab tshuaj rau mob malaria.31
Tetracyclines thiab macrolides yog cov tshuaj tiv thaiv kab mob qeeb qeeb siv los ua kev kho mob ntxiv rau quinine hauv falciparum malaria.Doxycycline kuj tseem siv rau cov tshuaj chemoprophylaxis hauv cov cheeb tsam uas muaj kev tiv thaiv siab.32 Lub tswv yim tam sim no siv los tawm tsam cov tshuaj tiv thaiv kab mob malarial yog kev kho siv tshuaj sib xyaw ua ke. Lub tswv yim tau siv yav dhau los los ntawm kev siv cov kev sib txuas ruaj khov.WHO pom zoo kom artemisinin-raws li kev kho mob sib xyaw ua ke (ACT) ua thawj kab kev kho mob rau cov kab mob tsis sib haum xeeb falciparum malaria.Qhov laj thawj yog tias kev sib xyaw ua ke ntawm cov tshuaj txo cov tshuaj tiv thaiv thiab cov kev mob tshwm sim.33
ACT muaj lub zog artemisinin tivthaiv uas tshem tawm cov kab mob sai sai, thiab cov tshuaj ua haujlwm ntev uas tshem tawm cov kab mob seem thiab txo cov artemisinin tsis kam.Cov ACTs pom zoo los ntawm WHO yog artesunate/amodiaquine, artemether/ benzfluorenol, artesunate/mefloquine, artesunate/dihydrintrolidem. piperaquine, Artesunate/sulfadoxine/pyrimethamine, artemether/piperaquine thiab artemisinin/piperaquine/primaquine.Chloroquine ntxiv rau primaquine tseem yog thawj kab tshuaj rau kev tshem tawm ntawm Plasmodium vivax.Quinine + tetracycline/doxycycline muaj mob hnyav, tab sis nws muaj qhov hnyav heev. Cov teebmeem thiab yog contraindicated rau cov menyuam yaus thiab cov poj niam cev xeeb tub34.
Mefloquine, atovaquone/proguanil, los yog doxycycline raug pom zoo nyob rau hauv chemoprevention regimens rau cov neeg taug kev los ntawm non-endemic mus rau endemic thaj chaw.35 Kev tiv thaiv kev tiv thaiv nyob rau hauv cov pab pawg muaj kev pheej hmoo siab yog tawm tswv yim, suav nrog sulfadoxine / pyrimethamine thaum cev xeeb tub thiab amodiaquine/sulfadoxine-pyrimethamine raws caij nyoog .36 Halofantrine tsis haum rau kev siv tshuaj kho mob vim nws cov tshuaj cardiotoxicity.Dapsone, mepalyline, amodiaquine, thiab sulfonamides raug tshem tawm los ntawm kev siv tshuaj kho mob vim lawv cov kev phiv. 1.
Tam sim no muaj cov tshuaj tiv thaiv kab mob malarial yog raws li qhov sib txawv ntawm txoj hauv kev loj hauv metabolic ntawm Plasmodium hom thiab lawv cov tswv.Cov kab mob cov kab mob loj metabolic xws li heme detoxification, fatty acid synthesis, nucleic acid synthesis, fatty acid synthesis, thiab oxidative stress, yog qee qhov tshiab. sites for drug design.38,39 Txawm hais tias feem ntau cov tshuaj antimalarial tau siv rau ntau xyoo, lawv siv tam sim no txwv vim muaj tshuaj tiv thaiv.Raws li cov ntaub ntawv, tsis muaj cov tshuaj tiv thaiv kab mob tau pom tias inhibit paub cov tshuaj hom phiaj.7,40 Hauv Piv txwv li, feem ntau cov tshuaj tiv thaiv kab mob tau pom nyob rau hauv cov tsiaj hauv vivo los yog hauv vitro qauv kev tshawb fawb.Yog li ntawd, hom kev ua ntawm cov tshuaj tiv thaiv kab mob feem ntau tseem tsis paub meej. Tsis tas li ntawd, cov txheej txheem ntawm kev tiv thaiv rau cov tshuaj tiv thaiv kab mob feem ntau tsis meej.39
Kev tswj tus kabmob malaria xav tau cov tswv yim sib koom ua ke xws li kev tswj hwm vector, cov tshuaj tiv thaiv kab mob zoo thiab nyab xeeb, thiab cov tshuaj tiv thaiv zoo.Xav txog kev tuag siab thiab mob malaria, thaum muaj xwm txheej ceev thiab kev sib kis ntawm cov tshuaj tiv thaiv, qhov tsis muaj txiaj ntsig ntawm cov tshuaj tiv thaiv kab mob uas twb muaj lawm tiv thaiv tsis yog erythrocyte thiab theem kev sib deev , kev txheeb xyuas cov tshuaj tiv thaiv kab mob tshiab los ntawm kev nkag siab txog cov txheej txheem metabolic ntawm malaria.Cov tshuaj malaria yog ib qho tseem ceeb.parasites.Yuav kom ua tiav lub hom phiaj no, kev tshawb fawb tshuaj yuav tsum tau tsom rau cov hom phiaj tshiab, siv tau los cais cov tshuaj txhuas tshiab.39,41
Muaj ob peb lub laj thawj rau qhov yuav tsum tau txheeb xyuas cov hom phiaj metabolic tshiab.Ua ntej, tshwj tsis yog cov tshuaj atovaquone thiab artemisinin-derived, cov tshuaj tiv thaiv kab mob feem ntau tsis muaj tshuaj lom neeg, uas yuav ua rau muaj kev sib kis. Thib ob, vim muaj ntau yam ntawm putative chemotherapeutic lub hom phiaj, muaj ntau yam tseem tsis tau validated.Yog validated, tej zaum yuav yields ib co tebchaw uas zoo thiab muaj kev nyab xeeb.Qhov kev txheeb xyuas ntawm cov hom phiaj tshuaj tshiab thiab kev tsim cov tshuaj tshiab uas ua rau lub hom phiaj tshiab tau siv dav thoob ntiaj teb niaj hnub no los hais txog. Cov teeb meem tshwm sim los ntawm qhov tshwm sim ntawm kev tawm tsam rau cov tshuaj uas twb muaj lawm.40,41 Yog li ntawd, txoj kev tshawb no ntawm cov tshiab lub hom phiaj protein-specific inhibitors ntawm Plasmodium tau siv rau cov hom phiaj tshuaj identification.Txij li thaum lub unveiling ntawm P. falciparum genome, ob peb lub hom phiaj tshiab rau tshuaj. Kev cuam tshuam tau tshwm sim.Cov tshuaj tiv thaiv kab mob muaj peev xwm no tsom cov metabolite biosynthesis tseem ceeb, kev thauj mus los ntawm daim nyias nyias thiab cov teeb liab, thiab cov txheej txheem hemoglobin degradation.40,42
Plasmodium protease yog ubiquitous catalytic thiab tswj enzyme uas plays lub luag haujlwm tseem ceeb hauv kev ciaj sia ntawm cov kab mob protozoan thiab cov kab mob uas lawv ua.Nws catalyzes hydrolysis ntawm peptide bonds.43 Lub luag hauj lwm ntawm proteases nyob rau hauv kab mob malaria pathogenesis muaj xws li cell/tissue penetration, tiv thaiv kab mob. evasion, ua kom o, erythrocyte ntxeem tau, tawg ntawm hemoglobin thiab lwm yam proteins, autophagy, thiab kab mob kev loj hlob.44
Malaria proteases (glutamic aspartic acid, cysteine, hlau, serine thiab threonine) tau cog lus rau cov hom phiaj kho mob vim tias kev cuam tshuam ntawm malaria protease gene inhibits qhov degradation ntawm hemoglobin thiab tus kab mob parasite's erythrocyte theem.kev loj hlob.45
Kev tawg ntawm erythrocytes thiab kev ntxeem tau tom qab ntawm merozoites yuav tsum tau malaria proteases.A hluavtaws peptide (GlcA-Val-Leu-Gly-Lys-NHC2H5) inhibits Plasmodium falciparum schizont cysteine protease Pf 68. qhia tias proteases ua lub luag haujlwm tseem ceeb hauv cov kab mob parasite ntxeem tau ntawm cov qe ntshav liab.Yog li ntawd, proteases yog lub hom phiaj zoo rau kev txhim kho tshuaj tiv thaiv kab mob.46
Hauv Plasmodium falciparum zaub mov vacuoles, ob peb aspartic proteases (plasma proteases I, II, III, IV) thiab cysteine proteases (falcipain-1, falcipain-2 /, falcipain-3) tau raug cais tawm, siv los ua kom tsis zoo hemoglobin, raws li qhia. hauv daim duab 2.
Incubation ntawm kab lis kev cai P. falciparum parasites nrog cov protease inhibitors leupeptin thiab E-64 ua rau cov tsub zuj zuj ntawm undegraded globin.Leupeptin inhibits cysteine thiab qee cov serine proteases, tab sis E-64 tshwj xeeb inhibits cysteine proteases.47,48bation. Ntawm cov kab mob parasites nrog cov aspartate protease inhibitor pepstatin, globin tsis tau khaws cia. Ntau cov kev tshawb fawb tau pom tias cystatin inhibitors tsis tsuas yog inhibit globin degradation, tab sis kuj inhibit cov theem pib ntawm hemoglobin tawg, xws li hemoglobin denaturation, heme tso tawm ntawm globin, thiab heme ntau lawm. .49 Cov txiaj ntsig no qhia tias cysteine protease yuav tsum tau ua rau thawj theem.Txawm li cas los xij, tsuas yog E-64 blocked globin hydrolysis xwb. 48,49 Ob peb cysteine protease inhibitors, xws li fluoromethyl ketone thiab vinyl sulfone, inhibit P. falciparum kev loj hlob thiab hemoglobin degra.Nyob rau hauv tus qauv tsiaj ntawm malaria, fluoromethyl ketone inhibits P. vinckei protease kev ua thiab kho 80% ntawm murine kab mob malaria.Yog li ntawd, protease inhibitors yog cov neeg sib tw rau cov tshuaj tiv thaiv malarial. Tom qab ua haujlwm tau txheeb xyuas cov tshuaj lom neeg muaj txiaj ntsig falcipain inhibitors, suav nrog chalthiazine. uas thaiv cov kab mob parasite metabolism thiab kev loj hlob.50
Serine proteases koom nrog schizont rupture thiab erythrocyte reinvasion thaum lub sij hawm Plasmodium falciparum lub neej voj voog.Nws tuaj yeem thaiv los ntawm ntau cov serine protease inhibitors thiab yog qhov kev xaiv zoo tshaj plaws txij li tsis muaj tib neeg enzyme homolog muaj. Cov protease inhibitor LK3 cais los ntawm Streptomyces sp.degrades tus malaria serine protease.51 Maslinic acid yog ib tug natural pentacyclic triterpenoid uas inhibits maturation ntawm parasites los ntawm lub nplhaib theem mus rau schizont theem, li no terminating kev tso tawm ntawm merozoites thiab lawv invasion.A series ntawm haib 2-pyrimidine nitrile inhibition ntawm falcipa. -2 thiab falcipain-3.52 statins thiab inhibition ntawm plasma proteases los ntawm allophenostatin-based inhibitors tiv thaiv hemoglobin degradation thiab tua kab mob. Muaj ntau cov cysteine protease blockers muaj, suav nrog Epoxomicin, lactacystin, MG132, WEHI-849, statins. .
Phosphoinositide lipid kinases (PIKs) yog ubiquitous enzymes uas phosphorylate lipids los tswj kev loj hlob, ciaj sia taus, kev lag luam, thiab intracellular signaling.Qhov kev kawm PIK cov chav kawm dav tshaj plaws hauv 53 kab mob yog phosphoinositide 3-kininase (PI3Kinase) thiab phosphoinositide (PI3K) Inhibition ntawm cov enzymes no tau raug txheeb xyuas tias yog lub hom phiaj rau kev txhim kho cov tshuaj tiv thaiv kab mob malarial nrog cov kev ua haujlwm uas tsim nyog rau kev tiv thaiv, kho thiab tshem tawm cov kab mob malaria.54 UCT943, imidazopyrazine (KAF156) thiab aminopyridines yog ib chav kawm tshiab ntawm cov tshuaj tiv thaiv kab mob sib kis uas tsom rau PI. (4) K thiab inhibit qhov kev loj hlob ntawm intracellular ntawm ntau hom Plasmodium nyob rau txhua theem ntawm tus kab mob tus tswv.Yog li ntawd, lub hom phiaj (PI3K) thiab PI(4)K yuav qhib txoj kev tshiab raws li kev tshawb nrhiav tshuaj tsom los txheeb xyuas cov tshuaj tiv thaiv kab mob tshiab.KAF156 tam sim no. nyob rau hauv Phase II soj ntsuam trials.55,56 MMV048 yog ib tug compound nrog zoo nyob rau hauv vivo prophylactic kev ua si tiv thaiv P. cynomolgi thiab muaj peev xwm as ib qho tshuaj tiv thaiv kab mob sib kis.MMV048 tam sim no tab tom tab tom sim Phase IIa kev sim tshuaj hauv Ethiopia.11
Rau kev loj hlob sai hauv cov qe ntshav liab, Plasmodium hom yuav tsum muaj cov substrates txaus los pab txhawb lawv cov metabolism hauv lub zog. Yog li, cov kab mob ua kom cov kab mob erythrocytes los ntawm inducing tshwj xeeb transporters uas txawv heev los ntawm tus tswv cell transporters nyob rau hauv uptake thiab tshem tawm ntawm metabolites. Yog li ntawd, transporters nyiam. Carrier proteins thiab channels yog lub hom phiaj tseem ceeb vim tias lawv lub luag haujlwm tseem ceeb hauv kev thauj cov metabolites, electrolytes thiab cov as-ham.57 Cov no yog Plasmodium deg anion channel (PSAC) thiab parasitic vacuolar membrane (PVM), uas muab txoj hauv kev txuas mus ntxiv rau cov as-ham. mus rau intracellular parasite.58
PSAC yog lub hom phiaj zoo tshaj plaws vim tias nws pom muaj ntau yam khoom noj (hypoxanthine, cysteine, glutamine, glutamate, isoleucine, methionine, proline, tyrosine, pantothenic acid thiab choline) kom tau txais lub luag haujlwm tseem ceeb hauv cov kab mob hauv lub cev.PSACs tsis muaj homology meej. kom paub tus tswv channel genes.58,59 Phloridizin, dantrolene, furosemide, thiab niflunomide yog cov muaj zog anion transporter blockers.Cov tshuaj xws li glyburide, meglitinide, thiab tolbutamide inhibit qhov nkag ntawm choline mus rau hauv cov kab mob parasitic-infected qe ntshav liab.60,61
Cov ntshav daim ntawv ntawm Plasmodium falciparum vam yuav luag tag nrho ntawm glycolysis rau lub zog tsim, tsis muaj zog cia;Nws tso siab rau qhov kev noj qab haus huv tas li.Cov kab mob hloov pauv pyruvate rau lactate los tsim ATP, uas yuav tsum tau ua kom rov ua dua tshiab hauv cov qe ntshav liab.62 Glucose yog thawj zaug thauj mus rau hauv cov kab mob erythrocytes los ntawm kev sib xyaw ntawm tus tswv tsev cell glucose transporter, GLUT1, hauv cov erythrocyte daim nyias nyias thiab cov kab mob parasite-induced 'txoj kev permeation tshiab'.63 Glucose raug thauj mus rau cov kab mob los ntawm Plasmodium falciparum hexose transporter (PFHT).PFHT muaj qee yam kev thauj cov piam thaj.GLUT1 yog xaiv rau D-glucose, thaum PFHT tuaj yeem thauj. D-glucose thiab D-fructose.Yog li, qhov sib txawv hauv GLUT1 thiab PFHT kev sib cuam tshuam nrog cov substrates qhia tias kev xaiv inhibition ntawm PFHT yog lub hom phiaj tshiab rau kev txhim kho cov tshuaj tiv thaiv kab mob tshiab.64 Ib txoj hlua ntev O-3-hexose derivative (compound 3361) inhibits qabzib thiab fructose uptake los ntawm PFHT, tab sis nws tsis inhibit hexose thauj los ntawm cov tsiaj nyeg loj thiab fructose transporters (GLUT1 thiab 5).Compound 3.361 kuj inhibited qabzib uptake los ntawm P. vivax ntawm PFHT.In yav dhau los kev tshawb fawb, compound 3361 tua P. falciparum nyob rau hauv kab lis kev cai thiab txo P. berghei reproduction nyob rau hauv nas qauv.65
Plasmodium cov ntshav pab pawg ntau yog nyob ntawm anaerobic glycolysis rau kev loj hlob thiab kev loj hlob.60 Parasite-infected cov qe ntshav liab nqus cov piam thaj 100 npaug sai dua li cov qe ntshav liab uas tsis muaj kab mob.Cov kab mob metabolizes qabzib los ntawm glycolysis rau lactate, uas yog xa tawm los ntawm cov cab los ntawm lactate: ib qho H + symporter mechanism rau hauv ib puag ncig sab nraud.66 Lactate export thiab qabzib uptake yog qhov tseem ceeb rau kev tswj hwm lub zog, pH intracellular, thiab parasite osmotic stability.Lactate: H + symporter system inhibition yog lub hom phiaj tshiab rau kev tsim cov tshuaj tshiab.Ob lub tebchaw, xws li MMV007839 thiab MMV000972, tua asexual blood-stage P. falciparum parasites los ntawm inhibiting lub lactate: H + transporter.67
Zoo li lwm hom ntawm tes, cov qe ntshav liab tswj cov qib Na + hauv qis.Txawm li cas los xij, cov kab mob ua kom cov permeability ntawm erythrocyte daim nyias nyias thiab pab txhawb Na + nkag, ua rau muaj kev nce hauv erythrocyte cytoplasmic Na + concentration mus rau qib ntawm extracellular nruab nrab. Yog li, kab mob. pom lawv tus kheej nyob rau hauv siab Na + xov xwm thiab yuav tsum tau ntiab Na + ions los ntawm lawv cov plasma membrane kom tsis txhob muaj cytoplasmic Na + ntau ntau thiaj li muaj sia nyob txawm tias lawv muaj nyob rau hauv intracellular chaw.Qhov no, Na + influx mus rau cov cab yog tswj los ntawm kev siv P-hom ATPase. transporter (PfATP4), uas ua raws li tus cab tus thawj Na +-efflux twj tso kua mis mechanism, raws li qhia nyob rau hauv daim duab 3.68, inhibiting no transporter Nws yuav ua rau kom ib tug nce nyob rau hauv Na+ nyob rau hauv lub parasite, uas thaum kawg yuav ua rau tuag ntawm tus kab mob. malaria parasite.Ob lub tebchaw, suav nrog sipagamin nyob rau theem 2, (+)-SJ733 nyob rau theem 1, thiab KAE609 nyob rau theem 2, muaj cov txheej txheem ntawm kev txiav txim siab PfATP4.67,69
Daim duab 3. Cov txheej txheem ntawm cov kab mob parasite-induced PfATP4 thiab V-hom H +-ATPase hauv cov kab mob erythrocyte tuag tom qab cipargamin inhibition.
Plasmodium hom tswj lawv cov qib Na + los ntawm kev siv P-hom ATPase transporter.Nws kuj import H + los ntawm txoj kev zoo sib xws.Kom tswj qhov nce H + concentration thiab tswj cov pH ntawm 7.3 intracellular, tus kab mob malaria siv cov V-hom ATPase transporter ntxiv rau. tshem tawm H+.Kev tsim cov tshuaj tshiab yog lub hom phiaj zoo.MMV253 inhibits V-hom H+ ATPase raws li nws cov txheej txheem ntawm kev txiav txim los ntawm kev hloov pauv thiab tag nrho-genome sequencing.70,71
Aquaporin-3 (AQP3) yog aquaglycerol channel protein uas pab txhawb kev txav ntawm cov dej thiab glycerol nyob rau hauv cov tsiaj cov tsiaj.AQP3 yog induced nyob rau hauv tib neeg hepatocytes teb rau kab mob cab thiab muaj lub luag hauj lwm tseem ceeb nyob rau hauv parasite replication.AQP3 muab kev nkag mus rau glycerol rau hauv P. . berghei thiab pab txhawb cov kab mob sib kis nyob rau hauv asexual erythrocyte theem.72 Genetic depletion ntawm AQP3 cuam tshuam cov cab cab hauv lub siab theem ntawm P. berghei. Tsis tas li ntawd, kev kho mob nrog AQP3 inhibitor auphen txo P. berghei parasitemia lub nra hauv hepatocytes thiab P. falciparum parasitemia nyob rau hauv erythrocytes, tawm tswv yim hais tias host proteins plays lub luag hauj lwm tseem ceeb nyob rau hauv lub neej sib txawv theem ntawm tus kab mob .73 Feem ntau intriguingly, kev cuam tshuam ntawm AQP3 nyob rau hauv cov nas genetic tsis ua rau tuag, qhia tias tus tswv tsev protein muaj peev xwm kho tau lub hom phiaj tshiab. kev nkag siab ntawm tus tswv tsev lub siab cov txheej txheem cuam tshuam los ntawm Plasmodium kab mob thiab qhia txog lub peev xwm ntawm cov pro nocesses raws li yav tom ntej antimalarial tshuaj.71,72
Phospholipids ua lub luag haujlwm tseem ceeb hauv lub neej voj voog intra-erythrocyte ntawm Plasmodium falciparum, ob qho tib si raws li cov txheej txheem ntawm daim nyias nyias thiab raws li kev tswj hwm molecules uas tswj cov dej num ntawm ntau yam enzymes.Cov molecules yog qhov tseem ceeb rau kev tsim cov kab mob hauv cov qe ntshav liab.Tom qab erythrocyte ntxeem tau, Cov qib phospholipid nce, ntawm cov phosphatidylcholine yog cov lipid loj hauv lawv cov cell membrane Cheebtsam.Parasites synthesize phosphatidylcholine de novo siv choline ua precursor.Qhov no de novo txoj kev yog ib qho tseem ceeb rau cab loj hlob thiab ciaj sia. ua rau cov cab tuag.74 Albitiazolium, cov tshuaj uas tau nkag mus rau theem II kev sim, ua haujlwm feem ntau los ntawm inhibiting kev thauj cov choline mus rau hauv cov cab.Albitiazolium accumulates txog 1000-fold hauv Plasmodium thiab inhibits parasite kev loj hlob yam tsis muaj kev rov qab los.Nws ua haujlwm hnyav. tej yam kev mob.Nco ntsoov, ib qho kev txhaj tshuaj kho siab parasitemia theem.75,76
Phosphocholine cytidyltransferase yog tus nqi-limiting kauj ruam nyob rau hauv lub de novo biosynthesis ntawm phosphatidylcholine.77 Lub diquaternary ammonium compound G25 thiab cov dicationic compound T3 inhibit phosphatidylcholine synthesis nyob rau hauv parasites.G25 yog 1000-fold tsawg tshuaj lom cov kab mob ntawm tes. cov tshuaj tiv thaiv kab mob malarial nrhiav pom thiab txhim kho.78,79
Ib kauj ruam tseem ceeb ntawm kev sib kis ntawm Plasmodium hom nyob rau hauv tib neeg lub tswv yim yog qhov dav thiab nrawm ntawm cov kab mob DNA, uas nyob ntawm qhov muaj cov metabolites tseem ceeb xws li pyrimidines.In Plasmodium, pyrimidine nucleotides ua lub luag haujlwm tseem ceeb hauv kev sib txuas ntawm DNA, phospholipids thiab glycoproteins.Nucleotide synthesis ua raws li ob txoj hauv kev tseem ceeb: txoj kev khaws cia thiab txoj kev de novo.Dihydroorotate dehydrogenase (DHODH) yog ib qho tseem ceeb enzyme uas catalyzes oxidation ntawm dihydroorotate rau orotate, tus nqi-txheej kauj ruam nyob rau hauv de novo pyrimidine synthesis. sawv cev rau lub hom phiaj uas muaj peev xwm cog lus rau kev txhim kho tshuaj tiv thaiv kab mob.80 Tib neeg lub hlwb tau txais pyrimidines los ntawm kev cawm cov pyrimidines uas twb muaj lawm los yog los ntawm de novo synthesis.Yog txoj kev de novo biosynthetic inhibited, lub cell yuav cia siab rau txoj kev cawm seej thiab lub cell yuav tsis tuag. Txawm li cas los xij, inhibition ntawm de novo pyrimidine biosynthesis hauv cov cab ua rau cov hlwb tuag vim tias covmalaria parasite tsis muaj pyrimidine salvage pathway, uas ua rau cov cab tsis muaj zog inhibition los ntawm DHODH.81 DSM190 thiab DSM265 yog xaiv inhibitors ntawm parasite DHODH enzyme, uas tam sim no nyob rau theem 2 kev sim tshuaj.P218 yog ib qho DHODH inhibitor-zoo tiv thaiv pyrimethamine. Cov kab mob resistant tam sim no nyob rau theem 1.KAF156 (Ganaplacide) yog tam sim no nyob rau hauv Phase 2b soj ntsuam nrog phenylfluorenol.82
Isoprenoids yog xav tau rau kev hloov pauv lipid tom qab kev hloov pauv ntawm cov protein thiab asexual replication ntawm Plasmodium falciparum.Isoprenoids yog synthesized los ntawm tsib-carbon precursor isopentyl diphosphate (IPP) los yog nws isomer, dimethylallyl diphosphate (DMAPP), los ntawm ib qho ntawm ob txoj kev ywj pheej. txoj hauv kev thiab 2C-methyl-D-erythritol 4-phosphate (MEP) pathway.Nyob rau hauv cov kab mob feem ntau, ob txoj kev no yog kev sib nrig sib. MEP txoj hauv kev tau tshawb nrhiav raws li qhov muaj peev xwm kho tau cov hom phiaj tshiab.Plasmodium falciparum 1-deoxy-xylulose-5-phosphate reductoisomerase (pfDxr) catalyzes tus nqi-txheej kauj ruam hauv MEP txoj hauv kev, ua rau cov kab mob cab no yog lub hom phiaj zoo rau kev txhim kho cov tshuaj tiv thaiv kab mob tshiab. .83,84 PfDXR inhibitors inhibit Plasmodium falciparum.Plasmodium falciparum hlob thiab tsis muaj tshuaj lom rau tib neeg lub hlwb.PfDXR yog lub hom phiaj tshiab hauvantimalarial tshuaj development.83 Fosmidomycin, MMV019313 thiab MMV008138 inhibit DOXP reductoisomerase, ib qho tseem ceeb enzyme ntawm DOXP txoj hauv kev uas tsis muaj nyob rau hauv tib neeg.Vim inhibition ntawm protein prenylation hauv Plasmodium cuam tshuam kev loj hlob ntawm asexual parasites.
Prenylated proteins ua lub luag haujlwm tseem ceeb hauv ntau cov txheej txheem ntawm tes nrog rau kev lag luam vesicle, kev hloov pauv ntawm cov teeb liab, kev tswj ntawm DNA replication, thiab cell division.Qhov kev hloov pauv tom qab kev hloov pauv no ua kom yooj yim rau kev khi ntawm cov proteins hauv cellular rau daim nyias nyias thiab pab txhawb kev sib cuam tshuam ntawm cov protein-protein.Farnesyltransferase catalyzes. kev hloov ntawm cov pab pawg Farnesyl, 15-carbon isoprenoid lipid unit, los ntawm farnesyl pyrophosphate mus rau C-terminus ntawm cov proteins uas muaj cov CaaX motif.Farnesyltransferase yog lub hom phiaj tshiab rau kev txhim kho cov tshuaj tiv thaiv kab mob vim nws inhibition tua cov cab.86.
Yav dhau los, kev hloov pauv ntawm kev tiv thaiv kab mob los ntawm farnesyltransferase inhibitor BMS-388,891 tetrahydroquinoline pom kev hloov pauv hauv cov protein ntawm peptide substrate-binding domain.Nyob rau hauv kev xaiv ntawm lwm tetrahydroquinoline nrog BMS-339,941, ib qho kev hloov pauv ntawm peptide binnesroquinoline tau pom hauv cov peptides .Hauv lwm txoj kev tshawb fawb, kev hloov pauv tau pom nyob rau hauv farnesyltransferase beta subunit ntawm MMV019066-resistant strain of P. falciparum.Modeling kev tshawb fawb tau pom tias qhov kev hloov pauv cuam tshuam qhov chaw tseem ceeb ntawm cov molecule me me nrog lub farnesylation active site, uas ua rau cov tshuaj tiv thaiv. .87 ib
Ib lub hom phiaj zoo rau kev tsim cov tshuaj tshiab yog txhawm rau thaiv P. falciparum ribosome, nrog rau lwm qhov ntawm cov tshuab txhais lus lub luag haujlwm rau cov protein synthesis.Plasmodium hom muaj peb genomes: nucleus, mitochondria, thiab acroplasts (los ntawm cov chloroplasts residual). Tag nrho cov genomes xav tau cov tshuab txhais lus kom ua haujlwm.Protein synthesis inhibitors muaj qhov ua tau zoo hauv kev kho mob raws li cov tshuaj tua kab mob zoo.Doxycycline, clindamycin, thiab azithromycin muaj cov tshuaj tua kab mob tiv thaiv kab mob vim tias lawv inhibit ribosomes hauv cov kab mob mitochondria thiab aplastoplasts, ua rau cov organelles 8. P. falciparum ribosome occupies ib evolutionary nruab nrab hauv av nruab nrab ntawm prokaryotes thiab eukaryotes, txawv nws markedly los ntawm tib neeg ribosome thiab yog li muab ib tug tseem ceeb promising lub hom phiaj.Plasmodium falciparum elongation factor 2 (pfEF2) yog ib feem ntawm lub ribosome ribosome uas yog transpendant-TP ntawm ribosomes nrog messenger RNA thiab yog ib qho tseem ceeb rau cov protein synthesis hauv eukaryotes.PfEF2 raug cais raws li lub hom phiaj tshiab rau kev txhim kho tshuaj tiv thaiv kab mob.87,89
Inhibition ntawm protein synthesis Siv lub discovery ntawm sordarin, ib yam khoom ntuj uas xaiv blocks fungal protein synthesis los ntawm inhibiting poov xab eukaryotic elongation factor 2.Ib yam li ntawd, M5717 (yav tas los DDD107498), ib tug xaiv inhibitor ntawm 80S ribosome-EF2, tam sim no nyob rau hauv cov theem Pf. 1 cov kev tshawb fawb, validating lub peev xwm ntawm PfEF2 raws li ib tug zoo lub hom phiaj rau antimalarial tshuaj.88,90
Cov yam ntxwv tseem ceeb ntawm tus mob malaria yog kev sib cais ntawm cov kab mob erythrocytes, o, thiab txhaws ntawm microvasculature.Plasmodium falciparum siv heparan sulfate raws li nws txuas rau endothelium thiab lwm cov qe ntshav, ua rau muaj kev cuam tshuam ntawm cov ntshav khiav.Inhibiting cov hlwb txawv txav thiab cov kab mob. -Drug interactions restores blocked blood flow and impacts parasite growth.91
Ntau cov kev tshawb fawb tau pom tias sevuparin, ib qho anti-adhesion polysaccharide ua los ntawm heparin, muaj antithrombin-tshem tawm cov teebmeem.Sevuparin inhibits merozoite ntxeem tau rau hauv erythrocytes, khi ntawm cov kab mob erythrocytes rau cov tsis muaj kab mob thiab kis kab mob erythrocytes, thiab khi rau cov kab mob vascular ntau dua. mus rau N-terminal extracellular heparan sulfate-binding qauv ntawm Plasmodium falciparum erythrocyte membrane protein 1, Duffy-binding-zoo li domain 1α (DBL1α), thiab xav tias yog ib qho tseem ceeb hauv sequestering kab mob erythrocytes.92,93 Qee Table 2 summarizes. kev sim tshuaj nyob rau ntau theem.
Post lub sij hawm: Mar-24-2022