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Tafere Mulaw Belete Department of Pharmacology, Faculty of Medicine and Health Sciences, Gondar University, Gondar, Ethiopia Kulemberana makalata: Tafere Mulaw Belete Tel +251 918045943Email [email protected] Abstract: Malungo ndi vuto lalikulu la thanzi padziko lonse lapansi lomwe limayambitsa kufa ndi kudwala kwambiri chaka chilichonse .Njira zochizira ndizosowa ndipo zimatsutsidwa kwambiri chifukwa cha kupezeka kwa tizilombo tosamva malungo, zomwe zimalepheretsa kwambiri kuwongolera malungo. Pofuna kupewa ngozi zomwe zingachitike paumoyo wa anthu, mankhwala atsopano othana ndi malungo okhala ndi mlingo umodzi wokha, kuchiza kwakukulu, ndi njira zatsopano zogwirira ntchito. akufunika mwachangu.Kupanga mankhwala oletsa malungo kungatsatire njira zosiyanasiyana, kuyambira kusinthidwa kwa mankhwala omwe alipo mpaka kupanga mankhwala atsopano omwe akutsata zolinga zatsopano.Kupita patsogolo kwamakono mu biology ya parasite ndi kupezeka kwa matekinoloje osiyanasiyana a genomic kumapereka zolinga zambiri zatsopano. kwa chitukuko chatsopano achire.Angapo kulonjeza targChifukwa chake, ndemangayi ikuyang'ana patsogolo za sayansi ndi zamakono zamakono pakupeza ndi chitukuko cha mankhwala oletsa malungo.Mapuloteni ochititsa chidwi kwambiri a antimalarial omwe amaphunzira mpaka pano akuphatikizapo proteases, protein kinases, plasmodium sugar. transporter inhibitors, aquaporin 3 inhibitors, choline transport inhibitors, dihydroorotate dehydrogenase inhibitors, pentadiene biosynthesis inhibitor, farnesyltransferase inhibitor ndi ma enzyme omwe amakhudzidwa ndi lipid metabolism ndi DNA replication.Kuwunikaku kukufotokozera mwachidule zolinga zatsopano za molekyulu m'mawu odana ndi malungo: kukana kwawo mankhwala osokoneza bongo. , zolinga zatsopano, mankhwala oletsa malungo, kachitidwe kachitidwe, tizilombo ta malungo
Malungo ndi matenda opatsirana a parasitic, makamaka kum'mwera kwa Sahara ku Africa, madera ena a Asia ndi South America.Ngakhale ayesetsa kangapo, lero ndi chimodzi mwa zifukwa zomwe zimayambitsa matenda ndi imfa makamaka kwa amayi apakati ndi ana.Malinga ndi World Health Bungwe (WHO) lipoti la 2018, panali matenda a malungo 228 miliyoni ndi imfa 405,000 padziko lonse. Amayi oyembekezera okwana 125 miliyoni amakhala pachiwopsezo chodwala malungo chaka chilichonse, ndipo ana 272,000 osakwanitsa zaka 5 amamwalira ndi malungo.1 Malungo amayambitsanso umphawi komanso cholepheretsa kwambiri chitukuko cha zachuma, makamaka ku Africa. Plasmodium yomwe imayambitsa malungo mwa anthu ndi P. vivax, P. knowlesi, P. ovale, P. malungo ndi P. falciparum. Mwa awa, Plasmodium falciparum ndi mitundu yakupha komanso yofala kwambiri ya Plasmodium.3
Popanda katemera wogwira ntchito, kugwiritsa ntchito mankhwala ochizira malungo kumakhalabe njira yokhayo yothetsera ndi kuteteza malungo.Kafukufuku wambiri wasonyeza kuti mphamvu ya mankhwala ambiri oletsa malungo imasokonezedwa ndi zochitika zadzidzidzi mu Plasmodium spp.4 Kukaniza mankhwala zakhala zikudziwika ndi pafupifupi mankhwala onse oletsa malungo, kulimbikitsa chitukuko cha mankhwala atsopano oletsa malungo motsutsana ndi zolinga zomwe zilipo kale zovomerezeka ndi kufufuza The gametophytic stage of transmission ingathenso kuchitapo kanthu pa kufalikira kwa asexual mkati mwa erythrocytes, makamaka mu mitundu yolimbana ndi tizilombo toyambitsa matenda.6 Ma enzyme angapo, ion mayendedwe, zonyamula, mamolekyu olumikizana Kuukira kwa maselo ofiira a magazi (RBC), ndi mamolekyu omwe amachititsa kuti tiziromboti tokhala ndi okosijeni, lipid metabolism, ndi kuwonongeka kwa hemoglobin ndizofunika kwambiri pakupanga mankhwala atsopano oletsa malungo motsutsana ndi malungo osintha mwachangu.
Kuthekera kwa mankhwala atsopano oletsa malungo kumayesedwa ndi zofunikira zingapo: njira yatsopano yochitira zinthu, palibe kutsutsana ndi mankhwala amakono a malungo, chithandizo cha mlingo umodzi, mphamvu yolimbana ndi siteji ya magazi a asexual ndi ma gametocyte omwe amachititsa kufalitsa. mankhwala oletsa malungo ayenera kukhala ndi mphamvu zopewera matenda (chemoprotectants) ndi kuchotsa chiwindi cha P. vivax hypnotics (anti-relapse agents).8
Kupeza mankhwala ochiritsira kumatsatira njira zingapo zodziwira mankhwala atsopano othana ndi malungo. Izi zikuphatikiza kuwongolera njira ndi makonzedwe a mankhwala omwe alipo, kusintha mankhwala oletsa malungo omwe alipo, kuyesa zinthu zachilengedwe, kudzipatula mankhwala othana ndi malungo, kugwiritsa ntchito njira zophatikizira zamankhwala, komanso kupanga mankhwala. ntchito zina.8,9
Kuphatikiza pa njira zachikhalidwe zopezera mankhwala omwe amagwiritsidwa ntchito pozindikiritsa mankhwala atsopano oletsa malungo, chidziwitso cha biology ya maselo a Plasmodium ndi genome yasonyezedwa kuti ndi chida champhamvu chovumbulutsira njira zolimbana ndi mankhwala, ndipo ili ndi kuthekera kopanga mankhwala okhala ndi antimalarial ndi anti malungo.Kuthekera kwakukulu kwa mankhwala atsopano.Kulimbana ndi kusokoneza kufalikira kwa malungo kamodzi kokha.10 Kuwunika kwa majini a Plasmodium falciparum anapeza majini 2680 ofunika kwambiri pa kukula kwa gawo la magazi, potero kuzindikira njira zazikulu zama cell zomwe ndizofunikira kwambiri popanga mankhwala atsopano.10,11 Zatsopano. mankhwala ayenera: (i) kuthetsa kukana mankhwala, (ii) kuchita zinthu mofulumira, (iii) kukhala otetezeka, makamaka kwa ana ndi amayi apakati, ndi (iv) kuchiza malungo ndi mlingo umodzi wokha.12 Vuto limakhala kupeza mankhwala amene amachiza Makhalidwe onsewa.Cholinga cha ndemangayi ndikupereka lingaliro lazolinga zatsopano zochizira matenda a malungo, omwe akuphunziridwa ndi makampani angapo, kuti owerenga adziwitsidwe za ntchito yapitayi.
Pakali pano, mankhwala ambiri oletsa malungo amalimbana ndi matenda a malungo omwe amayambitsa matenda a malungo. Gawo la pre-erythrocytic (chiwindi) silikuwoneka bwino chifukwa palibe zizindikiro zachipatala zomwe zimapangidwira. mankhwala achilengedwe, mankhwala opangidwa ndi semi-synthetic ndi opangidwa kuchokera ku 1940s.13 Mankhwala oletsa malungo omwe alipo kale amagwera m'magulu atatu akuluakulu: zotengera za quinoline, antifolates ndi artemisinin zotumphukira. Choncho, kuti athetse matenda a malungo, mankhwala osakaniza amaperekedwa nthawi imodzi.Quinoline ndi mankhwala oletsa malungo omwe amagwiritsidwa ntchito kwambiri pochiza malungo. kuchiza matenda m’zaka za zana la 17. Kuyambira pakati pa zaka za m’ma 1800 mpaka m’ma 1940, qui9 anali mankhwala ochizira malungo.14 Kuwonjezera pa poizoni, kupezeka kwa mitundu ya P. falciparum yosamva mankhwala kwachepetsa kuchiritsa kwa kwinini. mankhwala achiwiri kuti afupikitse nthawi ya chithandizo ndi kuchepetsa zotsatira zake.15,16
Chithunzi 1 Kayendedwe ka moyo wa Plasmodium mwa anthu.Magawo ndi mitundu ya tizilombo toyambitsa matenda momwe mitundu yosiyanasiyana ya mankhwala oletsa malungo amachitira.
Mu 1925, ofufuza a ku Germany adapeza mankhwala oyambirira a antimalarial, pamaquin, posintha methylene blue.Pamaquin ali ndi mphamvu zochepa komanso poizoni ndipo sangathe kugwiritsidwa ntchito pochiza malungo. chochokera ku methylene blue yomwe imagwiritsidwa ntchito pochiza malungo pa Nkhondo Yachiwiri Yadziko Lonse.17
Chloroquine anapangidwa pa nthawi ya nkhondo yachiwiri ya padziko lonse pofuna kuchiza malungo.Chloroquine ndi mankhwala osankhidwa bwino pochiza malungo chifukwa cha mphamvu zake, chitetezo chake komanso mtengo wake wotsika.Koma kugwiritsa ntchito kwake mopanda nzeru posakhalitsa kunachititsa kuti pakhale mitundu ya P. falciparum yosamva chloroquine. 18 Primaquine amagwiritsidwa ntchito pochiza matenda a Plasmodium vivax omwe amayamba chifukwa cha hypnosis.Primaquine ndi wamphamvu gameticidal motsutsana ndi Plasmodium falciparum.Primaquine imayambitsa hemolytic anemia kwa odwala omwe ali ndi vuto la glucose-6-phosphate dehydrogenase (G6PD). -P.Ntchito Yamasiku Onse.19
Mankhwala atsopano a quinoline anapangidwa, zomwe zinapangitsa kuti pakhale mankhwala atsopano monga piperaquine ndi amodiaquine. Pambuyo poonekera kwa chloroquine resistance, amodiaquine, analogi ya chloroquine yolowa m'malo mwa phenyl, inasonyeza mphamvu yabwino kwambiri yolimbana ndi mitundu ya Plasmoyrrrummadium Pr. base antimalarial mankhwala opangidwa ku China mu 1970.Ndiwothandiza motsutsana ndi mitundu yosamva mankhwala ya P. falciparum, P. vivax, P. malungo ndi P. ovale.Pyronadrine tsopano ikupezeka ngati ACT with artesunate, yomwe yawonetsa kuchita bwino kwambiri motsutsana ndi onse. tizilombo toyambitsa malungo.21 Mefloquine inapangidwa pakati pa zaka za m'ma 1980 ndipo panopa ikulimbikitsidwa kuti ichepetse malungo oyambitsidwa ndi mitundu yonse ya zamoyo, kuphatikizapo mitundu ina ya chloroquine-resistant. Amagwira ntchito makamaka pa siteji ya magazi a tizilombo toyambitsa matenda, koma mankhwala ena oletsa malungo amagwira ntchito pachiwindi. Mankhwalawa amalepheretsa kupanga complEx ndi heme mu chakudya cha parasite cha vacuoles.Choncho, heme polymerization imatsekedwa.Chotsatira chake, heme yomwe imatulutsidwa panthawi ya kusweka kwa hemoglobini imadziunjikira kumagulu oopsa, kupha tizilombo toyambitsa matenda ndi zinyalala zapoizoni.makumi awiri ndi atatu.
Antifolates ndi mankhwala antimalarial kuti ziletsa kaphatikizidwe wa kupatsidwa folic acid, amene n'kofunika kuti synthesis wa nucleotides ndi amino zidulo. (PABA), chigawo cha folic acid.Amalepheretsa dihydrofolate kaphatikizidwe mwa kuletsa dihydrofolate synthase, puloteni yofunika kwambiri mu nucleic acid biosynthesis.makumi awiri ndi anayi
Pyrimethamine ndi proguanil ndi mankhwala a schizont antimalarial omwe amagwira ntchito pamtundu wa asexual wa Plasmodium mitundu. Proguanil ndi prodrug metabolized to cyclic guanidine.Proguanil anali mankhwala oyamba a antifolate omwe amagwiritsidwa ntchito pochiza malungo.Chifukwa chake ndi chakuti amawononga maselo ofiira a magazi asanafike tizilombo toyambitsa matenda pamene amalowa m'magazi.Komanso, proguanil ndi yotetezeka. mankhwala.Pyrimethamine amagwiritsidwa ntchito makamaka ndi mankhwala ena othamanga.Komabe, kugwiritsidwa ntchito kwake kwachepa chifukwa cha kukana mankhwala.24,25
Atovaquone ndi mankhwala oyamba ovomerezeka oletsa malungo olunjika ku mitochondria ya Plasmodium parasite.Atovaquone imalepheretsa kunyamula ma elekitironi pochita ngati analogi ya ubiquinone kutsekereza gawo la cytochrome b la cytochrome bc1 complex.Akaphatikizidwa ndi proguanil, atovaquone ndi yabwino komanso yothandiza kwa amayi apakati. ndi ana.Atovaquone imagwira ntchito polimbana ndi siteji ya kugonana kwa tizilombo toyambitsa matenda ndi udzudzu.Chotero, imalepheretsa kufalikira kwa malungo kuchokera ku udzudzu kupita kwa anthu.Kuphatikizana kosakhazikika ndi proguanil opangidwa pansi pa dzina la malonda Malarone.24,26
Artemisinin inatengedwa kuchokera ku Artemisia annua mu 1972. Artemisinin ndi zotuluka zake kuphatikizapo artemether, dihydroartemisinin, artemether ndi artesunate ali ndi ntchito yotakata. a gametocytes kuchokera kwa anthu kupita ku udzudzu.27 Artemisinin ndi zotuluka zake zimagwira ntchito motsutsana ndi chloroquine- ndi mefloquine-resistant schizonts.Ndiwotetezeka, ogwira ntchito komanso othamanga kwambiri a schizonts a magazi ku mitundu yonse ya Plasmodium. Mankhwalawa amakhala ndi theka la moyo waufupi komanso kusapezeka bwino kwa bioavailability, zomwe zimapangitsa kuti asagwire ntchito ngati monotherapy.Chotero, zotumphukira za artemisinin zimalimbikitsidwa kuphatikiza ndi mankhwala ena oletsa malungo.28
Mphamvu ya antimalarial ya artemisinin ikhoza kukhala chifukwa cha kubadwa kwa ma radicals aulere omwe amayamba chifukwa cha kung'ambika kwa milatho ya artemisinin endoperoxide mu vesicles ya chakudya cha parasite, potero kulepheretsa tizilombo toyambitsa matenda a calcium ATPase ndi proteasome.29,30 Artemether amagwiritsidwa ntchito ngati monotherapy.Kuthamanga m'kamwa mofulumira Bioavavailability. kuwirikiza kawiri pamene kutumikiridwa pamaso pa chakudya.Kamodzi mu zokhudza zonse kufalitsidwa, artemether ndi hydrolyzed kuti dihydroartemisinin m'matumbo ndi chiwindi.
Artesunate ndi semi-synthetic derivative chifukwa cha mphamvu yake yolimbana ndi malungo mofulumira, kusowa kwa mankhwala osokoneza bongo komanso kusungunuka kwamadzi.
Tetracyclines ndi macrolides ndi mankhwala oletsa malungo osagwira ntchito pang'onopang'ono omwe amagwiritsidwa ntchito ngati adjunctive therapy to quinine mu falciparum malungo.Doxycycline amagwiritsidwanso ntchito pochiza chemoprophylaxis m'madera omwe ali ndi mphamvu zambiri.32 Njira yamakono yomwe imagwiritsidwa ntchito polimbana ndi malungo ndi kugwiritsa ntchito mankhwala osakaniza mankhwala. njira yakhala ikugwiritsidwa ntchito m'mbuyomu pogwiritsa ntchito zosakaniza zokhazikika.WHO imalimbikitsa artemisinin-based combination therapy (ACT) ngati njira yoyamba yothandizira malungo osavuta a falciparum.Chifukwa chake ndi chakuti kuphatikiza mankhwala kumachepetsa kukana kwa mankhwala ndi zotsatira zake.33
ACT ili ndi chigawo champhamvu cha artemisinin chomwe chimachotsa mwamsanga tizilombo toyambitsa matenda, ndi mankhwala oletsa tizilombo toyambitsa matenda omwe amachotsa mabakiteriya otsalira komanso amachepetsa kukana kwa artemisinin.Mchitidwe wovomerezeka ndi WHO ndi artesunate / amodiaquine, artemether / benzfluorenol, artesunate / mefloquine, artesunate / pyrroartelidine piperaquine, Artesunate/sulfadoxine/pyrimethamine, artemether/piperaquine ndi artemisinin/piperaquine/primaquine.Chloroquine plus primaquine akadali mankhwala oyamba othetsera Plasmodium vivax.Quinine + tetracycline/doxycycline ali ndi machiritso ochuluka kwambiri zotsatira ndi contraindicated ana ndi amayi apakati34.
Mefloquine, atovaquone/proguanil, kapena doxycycline amalangizidwa m'makonzedwe a chemoprevention kwa oyenda kuchokera kumadera omwe sali ofala kupita kumadera omwe ali ndi matendawa.35 Chithandizo chapakatikati chopewera m'magulu omwe ali pachiwopsezo chachikulu chimalimbikitsidwa, kuphatikiza sulfadoxine/pyrimethamine pa nthawi yapakati ndi amodiaquine/sulfadoxine-pyrimethamine monga nyengo. .36 Halofantrine si yoyenera kugwiritsira ntchito mankhwala chifukwa cha cardiotoxicity.Dapsone, mepalyline, amodiaquine, ndi sulfonamides anachotsedwa ku ntchito yochizira chifukwa cha zotsatira zake.36,37 Mankhwala ena odziwika bwino oletsa malungo ndi zotsatira zake zalembedwa mu Table. 1.
Pakalipano mankhwala oletsa malungo amachokera pa kusiyana kwa njira zazikulu za kagayidwe kagayidwe kachakudya pakati pa mitundu ya Plasmodium ndi zowasamalira. Njira zazikulu za kagayidwe ka tizilombo toyambitsa matenda, kuphatikizapo kuchotseratu poizoni wa heme, kaphatikizidwe ka mafuta acid, kaphatikizidwe ka nucleic acid, kaphatikizidwe ka mafuta acid, ndi kupsinjika kwa oxidative, ndi ena mwa bukuli. malo opangira mankhwala.38,39 Ngakhale kuti mankhwala ambiri oletsa malungo akhala akugwiritsidwa ntchito kwa zaka zingapo, ntchito yawo panopa ndi yochepa chifukwa cha kukana kwa mankhwala.Malinga ndi mabuku, palibe mankhwala oletsa malungo omwe apezeka kuti amaletsa zolinga zodziwika bwino za mankhwala.7,40 Mu mosiyana, mankhwala ambiri oletsa malungo amapezeka mu maphunziro a zinyama mu vivo kapena mu vitro model.Choncho, njira yogwiritsira ntchito mankhwala ambiri oletsa malungo imakhalabe yosadziwika.
Kuwongolera malungo kumafuna njira zogwirizanirana monga kuwongolera ma vector, mankhwala othandiza komanso otetezeka oletsa malungo, komanso katemera wogwira ntchito.Poganizira za kufa kwambiri komanso kudwala malungo, ngozi zadzidzidzi komanso kufalikira kwa kukana kwa mankhwala, kusagwira ntchito kwamankhwala omwe alipo kale motsutsana ndi osakhala erythrocyte komanso magawo ogonana. , kuzindikiritsa mankhwala atsopano oletsa malungo pomvetsetsa njira zoyambira za malungo.Kuti tikwaniritse cholingachi, kafukufuku wamankhwala akuyenera kutsata mipherezero yatsopano, yovomerezeka yopatula mankhwala atsopano.39,41
Pali zifukwa zingapo zomwe zimafunikira kuzindikira zolinga zatsopano za kagayidwe kachakudya.Choyamba, kupatulapo mankhwala opangidwa ndi atovaquone ndi artemisinin, mankhwala ambiri oletsa malungo sakhala ndi mankhwala osiyanasiyana, omwe angayambitse kusagwirizana.Chachiwiri, chifukwa cha mitundu yosiyanasiyana ya putative chemotherapeutic targets, ambiri sanatsimikizidwebe.Ngati atatsimikiziridwa, angapereke mankhwala ena omwe ali othandiza komanso otetezeka.Kuzindikiritsa zolinga zatsopano za mankhwala ndi mapangidwe atsopano omwe amagwira ntchito pazifukwa zatsopano amagwiritsidwa ntchito kwambiri padziko lonse lapansi lero kuti athetse. mavuto obwera chifukwa cha kukana kwa mankhwala omwe alipo.40,41 Choncho, kafukufuku wa mapuloteni enieni okhudzana ndi mapuloteni a Plasmodium akhala akugwiritsidwa ntchito pozindikiritsa chandamale cha mankhwala. kulowererapo kwatulukira. Mankhwalawa amatha kukhala ndi malungo omwe amayang'ana makiyi a metabolite biosynthesis, kayendedwe ka membrane ndi machitidwe owonetsera zizindikiro, ndi njira zowonongeka kwa hemoglobini.40,42
Plasmodium protease ndi puloteni yomwe imapezeka paliponse komanso yolamulira yomwe imathandizira kwambiri kuti tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda. kuthawa, kuyambitsa kutupa, kulowetsedwa kwa erythrocyte, kuwonongeka kwa hemoglobini ndi mapuloteni ena, autophagy, ndi chitukuko cha tizilombo.44
Malaria proteases (glutamic aspartic acid, cysteine, zitsulo, serine ndi threonine) akulonjeza zochizira chifukwa kusokonezeka kwa jini ya malungo kumalepheretsa kuwonongeka kwa hemoglobin ndi gawo la erythrocyte la parasite.chitukuko.45
Kuwonongeka kwa erythrocyte ndi kuukira kotsatira kwa merozoite kumafuna malungo a protease. Peptide yopangidwa (GlcA-Val-Leu-Gly-Lys-NHC2H5) imalepheretsa Plasmodium falciparum schizont cysteine protease Pf 68. akusonyeza kuti tizilombo toyambitsa matenda timathandiza kwambiri kuti tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda.
Mu Plasmodium falciparum chakudya vacuoles, angapo aspartic proteases (plasma proteases I, II, III, IV) ndi cysteine proteases (falcipain-1, falcipain-2/, falcipain-3) akhala olekanitsidwa, Amagwiritsidwa ntchito pochepetsa hemoglobin, monga momwe zasonyezedwera. mu Chithunzi 2.
Kumakulitsidwa kwa tizilombo toyambitsa matenda a P. falciparum ndi protease inhibitors leupeptin ndi E-64 kunapangitsa kuti globin yosasinthika ikhale yochuluka. Kafukufuku wambiri wasonyeza kuti cystatin inhibitors sikuti amangolepheretsa kuwonongeka kwa globin, komanso amalepheretsa kuyambika kwa hemoglobini, monga hemoglobin denaturation, heme kumasulidwa ku globin, ndi kupanga heme. .49 Zotsatira izi zikusonyeza kuti cysteine proteases amafunikira pa gawo loyambirira.Zomwe zingawononge hemoglobini ndi Plasmodium falciparum. Onse E-64 ndi pepstatin synergistically block P. falciparum development.Komabe, E-64 yokha inatsekereza globin hydrolysis. 48,49 angapo cysteine protease inhibitors, monga fluoromethyl ketone ndi vinyl sulfone, amaletsa P. falciparum kukula ndi hemoglobin degradation.Muchitsanzo cha nyama ya malungo, fluoromethyl ketone inhibits P. vinckei protease ntchito ndikuchiritsa 80% ya matenda a malungo a murine.Choncho, protease inhibitors ndi omwe amalonjeza mankhwala oletsa malungo. zomwe zimalepheretsa kagayidwe ka tiziromboti ndi chitukuko.50
Ma serine proteases amakhudzidwa ndi schizont rupture ndi erythrocyte reinvasion panthawi ya Plasmodium falciparum life cycle.Ikhoza kutsekedwa ndi serine protease inhibitors angapo ndipo ndiyo yabwino kwambiri popeza palibe munthu wa enzyme homolog yomwe ilipo.Protease inhibitor LK3 yotalikirana ndi Streptomyces sp.imachepetsa malungo a serine protease.51 Maslinic acid ndi pentacyclic triterpenoid yachilengedwe yomwe imalepheretsa kukhwima kwa tizilombo toyambitsa matenda kuchokera pa ring stage kufika pa schizont stage, potero imathetsa kutulutsidwa kwa merozoite ndi kuukira kwawo. -2 ndi falcipain-3.52 statins ndi inhibition ya plasma proteases pogwiritsa ntchito allophenostatin-based inhibitors amaletsa kuwonongeka kwa hemoglobin ndi kupha tizilombo toyambitsa matenda. .
Phosphoinositide lipid kinases (PIKs) ndi ma enzyme omwe amapezeka ponseponse omwe phosphorylate lipids kuti athetse kufalikira, kupulumuka, kugulitsa malonda, ndi chizindikiro cha intracellular.Makalasi a PIK omwe amaphunzira kwambiri m'magulu a 53 ndi phosphoinositide 3-kinase (PI3K) ndi phosphoinoselsephatidyli4 (K) PIC4. Kuletsa kwa ma enzymes awa kwadziwika kuti ndi njira yomwe ingatheke kupanga mankhwala oletsa malungo omwe ali ndi mbiri yabwino yoletsa malungo. (4)K ndikulepheretsa kukula kwa mitundu ingapo ya Plasmodium pagawo lililonse la matenda obwera chifukwa cha matendawa.Chotero, kutsata (PI3K) ndi PI(4)K kungatsegule njira zatsopano potengera kupezedwa kwa mankhwala omwe amawunikira kuti azindikire mankhwala oletsa malungo.KAF156 pano ndi m'mayesero achipatala a Phase II.55,56 MMV048 ndi gulu lomwe lili ndi ntchito yabwino ya vivo prophylactic motsutsana ndi P. cynomolgi komanso kuthekera kwaMMV048 ikuyesa mayeso achipatala a Phase IIa ku Ethiopia.11
Kuti kukula msanga kwa maselo ofiira a m'magazi, mitundu ya Plasmodium imafuna magawo okwanira okwanira kuti azitha kuwongolera kagayidwe kawo.Chotero, majeremusi amakonzekeretsa ma erythrocyte poyambitsa onyamula apadera omwe amasiyana kwambiri ndi onyamula ma cell omwe amanyamula ndikuchotsa metabolites. mapuloteni onyamulira ndi njira zomwe zingatheke chifukwa cha udindo wawo wofunikira pa kayendetsedwe ka metabolites, electrolytes ndi zakudya.57 Awa ndi Plasmodium surface anion channel (PSAC) ndi parasitic vacuolar membrane (PVM), yomwe imapereka njira yowonjezera yowonjezera zakudya. kulowa m'thupi.58
PSAC ndiyo yodalirika kwambiri chifukwa imapezeka mumitundu yosiyanasiyana ya zakudya (hypoxanthine, cysteine, glutamine, glutamate, isoleucine, methionine, proline, tyrosine, pantothenic acid ndi choline) kuti apeze maudindo akuluakulu mu tizilombo toyambitsa matenda.PSACs alibe homology yodziwika bwino. ku ma genes odziwika a host channel.58,59 Phloridizin, dantrolene, furosemide, ndi niflunomide ndi amphamvu anion transporter blockers. Mankhwala monga glyburide, meglitinide, ndi tolbutamide amalepheretsa choline kulowa m'maselo ofiira a parasitic.60,61
Magazi a Plasmodium falciparum amadalira pafupifupi glycolysis kuti apange mphamvu, popanda kusunga mphamvu;Zimadalira kuchuluka kwa glucose nthawi zonse. Tizilombo toyambitsa matenda timatembenuza pyruvate kukhala lactate kupanga ATP, yomwe imafunika kuti ibwerezeke mkati mwa maselo ofiira a magazi. erythrocyte membrane ndi 'new permeation pathway' yopangidwa ndi tiziromboti.63 Glucose amasamutsidwa kupita ku tizirombo ndi Plasmodium falciparum hexose transporter (PFHT).PFHT ili ndi mikhalidwe yonyamula shuga.GLUT1 imasankha D-glucose, pomwe PFHT imatha kunyamula D-glucose ndi D-fructose.Choncho, kusiyana kwa GLUT1 ndi PFHT kuyanjana ndi magawo apakati kumasonyeza kuti kuletsa kusankha kwa PFHT ndi cholinga chatsopano chopanga mankhwala oletsa malungo. 3361) imalepheretsa kutengeka kwa glucose ndi fructose ndi PFHT, koma sikulepheretsa kuyenda kwa hexose ndi ma mammalian glucose ndi fructose transporters (GLUT1 ndi 5).361 inalepheretsanso kutengeka kwa shuga ndi P. vivax wa PFHT.M'maphunziro apitalo, chigawo 3361 chinapha P. falciparum mu chikhalidwe ndikuchepetsa kubereka kwa P. berghei muzithunzi za mbewa.65
Magulu a magazi a Plasmodium amadalira kwambiri anaerobic glycolysis kuti akule ndi chitukuko.60 Maselo ofiira a m'magazi omwe ali ndi tizilombo amamwa shuga mofulumira kuwirikiza ka 100 kuposa maselo ofiira a m'magazi omwe alibe kachilomboka. njira ya H + symporter ku chilengedwe chakunja.66 Lactate yotumiza kunja ndi kutengeka kwa shuga ndizofunikira kwambiri kuti mukhalebe ndi mphamvu zamagetsi, pH intracellular, ndi parasite osmotic bata.Kuletsa kwa Lactate:H+ symporter system inhibition ndi chiyembekezo chatsopano chopanga mankhwala atsopano.Mitundu ingapo, monga MMV007839 ndi MMV000972, imapha tizilombo ta asexual blood-stage P. falciparum poletsa lactate:H+ transporter.67
Mofanana ndi mitundu ina ya maselo, maselo ofiira a m'magazi amakhala otsika kwambiri mkati mwa Na +. adzipeza okha pamtundu wapamwamba wa Na + ndipo ayenera kutulutsa ma Na + ions ku membrane yawo ya plasma kuti akhalebe otsika kwambiri a cytoplasmic Na + kuti apulumuke ngakhale atakhalapo m'malo a intracellular. transporter (PfATP4), yomwe imakhala ngati makina oyambira a Na+-efflux a parasite, monga momwe tawonetsera pa Chithunzi 3.68, kuletsa chonyamulira ichi Zidzabweretsa kuchuluka kwa Na+ mkati mwa tiziromboti, zomwe pamapeto pake zidzatsogolera ku imfa ya Majeremusi a malungo.Mipangidwe ingapo, kuphatikizapo sipagamin mu gawo 2, (+) -SJ733 mu gawo 1, ndi KAE609 mu gawo 2, ali ndi njira yogwirira ntchito yomwe imayang'ana PfATP4.67,69
Chithunzi 3. Njira yopangira tizilombo toyambitsa matenda PfATP4 ndi V-mtundu wa H + -ATPase mu imfa ya erythrocyte yomwe ili ndi kachilombo pambuyo poletsa cipargamin.
Mitundu ya Plasmodium imayang'anira ma Na+ awo pogwiritsa ntchito P-mtundu wa ATPase transporter. Imalowetsanso H + kudzera munjira yofanana. tulutsani H+.Kupanga mankhwala atsopano ndi cholinga chodalirika.MMV253 imalepheretsa V-mtundu wa H+ ATPase monga njira yake yochitira zinthu mwa kusankha masinthidwe ndi kutsatizana kwa ma genome onse.70,71
Aquaporin-3 (AQP3) ndi puloteni ya aquaglycerol yomwe imathandizira kuyenda kwa madzi ndi glycerol m'maselo a mammalian.AQP3 imapangidwira mu hepatocyte yaumunthu chifukwa cha matenda a tizilombo toyambitsa matenda ndipo imakhala ndi ntchito yofunikira pa kubwereza kwa tizilombo toyambitsa matenda.AQP3 imapereka mwayi wa glycerol mu P .berghei ndikuthandizira kugawanika kwa tizilombo toyambitsa matenda mu gawo la asexual erythrocyte.72 Kuchepa kwa chibadwa kwa AQP3 kumachepetsa kwambiri katundu wa tizilombo toyambitsa matenda mu chiwindi cha P. berghei.Kuwonjezerapo, chithandizo cha AQP3 inhibitor auphen chinachepetsa kuchuluka kwa P. berghei parasites ndi hepatocytes mu hepatocytes. falciparum parasitemia mu erythrocytes, kutanthauza kuti mapuloteni omwe amachitira nawo amagwira ntchito yofunika kwambiri pamagulu osiyanasiyana a moyo wa tizilombo toyambitsa matenda .73 Chochititsa chidwi kwambiri, kusokonezeka kwa AQP3 mu mbewa zamtundu wa mbewa sikupha, kutanthauza kuti mapuloteni omwe ali nawo amatha kukhala ndi chithandizo chatsopano. kumvetsetsa kwa njira zachiwindi zomwe zimakhudzidwa ndi matenda a Plasmodium ndikuwunikira kuthekera kwa proamasiya ngati mankhwala oletsa malungo amtsogolo.71,72
Phospholipids amagwira ntchito yofunika kwambiri pa moyo wa intra-erythrocyte wa Plasmodium falciparum, monga zigawo zamapangidwe a nembanemba komanso monga mamolekyu owongolera omwe amayendetsa ntchito za ma enzymes osiyanasiyana. Kuchuluka kwa phospholipid, komwe phosphatidylcholine ndiye lipid yayikulu m'magawo a cell membrane.Tizilombo toyambitsa matenda timapanga phosphatidylcholine de novo pogwiritsa ntchito choline ngati kalambulabwalo.Njira iyi ya de novo ndiyofunikira kwambiri pakukula kwa tiziromboti ndi kupulumuka.Imalepheretsa choline kupita ku tiziromboti ndikuletsa phosphatidylcholine, kuchititsa kufa kwa tizilombo.74 Albitiazolium, mankhwala omwe alowa m'mayesero a Phase II, amagwira ntchito makamaka poletsa kayendedwe ka choline kupita ku tizilombo toyambitsa matenda. condition.Notably, jekeseni mmodzi anachiritsa mkulu pmisinkhu ya arasitemia.75,76
Phosphocholine cytidyltransferase ndi sitepe yochepetsera mlingo mu de novo biosynthesis ya phosphatidylcholine.77 The diquaternary ammonium compound G25 ndi dicationic compound T3 inhibit phosphatidylcholine synthesis in parasites.G25 ndi 1000-folds zochepa zowopsa za mankhwala omwe amatsogolera mammalian cell. mankhwala ophatikizika pakupeza ndi chitukuko cha mankhwala oletsa malungo.78,79
Chinthu chofunika kwambiri pa kufalikira kwa mitundu ya Plasmodium m'magulu a anthu ndi kugawidwa kwakukulu komanso kofulumira kwa DNA ya tizilombo toyambitsa matenda, zomwe zimadalira kupezeka kwa metabolites yofunika kwambiri monga pyrimidines. glycoproteins.Nucleotide kaphatikizidwe amatsatira njira ziwiri zazikulu: njira yopulumutsira ndi njira ya de novo.Dihydroorotate dehydrogenase (DHODH) ndi puloteni yofunikira yomwe imapangitsa kuti oxidation ya dihydroorotate ikhale orotate, sitepe yochepetsera mlingo mu de novo pyrimidine synthesis, DHODH. imayimira cholinga chomwe chingakhale chodalirika cha chitukuko cha mankhwala oletsa malungo.80 Maselo aumunthu amapeza pyrimidines mwa kupulumutsa pyrimidines yomwe inapangidwa kale kapena ndi de novo synthesis.Ngati njira ya de novo biosynthetic italetsedwa, selo lidzadalira njira yopulumutsira ndipo selo silidzafa. Komabe, kuletsa kwa de novo pyrimidine biosynthesis mu tiziromboti kumabweretsa kufa kwa maselowa chifukwatizilombo toyambitsa malungo tilibe njira yopulumutsira pyrimidine, zomwe zimapangitsa kuti tizilombo toyambitsa matenda tisawonongeke ndi DHODH.81 DSM190 ndi DSM265 ndizosankha zoletsa tizilombo toyambitsa matenda a DHODH enzyme, yomwe pakali pano ili m'mayesero achipatala a Phase 2. P218 ndi DHODH inhibitor yogwira ntchito ku pyrimethamine- matenda osagonjetsedwa omwe ali mu Phase 1.KAF156 (Ganaplacide) pakali pano ali muyeso lachipatala la Phase 2b ndi phenylfluorenol.82
Ma Isoprenoids amafunikira pakusinthidwa kwa lipids pambuyo pomasulira kwa mapuloteni ndi kubwereza kwa asexual kwa Plasmodium falciparum.Isoprenoids amapangidwa kuchokera ku carbon precursor isopentyl diphosphate (IPP) kapena isomeri yake, dimethylallyl diphosphate (DMAPP), ndi imodzi mwa njira ziwiri zodziimira. pathway ndi 2C-methyl-D-erythritol 4-phosphate (MEP) pathway.Mu tizilombo toyambitsa matenda, njira ziwirizi zimakhala zosiyana.Bacteria ndi Plasmodium falciparum zimadalira kwathunthu njira ya MEP, pamene anthu sali.Choncho, ma enzymes mu Plasmodium falciparum 1-deoxy-xylulose-5-phosphate reductoisomerase (pfDxr) imathandizira kuchepetsa mlingo wa njira ya MEP, kupanga enzyme iyi kukhala chandamale chothandizira kupanga mankhwala atsopano oletsa malungo. .83,84 PfDXR inhibitors inhibit Plasmodium falciparum.Plasmodium falciparum imakula ndipo ilibe poizoni ku maselo a anthu.PfDXR ndi chandamale chatsopano chomwe chingathekechitukuko cha mankhwala oletsa malungo.83 Fosmidomycin, MMV019313 ndi MMV008138 amaletsa DOXP rectoisomerase, enzyme yofunika kwambiri ya DOXP njira yomwe kulibe mwa anthu.
Mapuloteni opangidwa ndi prenylated amagwira ntchito yofunika kwambiri m'njira zosiyanasiyana zama cell kuphatikiza kugulitsa ma vesicle, kutumiza ma sign, kuwongolera kubwereza kwa DNA, komanso kugawikana kwa maselo. kusamutsidwa kwa gulu la farnesyl, 15-carbon isoprenoid lipid unit, kuchokera ku farnesyl pyrophosphate kupita ku C-terminus ya mapuloteni omwe ali ndi CaaX motif.Farnesyltransferase ndi cholinga chatsopano cha chitukuko cha mankhwala oletsa malungo chifukwa choletsa chake chimapha tizilombo toyambitsa matenda.86
M'mbuyomu, kusintha kwa kukana tizilombo toyambitsa matenda ndi farnesyltransferase inhibitor BMS-388,891 tetrahydroquinoline kunawonetsa kusintha kwa mapuloteni a peptide substrate-binding domain. Posankha tetrahydroquinoline ina ndi BMS-339,941, kusintha kunapezeka mu farnesyl binding pocket pyrophosphate. .Mu kafukufuku wina, masinthidwe anapezeka mu gawo la farnesyltransferase beta la MMV019066-resistant strain ya P. falciparum.Kufufuza kwachitsanzo kwawonetsa kuti kusinthaku kumasokoneza malo ofunikira ogwirizanitsa a molekyulu yaing'ono ndi malo ogwira ntchito a farnesylation, zomwe zimabweretsa kukana mankhwala. .87
Chimodzi mwa zolinga zolimbikitsa kupanga mankhwala atsopano ndi kutsekereza P. falciparum ribosome, komanso mbali zina za makina omasulira omwe ali ndi mapuloteni opangidwa ndi mapuloteni. Mitundu ya Plasmodium ili ndi ma genome atatu: nucleus, mitochondria, ndi acroplasts (kuchokera ku ma chloroplasts otsalira). Ma genome onse amafunikira makina omasulira kuti agwire ntchito.Maprotein synthesis inhibitors ali ndi chipambano chachikulu chachipatala monga maantibayotiki ogwira mtima.Doxycycline, clindamycin, ndi azithromycin ali ndi chithandizo chochizira malungo chifukwa amalepheretsa ma ribosomes mu ma parasite mitochondria ndi aplastoplast, kupangitsa kuti organelles asagwire ntchito.88 P. falciparum ribosome imakhala ndi chisinthiko chapakati pakati pa prokaryotes ndi eukaryotes, kuisiyanitsa kwambiri ndi ribosome yaumunthu motero imapereka chandamale chatsopano chodalirika. ma ribosomes pamphepete mwa chisokonezoenger RNA ndipo ndiyofunika kuti mapuloteni apangidwe mu eukaryotes.PfEF2 inapatulidwa ngati cholinga chatsopano cha chitukuko cha mankhwala oletsa malungo.87,89
Kuletsa kaphatikizidwe ka mapuloteni Tengani kupezeka kwa sordarin, mankhwala achilengedwe omwe amalepheretsa kaphatikizidwe ka mapuloteni a fungal poletsa yisiti eukaryotic elongation factor 2. Mofananamo, M5717 (omwe kale anali DDD107498), inhibitor yosankha ya 80S ribosome-interacting, P pakali pano ndi infF. Maphunziro a 1, kutsimikizira kuthekera kwa PfEF2 monga chandamale chothandiza cha mankhwala oletsa malungo.88,90
Mbali yaikulu ya malungo aakulu ndi kuchotsedwa kwa tizilombo toyambitsa matenda erythrocytes, kutupa, ndi kutsekeka kwa microvasculature.Plasmodium falciparum imagwiritsa ntchito heparan sulfate pamene imamangiriza ku endothelium ndi maselo ena a magazi, zomwe zimapangitsa kuti magazi asayende bwino. -Kuyanjana kwamankhwala kumabwezeretsa magazi otsekeka komanso kumakhudza kukula kwa tiziromboti.91
Kafukufuku wambiri wasonyeza kuti sevuparin, anti-adhesion polysaccharide yopangidwa kuchokera ku heparin, imakhala ndi antithrombin-kuchotsa zotsatira. ku N-terminal extracellular heparan sulfate-binding structure ya Plasmodium falciparum erythrocyte membrane protein 1, Duffy-binding-like domain 1α (DBL1α), ndipo imaganiziridwa kuti ndi chinthu chofunika kwambiri pakuchotsa erythrocytes.92,93 Table 2 ikufotokoza mwachidule mayesero azachipatala pazigawo zosiyanasiyana.
Nthawi yotumiza: Mar-24-2022