I-Javascript ivaliwe esipheqululini sakho okwamanje.Ezinye izici zale webhusayithi ngeke zisebenze uma i-javascript ivaliwe.
Bhalisa ngemininingwane yakho ethile kanye nomuthi othile othakaselayo futhi sizofanisa ulwazi olunikezayo nama-athikili kusizindalwazi sethu esibanzi futhi sikuthumelele ikhophi ye-PDF ngokushesha.
Tafere Mulaw Belete Department of Pharmacology, Faculty of Medicine and Health Sciences, Gondar University, Gondar, Ethiopia Imbalelwano: Tafere Mulaw Belete Tel +251 918045943Email [i-imeyili evikelwe] Abstract: Umalaleveva uyinkinga enkulu yezempilo emhlabeni wonke ebangela ukufa nokugula okuphawulekayo minyaka yonke. .Izinketho zokwelapha ziyindlala futhi zibekela inselele kakhulu ukuvela kwezinhlobo zezimuncagazi ezingazweli, ezibeka isithiyo esikhulu ekulawuleni umalaleveva.Ukuvimbela izimo eziphuthumayo ezingaba khona zezempilo yomphakathi, inoveli yemithi elwa nomalaleveva enokwelashwa ngomthamo owodwa, amandla okwelapha abanzi, kanye nezindlela ezintsha zokwenza. zidingeka ngokushesha.Ukuthuthukiswa kwemithi elwa nomalaleveva kungalandela izindlela ezehlukene, kusukela ekuguqulweni kwemithi ekhona kuya ekwakhiweni kwemishanguzo emisha eqondiswe ekuhlosweni okusha.Intuthuko yesimanje kubhayoloji ye-parasite kanye nokuba khona kobuchwepheshe obuhlukahlukene be-genomic inikeza izinhlobonhlobo zezinhloso ezintsha. ukuze kuthuthukiswe izindlela zokwelapha ezintsha.Amathagi amaningi athembisayoAma-ets okungenelela kwezidakamizwa abonakalisiwe eminyakeni yamuva.Ngakho-ke, lokhu kubuyekezwa kugxile ekuthuthukisweni kwakamuva kwesayensi nezobuchwepheshe ekutholakaleni nasekuthuthukisweni kwemithi ye-antimalarial inoveli.Amaprotheni ahloswe kakhulu e-antimalarial target acwaningwe kuze kube manje ahlanganisa ama-proteases, amaprotheni kinases, ushukela we-plasmodium. i-transporter inhibitors, i-aquaporin 3 inhibitors, i-choline transport inhibitors, i-dihydroorotate dehydrogenase inhibitors, i-pentadiene biosynthesis inhibitor, i-farnesyltransferase inhibitor kanye nama-enzyme ahilelekile ku-lipid metabolism kanye nokuphindaphinda kwe-DNA.Lokhu kubuyekezwa kufingqa izinhloso ezintsha ze-molecular for antimalarial drug development: Ke ukuphikiswa kwezidakamizwa zabo. , okuhlosiwe okusha, imishanguzo yokunqanda umalaleveva, indlela yokwenza, igciwane likamalaleveva
Umalaleveva uyisifo esibulalayo esithathelwanayo, ikakhulukazi emazweni ase-Afrika eseningizimu yeSahara, ezingxenyeni ezithile ze-Asia naseNingizimu Melika.Naphezu kwemizamo eminingana, namuhla ungenye yezimbangela eziphambili zokugula nokufa ikakhulukazi kwabesifazane abakhulelwe nezingane.Ngokombiko Wezempilo Womhlaba. Umbiko wenhlangano (WHO) 2018, kube nezigameko zikamalaleveva eziyizigidi ezingama-228 nokufa kwabantu abayizi-405,000 emhlabeni jikelele.Cishe ingxenye yabantu emhlabeni isengcupheni yokungenwa umalaleveva, kanti iningi labagulayo (93%) kanye nokufa (94%) kwenzeka e-Afrika.Mayelana Abesifazane abakhulelwe abayizigidi ezingu-125 basengozini yokungenwa umalaleveva unyaka ngamunye, futhi izingane ezingu-272 000 ezineminyaka engaphansi kweminyaka emihlanu zibulawa umalaleveva.1 Umalaleveva nawo uyimbangela yobumpofu nesithiyo esikhulu ekuthuthukisweni komnotho, ikakhulukazi e-Afrika. I-Plasmodium ebanga umalaleveva kubantu i-P. vivax, P. knowlesi, P. ovale, P. umalaleveva kanye ne-P. falciparum.Kulezi, i-Plasmodium falciparum iwuhlobo olubulalayo futhi oluvame kakhulu lwe-Plasmodium.3
Uma ungekho umgomo ophumelelayo, ukusetshenziswa kokwelapha kwemithi elwa nomalaleveva kusewukuphela kwendlela yokulawula nokuvimbela isifo sikamalaleveva.Ucwaningo oluningana lubonise ukuthi ukuphumelela kwemithi eminingi elwa nomalaleveva kuphazanyiswa izimo eziphuthumayo zePlasmodium spp.4 Ukungazweli emishanguzweni kuye kwabikwa cishe nazo zonke izidakamizwa ezitholakalayo zokulwa nomalaleveva, okuqinisa ukuthuthukiswa kwemithi emisha yokulwa nomalaleveva ngokumelene nezinhloso eziqinisekisiwe ezikhona kanye nokusesha Isigaba se-gametophytic sokudlulisela singasebenza futhi ekwandeni kwe-asexual ngaphakathi kwe-erythrocyte, ikakhulukazi ezinhlotsheni ze-parasite eziphikisanayo.6 Ama-enzyme amaningana, i-ion imigudu, izithuthi, ama-molecule asebenzisanayo Ukuhlasela kwamangqamuzana egazi abomvu (RBC), nama-molecule abangela i-parasite oxidative stress, lipid metabolism, kanye nokuwohloka kwe-hemoglobin kuyisihluthulelo sokwakhiwa kwemishanguzo emisha elwa nomalaleveva emelene nomalaleveva oguquka ngokushesha Othembisa izinhloso ezintsha ze-protozoa.7
Amandla emishanguzo emisha elwa nomalaleveva anqunywa ngezidingo ezimbalwa: indlela entsha yokwenza, akukho ukumelana nemithi yamanje ye-antimalarial, ukwelashwa ngedosi elilodwa, ukusebenza ngempumelelo ngokumelene nesigaba segazi le-asexual kanye nama-gametocyte abhekele ukudluliselwa. izidakamizwa ezilwa nomalaleveva kufanele zibe nempumelelo ekuvimbeleni ukutheleleka (ama-chemoprotectants) kanye nokususa isibindi se-P. vivax hypnotics (ama-anti-relapse agents).8
Ukutholakala kwemithi yendabuko kulandela izindlela eziningi zokuhlonza umuthi omusha wokulwa nomalaleveva. Lokhu wukuthuthukisa izigaba zemithi yamanje kanye nokwakheka, ukulungisa imishanguzo ekhona yokulwa nomalaleveva, ukuhlola imikhiqizo yemvelo, ukuhlukanisa ama-ejenti aqeda ukumelana nomalaleveva, ukusebenzisa inhlanganisela yezindlela zokwelashwa ngamakhemikhali, nokuthuthukisa imithi. okunye ukusetshenziswa.8,9
Ngokungeziwe ezindleleni zendabuko zokutholwa kwezidakamizwa ezisetshenziselwa ukuhlonza inoveli yemithi elwa nomalaleveva, ulwazi lwe-Plasmodium cell biology kanye ne-genome luboniswe njengethuluzi elinamandla lokwembula izindlela zokumelana nomuthi, futhi linamandla okuklama imithi enomsebenzi ophezulu wokulwa nomalaleveva.Amandla amakhulu emishanguzo emisha.Ukulwa nokuphazanyiswa okungenzeka kokudluliswa kukamalaleveva unomphela.10 Ukuhlolwa kofuzo kwePlasmodium falciparum kuhlonze izakhi zofuzo ezingu-2680 ezibalulekile ekukhuleni kwesigaba segazi esingenabulili, ngaleyo ndlela kuhlonzwe izinqubo ezibalulekile zamangqamuzana ezibaluleke kakhulu ekwenzeni imithi emisha.10,11 Okusha. imithi kufanele: (i) ibhekane nokungazweli emishanguzweni, (ii) isebenze ngokushesha, (iii) iphephe, ikakhulukazi ezinganeni nakwabesifazane abakhulelwe, futhi (iv) yelaphe umalaleveva ngomthamo owodwa.12 Inselele iwukuthola umuthi okhulumayo. zonke lezi zici.Inhloso yalokhu kubuyekezwa ukunikeza umbono wezinto ezintsha ezihlosiwe zokwelapha izimuncagazi zikamalaleveva, ezifundwa izinkampani eziningana, ukuze abafundi baziswe ngomsebenzi odlule.
Njengamanje, imishanguzo eminingi elwa nomalaleveva ihlose isigaba se-asexual sokutheleleka nge-malaria esidala isifo esinezimpawu.Isigaba se-pre-erythrocytic (isibindi) sihlala singakhangi ngenxa yokuthi azikho izimpawu zomtholampilo ezikhiqizwayo.Imithi elwa nomalaleveva ibonisa ukukhetha kwesigaba esikhulu (bona uMfanekiso 1).Ukwelashwa kukamalaleveva okusekelwe ku- imikhiqizo yemvelo, i-semi-synthetic kanye ne-synthetic compounds eyakhiwe kusukela ngawo-1940.13 Imithi elwa nomalaleveva ekhona ingena ezigabeni ezintathu ezibanzi: okuphuma kuyo i-quinoline, ama-antifolate kanye nokuphuma kwe-artemisinin.Awukho umuthi owodwa osatholakele noma owenziwe ongaqeda zonke izinhlobo zezimuncagazi zikamalaleveva. Ngakho-ke, ukuze iphumelele ekulweni nomalaleveva, inhlanganisela yezidakamizwa ivame ukunikezwa ngesikhathi esisodwa.I-Quinoline umuthi osetshenziswa kakhulu wokulwa nomalaleveva ekwelapheni umalaleveva.I-Quinine, i-alkaloid eqhelelene namagxolo esihlahla se-cinchona, kwaba umuthi wokuqala wokunqanda umalaleveva owasetshenziswa. ukwelapha izifo ngekhulu le-17. Kusukela maphakathi nawo-1800 kuya ku-1940s, quieyisishiyagalolunye yayiyindlela evamile yokwelapha umalaleveva.14 Ngaphezu kobuthi, ukuvela kwezinhlobo ezimelana nomuthi ze-P. falciparum kuye kwakhawulela ukusetshenziswa kwe-quinine ekwelapheni. umuthi wesibili wokunciphisa isikhathi sokwelashwa futhi unciphise imiphumela emibi.15,16
Umfanekiso 1 Umjikelezo wempilo ye-Plasmodium kubantu.Izigaba kanye nezinhlobo zezimuncagazi lapho kusebenza khona izinhlobo ezahlukene zemithi elwa nomalaleveva.
Ngo-1925, abacwaningi baseJalimane bathola umuthi wokuqala wokwenziwa we-antimalarial, i-pamaquin, ngokushintsha i-methylene blue.I-Pamaquin inokusebenza okulinganiselwe kanye nobuthi futhi ayikwazi ukusetshenziselwa ukwelapha umalaleveva.Kodwa i-pamaquin inikeza izinhlanganisela zokuhola ukuthuthukisa izidakamizwa ezingcono zokulwa nomalaleveva.I-Mepacrine (quinacrine) ingenye okuphuma ku-methylene blue esetshenziselwa ukwelapha umalaleveva phakathi neMpi Yezwe II.17
I-Chloroquine yasungulwa phakathi neMpi Yezwe II ukuze yelaphe umalaleveva.I-Chloroquine iyisidakamizwa esikhethwayo sokwelapha umalaleveva ngenxa yokusebenza kwayo kahle, ukuphepha kanye nezindleko eziphansi.Kodwa ukusetshenziswa kwayo okungenangqondo ngokushesha kwaholela ekuqhamukeni kwezinhlobo ze-P. falciparum ezimelana ne-chloroquine. 18 I-Primaquine isetshenziselwa ukwelapha ukwelapha i-Plasmodium vivax ebuyela emuva ebangelwa i-hypnosis.I-Primaquine iyi-gameticidal enamandla ngokumelene ne-Plasmodium falciparum.I-Primaquine ibangela i-hemolytic anemia ezigulini ezinokuntuleka kwe-glucose-6-phosphate dehydrogenase (G6PD). -P.Umsebenzi wansuku zonke.19
Okuphuma kokusha kwe-quinoline kwahlanganiswa, okwaholela emithini emisha efana ne-piperaquine ne-amodiaquine.Ngemva kokuvela kokumelana ne-chloroquine, i-amodiaquine, i-analog ye-chloroquine ethathelwe esikhundleni se-phenyl, yabonisa ukusebenza kahle kakhulu kwezinhlobo ezimelana ne-chloroquine ze-Plasmoyrrm i-Plasmodium 20 falsil isisekelo somuthi wokulwa nomalaleveva owakhiwa eShayina ngo-1970.Usebenza ngempumelelo ngokumelene nezinhlobo ezimelana nezidakamizwa ze-P. falciparum, P. vivax, P. umalaleveva kanye ne-P. ovale.Pyronadrine isiyatholakala njenge-ACT with artesunate, ebonise ukusebenza kahle kakhulu kubo bonke. izimuncagazi zikamalaleveva.21 I-Mefloquine yasungulwa phakathi neminyaka yawo-1980 futhi njengamanje ituswa ukuvimbela umalaleveva obangelwa yizo zonke izinhlobo zezilwane, kuhlanganise nezinhlobo ezimelana ne-chloroquine.Nokho, ukusetshenziswa kwayo kuhlotshaniswa nemiphumela ethile engemihle kanye nokungazweli emithini.22 Imithi etholakala kwi-quinoline Isebenza ikakhulukazi esigabeni segazi se-parasite, kodwa eminye imithi elwa nomalaleveva isebenza esigabeni sesibindi.Le mithi ivimbela ngokwenza i-comlex ne-heme kuma-vacuoles okudla we-parasite.Ngakho-ke, i-heme polymerization ivinjiwe.Ngenxa yalokho, i-heme ekhishwe ngesikhathi sokuwohloka kwe-hemoglobin iqoqana emazingeni anobuthi, ibulale i-parasite ngemfucuza enobuthi.amashumi amabili nantathu
Ama-Antifolates yizidakamizwa ze-antimalarial ezivimbela ukuhlanganiswa kwe-folic acid, okubalulekile ekuhlanganiseni kwe-nucleotides nama-amino acids.I-Antifolates ivimbela ukuhlukaniswa kwe-nuclear yezinhlobo ze-Plasmodium ngesikhathi se-schizont ku-erythrocytes kanye ne-hepatocytes.I-Sulfadoxine inesakhiwo esifanayo ne-para-aminobenzoic acid (PABA), ingxenye ye-folic acid.Zivimbela ukuhlanganiswa kwe-dihydrofolate ngokuvimbela i-dihydrofolate synthase, i-enzyme eyinhloko ku-nucleic acid biosynthesis.amashumi amabili nane
I-Pyrimethamine ne-proguanil yizidakamizwa ze-schizont antimalarial ezenza uhlobo lwe-asexual lwezinhlobo ze-Plasmodium.Lezi zidakamizwa zivimbela i-enzyme i-dihydrofolate reductase (DHFR), evimbela ukuncishiswa kwe-dihydrofolate ku-tetrahydrofolate, okubalulekile ku-biosynthesis yama-amino acids nama-nucleic acid. I-Proguanil iyi-prodrug metabolized to cyclic guanidine.I-Proguanil kwakuyisidakamizwa sokuqala se-antifolate esasetshenziswa ekwelapheni umalaleveva.Isizathu siwukuthi ibhubhisa amangqamuzana egazi abomvu ngaphambi kokuba i-parasite iwahlasele ngesikhathi ingena egazini.Futhi, i-proguanil iphephile. isidakamizwa.I-pyrimethamine isetshenziswa ngokuyinhloko nezinye izidakamizwa ezisebenza ngokushesha.Nokho, ukusetshenziswa kwayo kwehlile ngenxa yokungazweli emthini.24,25
I-Atovaquone umuthi wokuqala ogunyazwe wokulwa nomalaleveva oqondise i-mitochondria ye-Plasmodium parasite.I-Atovaquone ivimbela ukuthuthwa kwe-electron ngokwenza njenge-analog ye-ubiquinone ukuvimba ingxenye ye-cytochrome b ye-cytochrome bc1 complex.Uma ihlanganiswa ne-proguanil, i-atovaquone iphephile futhi iyasebenza kwabesifazane abakhulelwe kanye nezingane.I-Atovaquone iyasebenza ngokumelene nesigaba socansi se-parasite yomninikhaya kanye nomiyane.Ngakho, ivimbela ukudluliswa kukamalaleveva usuka omiyane uye kubantu.Inhlanganisela engaguquki ne-proguanil eyakhiwe ngaphansi kwegama lokuhweba elithi Malarone.24,26
I-Artemisinin yakhishwa ku-Artemisia annua ngo-1972. I-Artemisinin kanye nokuphuma kwayo okuhlanganisa i-artemether, i-dihydroartemisinin, i-artemether kanye ne-artesunate inomsebenzi obanzi. ama-gametocyte asuka kubantu aya omiyane.27 I-Artemisinin kanye nokuphuma kwayo kuyasebenza ekumelaneni ne-chloroquine- kanye nezinhlobo ezimelana ne-mefloquine.Ziphephile, ziyasebenza futhi zisebenza ngokushesha i-schizonts yegazi kuzo zonke izinhlobo ze-Plasmodium.Nokho, i-artemisinin ayizange isuse ukubambezeleka kwesibindi kwesibindi i-parasite.Le mithi inokuphila okufushane okufushane kanye nokungabibikho kahle kwe-bioavailability, okuholela ekuphikisweni kwezidakamizwa, okuyenza ingasebenzi njenge-monotherapy.Ngakho-ke, okuphuma kwe-artemisinin kunconywa ngokuhlanganiswa neminye imithi elwa nomalaleveva.28
Umphumela wokulwa nomalaleveva we-artemisinin ungase ubangelwe ukukhiqizwa kwama-radicals mahhala avela ekuqhekekeni kwamabhuloho e-artemisinin endoperoxide kuma-vesicles okudla kwe-parasite, ngaleyo ndlela kuvimbele i-parasite calcium ATPase kanye ne-proteasome.29,30 I-Artemether isetshenziswa njenge-monotherapy.Ukumuncwa oral okusheshayo Bioavailability. iphindwe kabili lapho isetshenziswa lapho kukhona ukudla.Lapho isisendaweni yesistimu, i-artemether igaywa nge-hydrolyzed ibe yi-dihydroartemisinin emathunjini nasesibindini.
I-Artesunate iyi-semi-synthetic derivative ngenxa yomphumela wayo osheshayo wokulwa nomalaleveva, ukuntuleka kokumelana nezidakamizwa okuphawulekayo kanye nokuncibilika okukhulu kwamanzi.Kutuswa njengomuthi womugqa wokuqala we-malaria oyingozi.31
I-Tetracyclines kanye nama-macrolides imithi elwa nomalaleveva esebenza kancane esetshenziswa njenge-adjunctive therapy ku-quinine ku-falciparum malaleveva.I-Doxycycline iphinde isetshenziselwe i-chemoprophylaxis ezindaweni ezinokumelana okuphakeme.32 Isu lamanje elisetshenziselwa ukulwa nemithi elwa nomalaleveva ukusetshenziswa kokwelapha kwezinhlanganisela zemithi. isu lalisetshenziswa esikhathini esidlule ngokusebenzisa inhlanganisela engaguquki.I-WHO incoma i-artemisinin-based combination therapy (ACT) njengokwelashwa komugqa wokuqala we-falciparum Malaria engaxakile.Isizathu siwukuthi inhlanganisela yemithi kunciphisa ukumelana nomuthi kanye nemiphumela engemihle.33
I-ACT iqukethe ingxenye ye-artemisinin enamandla eqeda ngokushesha izimuncagazi, kanye nomuthi osebenza isikhathi eside oqeda izimuncagazi ezisele futhi wehlise ukumelana ne-artemisinin.IIMITHETHO etuswa i-WHO i-artesunate/amodiaquine, i-artemether/i-benzfluorenol, i-artesunate/mefloquine, i-artesunate/i-dihydroartenin/i-dihydroartenin i-piperaquine, i-Artesunate/sulfadoxine/pyrimethamine, i-artemether/piperaquine kanye ne-artemisinin/piperaquine/primaquine.I-Chloroquine plus primaquine isewumuthi wokuqala wokuqeda i-Plasmodium vivax.I-Quinine + tetracycline/doxycycline inezinga eliphezulu lokwelapha, kodwa linezinga eliphezulu lokwelapha, imiphumela futhi iyavinjelwa ezinganeni nakwabesifazane abakhulelwe34.
I-Mefloquine, i-atovaquone/proguanil, noma i-doxycycline iyatuswa ezinhlotsheni ze-chemoprevention kubahambi abavela ezindaweni ezingezona eziwumqedazwe kuya ezindaweni eziwumqedazwe.35 Kuyakhuthazwa ukwelapha okuvimbela ngezikhathi ezithile emaqenjini asengozini enkulu, okuhlanganisa i-sulfadoxine/pyrimethamine ngesikhathi sokukhulelwa kanye ne-amodiaquine/sulfadoxine-pyrimethamine njengesizini .36 I-Halofantrine ayifanele ukusetshenziswa kokwelapha ngenxa ye-cardiotoxicity yayo.I-Dapsone, i-mepalyline, i-amodiaquine, ne-sulfonamides yahoxiswa ekusetshenzisweni kokwelapha ngenxa yemiphumela yayo engemihle.36,37 Eminye imithi elwa nomalaleveva eyaziwa kakhulu kanye nemiphumela yayo engemihle ibhalwe kuThebula. 1.
Imithi elwa nomalaleveva etholakalayo njengamanje isekelwe ekwehlukeni emigudwini emikhulu ye-metabolic phakathi kwezinhlobo ze-Plasmodium nezizisingathile.Izindlela ezinkulu ze-parasite zokugaya umzimba, okuhlanganisa i-heme detoxification, i-fatty acid synthesis, i-nucleic acid synthesis, i-fatty acid synthesis, kanye ne-oxidative stress, ezinye zenoveli. izindawo zokwakhiwa kwezidakamizwa.38,39 Nakuba imithi eminingi yokulwa nomalaleveva isetshenziswe iminyaka eminingana, ukusetshenziswa kwayo okwamanje kulinganiselwe ngenxa yokungazweli emishanguzweni.Ngokwezincwadi, azikho izidakamizwa ezilwa nomalaleveva ezitholakele ezivimbela okuhlosiwe kwezidakamizwa ezaziwayo.7,40 In ngokuphambene, izidakamizwa eziningi zokulwa nomalaleveva zitholwa esifundweni semodeli yezilwane e-vivo noma in vitro.Ngakho-ke, indlela yokusebenza yezidakamizwa eziningi zokulwa nomalaleveva ayiqinisekile.Ngaphezu kwalokho, izindlela zokumelana nemithi eminingi ye-antimalarial azicacile.39
Ukulawulwa kukamalaleveva kudinga amasu adidiyelwe njengokulawula i-vector, imishanguzo ephumelelayo nephephile yokulwa nomalaleveva, kanye nemithi yokugoma ephumelelayo. Uma kucatshangelwa izinga eliphezulu lokufa nokugula kukamalaleveva, izimo eziphuthumayo kanye nokusabalala kokumelana nemithi, ukungasebenzi kwemithi elwa nomalaleveva ekhona ngokumelene nezigaba ezingezona i-erythrocyte kanye nezigaba zocansi. , ukuhlonzwa kwemithi emisha elwa nomalaleveva ngokuqonda izindlela eziyisisekelo zokugayeka kokudla umalaleveva.Imithi kamalaleveva ibalulekile.izimuncagazi.Ukufeza lo mgomo, ucwaningo lwezidakamizwa kufanele luqondise izinjongo ezintsha, eziqinisekisiwe zokuhlukanisa izinhlanganisela ezintsha zomthofu.39,41
Kunezizathu ezimbalwa zesidingo sokuhlonza okuhlosiwe kwezinqubo ze-metabolic.Okokuqala, ngaphandle kwemithi etholakala ku-atovaquone kanye ne-artemisinin, imithi eminingi elwa nomalaleveva ayihlukene ngamakhemikhali, okungase kuholele ekungazweli.Okwesibili, ngenxa yezinhlobonhlobo eziningi putative chemotherapeutic targets, eziningi azikaqinisekiswa.Uma ziqinisekisiwe, zingase ziveze ezinye izinhlanganisela ezisebenzayo neziphephile.Ukuhlonzwa kwemigomo emisha yemishanguzo kanye nokuklanywa kwenhlanganisela emisha esebenza kulokho okuhlosiwe kusetshenziswa kabanzi emhlabeni wonke namuhla izinkinga ezivela ekuveleni kokumelana nemithi ekhona.40,41 Ngakho-ke, ucwaningo lwenoveli oluhlosiwe lwe-protein-specific inhibitors lwe-Plasmodium lusetshenziselwe ukuhlonza okuhlosiwe kwezidakamizwa. ukungenelela kuye kwavela.Le mithi engase ibe ne-antimalarial ihlose ukhiye we-metabolite biosynthesis, ukuthutha ulwelwesi kanye nezinhlelo zokubonisa izimpawu, kanye nezinqubo zokuwohloka kwe-hemoglobin.40,42
I-Plasmodium protease iyi-enzyme eyi-catalytic ne-regulatory ubiquitous edlala indima ebalulekile ekusindeni kwezimuncagazi ze-protozoan kanye nezifo ezizibangelayo.Ikhuthaza i-hydrolysis yamabhondi e-peptide.43 Imisebenzi yama-protease ku-pathogenesis yesifo sikamalaleveva ihlanganisa ukungena kwamaseli/izicubu, amasosha omzimba. ukugwema, ukusebenza kokuvuvukala, ukuhlasela kwe-erythrocyte, ukuwohloka kwe-hemoglobin namanye amaprotheni, i-autophagy, nokuthuthukiswa kwe-parasite.44
Ama-proteases kamalaleveva (i-glutamic aspartic acid, i-cysteine, insimbi, i-serine ne-threonine) athembisa ukwelapha okuhlosiwe ngoba ukuphazamiseka kofuzo lwe-malaria protease kuvimbela ukuwohloka kwe-hemoglobin kanye nesigaba se-erythrocyte se-parasite.intuthuko.45
Ukuwohloka kwama-erythrocyte nokuhlasela okulandelayo kwama-merozoite kudinga i-malaria protease.I-peptide yokwenziwa (GlcA-Val-Leu-Gly-Lys-NHC2H5) ivimbela i-Plasmodium falciparum schizont cysteine protease Pf 68. lisikisela ukuthi ama-protease adlala indima ebalulekile ekuhlaseleni kwamagciwane amangqamuzana abomvu egazi.Ngakho-ke, ama-protease ayisisulu esithembisayo sokuthuthukiswa kwemithi elwa nomalaleveva.46
Ku-Plasmodium falciparum vacuoles yokudla, ama-aspartic proteases amaningana (i-plasma proteases I, II, III, IV) nama-cysteine proteases (falcipain-1, falcipain-2/, falcipain-3) ahlukanisiwe, Asetshenziselwa ukwehlisa i-hemoglobin, njengoba kubonisiwe. kuMfanekiso 2.
Ukufakwa kwezimuncagazi ezithuthukisiwe ze-P. falciparum ezine-protease inhibitors i-leupeptin kanye ne-E-64 kuholele ekuqongeleleni kwe-globin engashintshile. Izimuncagazi ezine-aspartate protease inhibitor pepstatin, iglobin ayizange inqwabelane.Izifundo ezimbalwa zibonise ukuthi ama-cystatin inhibitors awavimbi nje kuphela ukuwohloka kweglobin, kodwa futhi avimbele izinyathelo zokuqala zokuwohloka kwe-hemoglobin, njengokukhishwa kwe-hemoglobin, ukukhululwa kwe-heme ku-globin, nokukhiqizwa kwe-heme. .49 Le miphumela iphakamisa ukuthi i-cysteine proteases iyadingeka esigabeni sokuqala.Izinyathelo zokuwohloka kwe-hemoglobin nge-Plasmodium falciparum.Kokubili i-E-64 ne-pepstatin ivimba ukuthuthukiswa kwe-P. falciparum. Nokho, i-E-64 kuphela ivimbe i-globin hydrolysis. 48,49 Ama-cysteine protease inhibitors amaningana, afana ne-fluoromethyl ketone ne-vinyl sulfone, avimbela ukukhula kwe-P. falciparum kanye ne-hemoglobin degradation.Esibonelo sesilwane sikamalaleveva, i-fluoromethyl ketone inhibits P. vinckei protease umsebenzi futhi yelapha u-80% wezifo zikamalaleveva we-murine.Ngakho-ke, ama-protease inhibitors athembisayo emithi elwa nomalaleveva.Umsebenzi olandelayo wahlonza ama-falcipain inhibitors asebenzayo, okuhlanganisa i-chalcone, ne-phenothiazine ezivimba i-parasite metabolism kanye nentuthuko.50
I-Serine proteases ihileleke ekuqhekekeni kwe-schizont kanye nokuvuselelwa kwe-erythrocyte phakathi nomjikelezo wokuphila we-Plasmodium falciparum.Ingavinjelwa ama-serine protease inhibitors amaningana futhi iyisinqumo esihle kakhulu njengoba ingekho i-homolog ye-enzyme yomuntu etholakalayo.I-protease inhibitor LK3 ehlukanisiwe ne-Streptomyces sp.yehlisa isithunzi se-malaria serine protease.51 I-Maslinic acid iyi-pentacyclic triterpenoid yemvelo evimbela ukuvuthwa kwezimuncagazi ukusuka esigabeni esiyindandatho kuya esigabeni se-schizont, ngaleyo ndlela inqamule ukukhululwa kwama-merozoite nokuhlasela kwawo. -2 kanye ne-falcipain-3.52 statins kanye nokuvinjelwa kwama-plasma proteases ngama-allophenostatin-based inhibitors avimbela ukuwohloka kwe-hemoglobin futhi abulale ama-parasites.Kuyatholakala ama-blocker amaningi e-cysteine protease, okuhlanganisa i-Epoxomicin, i-lactacystin, i-MG132, i-WEHI-8416, i-WEHI-8416, i-WEHI-8416, i-WEHI-8916 .
I-Phosphoinositide lipid kinases (PIKs) ama-enzyme atholakala yonke indawo ukuthi i-phosphorylate lipids ukulawula ukwanda, ukusinda, ukushushumbiswa, kanye nokusayina kwe-intracellular.Amakilasi e-PIK afundwa kakhulu kuma-parasites angu-53 yi-phosphoinositide 3-kinase (PI3K) kanye ne-phosphotoselselseprosel4 (K) kanye ne-phosphatoselsenaldidylidyli44. Ukuvinjelwa kwalawa ma-enzyme kuye kwaphawulwa njengento engase iqondiswe ekwakhiweni kwemithi elwa nomalaleveva enamaphrofayili omsebenzi afiselekayo wokuvimbela, ukwelashwa kanye nokuqedwa kwe-malaria.54 UCT943, imidazopyrazine (KAF156) kanye nama-aminopyridines ikilasi elisha lezinhlanganisela ze-antimalarial eziqondiswe ku-PI. (4)K futhi ivimbele ukukhula kwe-intracellular yezinhlobo eziningi ze-Plasmodium kuzo zonke izigaba zokutheleleka komsingathi.Ngakho-ke, ukukhomba (PI3K) kanye ne-PI(4)K kungase kuvule izindlela ezintsha ngokusekelwe ekutholweni kwezidakamizwa okuhlosiwe ukuze kuhlonzwe inoveli yemithi elwa nomalaleveva.I-KAF156 okwamanje itholakala ezivivinyweni zomtholampilo zeSigaba II. I-55,56 MMV048 iyinhlanganisela enomsebenzi omuhle we-vivo prophylactic ngokumelene ne-P. cynomolgi kanye namandlaI-MMV048 okwamanje ibhekene nokuhlolwa komtholampilo kweSigaba IIa e-Ethiopia.11
Ukuze kukhule ngokushesha kumangqamuzana abomvu egazi anegciwane, izinhlobo ze-Plasmodium zidinga inani elanele lama-substrates ukuze kube lula ukugaywa kwazo komzimba. amaprotheni kanye neziteshi zenethiwekhi yizinjongo ezingase zibe khona ngenxa yezindima zabo ezibalulekile ekuthuthweni kwama-metabolites, ama-electrolyte kanye nezakhi.57 Lawa yi-Plasmodium surface anion channel (PSAC) kanye ne-parasitic vacuolar membrane (PVM), ehlinzeka ngendlela eqhubekayo yokusabalalisa izakhi. ku-intracellular parasite.58
I-PSAC iyinkomba ethembisa kakhulu ngoba itholakala ezinhlotsheni ezahlukene zezakhamzimba (hypoxanthine, cysteine, glutamine, glutamate, isoleucine, methionine, proline, tyrosine, pantothenic acid kanye ne-choline) ukuthola izindima ezibalulekile kuma-intracellular parasites.I-PSAC ayinayo i-homology ecacile ezakhini zofuzo ezaziwayo zesiteshi.I-Phloridizin, i-dantrolene, i-furosemide, ne-niflunomide yizivimba ezinamandla ze-anion transporter.Izidakamizwa ezifana ne-glyburide, i-meglitinide, ne-tolbutamide zivimbela ukungena kwe-choline kumangqamuzana egazi abomvu anegciwane le-parasitic.60,61
Igazi le-Plasmodium falciparum lincike cishe ngokuphelele ku-glycolysis ukuze kukhiqizwe amandla, ngaphandle kokugcinwa kwamandla;ithembele ekumukelweni njalo kweglucose.I-parasite iguqula i-pyruvate ibe i-lactate ukuze ikhiqize i-ATP, edingekayo ukuze iphindaphindeke ngaphakathi kwamangqamuzana abomvu egazi.62 I-Glucose iqala ithuthelwe kuma-erythrocyte aphethwe yi-parasite ngenhlanganisela yesithuthi se-glucose yeseli eliphethe, i-GLUT1, i-erythrocyte membrane kanye 'new permeation pathway' eyenziwe yi-parasite.63 IGlucose ithuthwa ezinambuzaneni yi-Plasmodium falciparum hexose transporter (PFHT).I-PFHT inezici ezithile ezijwayelekile zesithuthi sikashukela.I-GLUT1 ikhetha i-D-glucose, kuyilapho i-PFHT ingakwazi ukuthutha I-D-glucose ne-D-fructose.Ngakho, umehluko ekusebenzisaneni kwe-GLUT1 kanye ne-PFHT nama-substrates aphakamisa ukuthi ukuvinjelwa okukhethiwe kwe-PFHT kuyinjongo entsha ethembisayo yokuthuthukiswa kwezidakamizwa ze-antimalarial ezinoveli.64 I-O-3-hexose derivative ye-long-chain (inhlanganisela 3361) ivimbela ukumuncwa kwe-glucose ne-fructose nge-PFHT, kodwa ayikuvimbeli ukuthuthwa kwe-hexose ngabathuthi abakhulu be-mammalian glucose kanye ne-fructose (GLUT1 kanye no-5).I-361 iphinde ivimbele ukutholwa kwe-glucose ngu-P. vivax we-PFHT.Ocwaningweni lwangaphambilini, i-compound 3361 yabulala i-P. falciparum ngesiko futhi yanciphisa ukukhiqizwa kwe-P. berghei kumamodeli wamagundane.65
Iqembu legazi le-Plasmodium lincike kakhulu ku-anaerobic glycolysis ukuze ikhule futhi ithuthuke.60 Amangqamuzana egazi abomvu anegciwane lesandulela ngculazi amunca i-glucose ngokushesha izikhathi eziyi-100 kunamangqamuzana egazi abomvu angenagciwane.I-parasite igaya i-glucose nge-glycolysis ukuze ikhiphe i-lactate, ekhishwa kumagciwane nge-lactate: i-H+ symporter mechanism endaweni yangaphandle.66 Ukuthekelisa kwe-lactate kanye nokuthathwa kweglucose kubalulekile ekugcineni izidingo zamandla, i-intracellular pH, kanye ne-parasite osmotic stability.I-Lactate:H+ symporter system inhibition iyinhloso entsha ethembisayo yokwakhiwa kwemithi emisha.Izinhlanganisela eziningana, njenge-MMV007839 kanye ne-MMV000972, zibulala ama-asexual blood-stage P. falciparum parasites ngokuvimbela i-lactate:H+ transporter.67
Njengezinye izinhlobo zamangqamuzana, amangqamuzana egazi abomvu agcina amazinga aphansi e-Na + yangaphakathi.Nokho, ama-parasites akhulisa ukufinyeleleka kwe-membrane ye-erythrocyte futhi enze lula ukungena kwe-Na +, okuholela ekwandeni kokuhlushwa kwe-erythrocyte cytoplasmic Na + ezingeni le-extracellular medium.Ngakho, ama-parasites bazithole bekwimithombo yezindaba ye-Na+ ephezulu futhi kufanele bakhiphe ama-Na+ ion kulwelwesi lwe-plasma ukuze balondoloze amazinga aphansi e-cytoplasmic Na+ ukuze baphile naphezu kokuba khona kumasayithi angaphakathi kwe-intracellular.Kulokhu, ukungena kwe-Na+ ku-parasite kulawulwa ngokusebenzisa uhlobo lwe-P-ATPase. i-transporter (PfATP4), esebenza njengendlela eyinhloko yepompo ye-Na+-efflux ye-parasite, njengoba kukhonjisiwe kuMfanekiso 3.68, evimbela lesi sithuthi Kuzoholela ekwenyukeni kwenani le-Na+ ngaphakathi kwe-parasite, okuzogcina kuholele ekufeni kwesilwane. I-parasite ye-malaria.Izinhlanganisela eziningana, ezihlanganisa i-sipagamin esigabeni 2, (+)-SJ733 esigabeni 1, kanye ne-KAE609 esigabeni sesi-2, zinezindlela zokusebenza eziqondise i-PfATP4.67,69
Umfanekiso 3. Indlela ehlongozwayo ye-parasite-induced PfATP4 kanye ne-V-type H+-ATPase ekufeni kwe-erythrocyte okuthelelekile kulandela ukuvinjelwa kwe-cipargamin.
Izinhlobo ze-Plasmodium zilawula amazinga azo we-Na+ ngokusebenzisa i-P-type ATPase transporter.Iphinde ingenise i-H+ ngendlela efanayo.Ukulawula ukugxila okukhulayo kwe-H+ nokugcina i-intracellular pH engu-7.3, i-parasite ye-malaria isebenzisa i-V-type ATPase transporter ehambisanayo ukuze khipha i-H+.Ukuthuthukisa umuthi omusha kuwumgomo othembisayo.I-MMV253 ivimbela i-V-type H+ ATPase njengendlela yayo yokusebenza ngokukhetha ukuguqulwa kwezakhi zofuzo kanye nokulandelana kwezakhi zofuzo lonke.70,71
I-Aquaporin-3 (AQP3) iyiprotheni yesiteshi se-aquaglycerol eyenza kube lula ukuhamba kwamanzi ne-glycerol kumaseli ezilwane ezincelisayo.I-AQP3 ifakwa kuma-hepatocyte abantu ekuphenduleni ukutheleleka kwe-parasite futhi inendima ebalulekile ekuphindaphindeni kwe-parasite.I-AQP3 inikeza ukufinyelela ku-glycerol ku-P .berghei futhi kusiza ukuphindaphinda kwe-parasite esigabeni se-asexual erythrocyte.72 Ukuncipha kofuzo kwe-AQP3 kwacindezelwa kakhulu umthwalo we-parasite esigabeni sesibindi se-P. berghei.Ngaphezu kwalokho, ukwelashwa nge-AQP3 inhibitor auphen kwehlisa umthwalo we-P. berghei parasitemias ku-hepatocytes. I-falciparum parasitemia kuma-erythrocytes, okuphakamisa ukuthi amaprotheni abamba iqhaza adlala indima ebalulekile ezigabeni ezihlukahlukene zokuphila ze-parasite .73 Okuthakazelisa kakhulu ukuthi ukuphazamiseka kwe-AQP3 kumagundane ofuzo akubulali, okuphakamisa ukuthi iphrotheni ephethe inethagethi entsha yokwelapha. ukuqonda kwezinqubo zesibindi esithintekayo ukutheleleka nge-Plasmodium futhi kugqamisa amandla alaba proiyaphela njengemithi yokulwa nomalaleveva yesikhathi esizayo.71,72
Ama-phospholipids adlala indima ebalulekile emjikelezweni wokuphila we-intra-erythrocyte we-Plasmodium falciparum, kokubili njengezingxenye zesakhiwo solwelwesi nanjengama-molecule alawulayo alawula imisebenzi yama-enzyme ahlukahlukene.Lawa ma-molecule abalulekile ekuzaleni kwe-parasite ngaphakathi kwamangqamuzana abomvu egazi.Ngemva kokuhlasela kwe-erythrocyte, Amazinga e-phospholipid ayanda, lapho i-phosphatidylcholine iyi-lipid eyinhloko ezingxenyeni zabo zolwelwesi lwamangqamuzana. Ama-Parasites ahlanganisa i-phosphatidylcholine de novo esebenzisa i-choline njengesandulela. okuholela ekufeni kwe-parasite.74 I-Albitiazolium, isidakamizwa esingene ekuhlolweni kweSigaba II, sisebenza ngokuyinhloko ngokuvimbela ukuthuthwa kwe-choline ku-parasite.I-Albitiazolium iqongelela izikhathi ezingu-1000 ku-Plasmodium futhi ivimbela ukukhula kwe-parasite ngaphandle kokuphindeka. izimo.Ngokuphawulekayo, umjovo owodwa welapha izinga eliphezuluamazinga e-arasitemia.75,76
I-Phosphocholine cytidyltransferase isinyathelo sokunciphisa izinga ku-de novo biosynthesis ye-phosphatidylcholine.77 I-diquaternary ammonium compound G25 kanye ne-dicic compound T3 inhibit phosphatidylcholine synthesis kuma-parasites.I-G25 iphindwe izikhathi ezingu-1000 imigqa ewukhiye we-mammalian enobuthi obuncane kakhulu ku-mammalian. izinhlanganisela ekutholakaleni nasekuthuthukisweni kwezidakamizwa ezilwa nomalaleveva.78,79
Isinyathelo esibalulekile ekusabalaleni kwezinhlobo ze-Plasmodium kubantu ukuhlukaniswa okubanzi nokusheshayo kwe-DNA ye-parasite, okuncike ekutholakaleni kwama-metabolites abalulekile njenge-pyrimidines. i-glycoprotein.I-Nucleotide synthesis ilandela izindlela ezimbili eziyinhloko: indlela yokusindisa kanye nendlela ye-de novo.I-Dihydroorotate dehydrogenase (DHODH) iyi-enzyme ebalulekile eyenza i-oxidation ye-dihydroorotate i-orotate, isinyathelo sokunciphisa izinga ku-de novo pyrimidine synthesis, DHODH Ngakho-ke. imelela ithagethi engase ithembise ukuthuthukiswa kwezidakamizwa ezilwa nomalaleveva.80 Amangqamuzana abantu athola i-pyrimidines ngokuhlenga ama-pyrimidines asevele enziwe noma nge-de novo synthesis.Uma indlela ye-de novo biosynthetic ivinjelwa, iseli lizothembela endleleni yokusindisa futhi iseli ngeke life. Kodwa-ke, ukuvinjelwa kwe-de novo pyrimidine biosynthesis kuma-parasite kubangela ukufa kwala maseli ngobai-malaria ayinayo indlela ye-pyrimidine salvage, okwenza i-parasite ibe sengozini yokuvinjelwa yi-DHODH.81 DSM190 kanye ne-DSM265 bayizinqamuleli ezikhethiwe ze-enzyme ye-DHODH, okwamanje esesigabeni sesi-2 sokuhlolwa kwemitholampilo. izinhlobo ezingazweli okwamanje eziseSigabeni 1.KAF156 (Ganaplacide) okwamanje isesivivinyweni somtholampilo seSigaba 2b nge-phenylfluorenol.82
Ama-Isoprenoid ayadingeka ekuguqulweni kwe-lipid yangemuva kokuhumusha kwamaprotheni kanye nokuphindaphinda kwe-asexual kwe-Plasmodium falciparum.I-Isoprenoid ihlanganiswa kusukela ku-five-carbon precursor isopentyl diphosphate (IPP) noma i-isomer yayo, i-dimethylallyl diphosphate (DMAPP), ngenye yezindlela ezimbili ezizimele.I-Mevalonate. i-pathway kanye nendlela ye-2C-methyl-D-erythritol 4-phosphate (MEP).Ezincane ezincane kakhulu, lezi zindlela ezimbili zihlukile.Amagciwane kanye ne-Plasmodium falciparum ancike ngokuphelele endleleni ye-MEP, kuyilapho abantu bengenjalo.Ngakho-ke, ama-enzyme Indlela ye-MEP icutshungulwa njengokungaba khona okuhlosiwe kokwelapha okusha.I-Plasmodium falciparum 1-deoxy-xylulose-5-phosphate reductoisomerase (pfDxr) ivuselela isinyathelo sokunciphisa izinga kumzila we-MEP, okwenza le enzyme ye-parasite ibe umgomo othembisayo wokuthuthukiswa kwemishanguzo ye-antimalarial inoveli. .83,84 PfDXR inhibitors inhibit Plasmodium falciparum.Plasmodium falciparum iyakhula futhi ayinabo ubuthi emangqamuzaneni omuntu.I-PfDXR iyithagethi entsha engase ibe khonaukuthuthukiswa kwezidakamizwa ezilwa nomalaleveva.83 I-Fosmidomycin, i-MMV019313 kanye ne-MMV008138 ivimbela i-DOXP rectoisomerase, i-enzyme eyinhloko yendlela ye-DOXP engekho kubantu.Ngenxa yokuthi ukuvinjelwa kwe-protein prenylation ku-Plasmodium kuphazamisa ukukhula kwe-asexual target yi-asexual parasites i-antimalari5.
Amaprotheni afakwe ngaphambili adlala indima ebalulekile ezinqubweni ezihlukahlukene zamaselula okuhlanganisa ukushushumbiswa kwe-vesicle, ukuguqulwa kwesignali, ukulawulwa kokuphindaphinda kwe-DNA, kanye nokuhlukaniswa kwamaseli.Lokhu kuguqulwa kokuhumusha ngemva kokuhumusha kusiza ukubophezela kwamaprotheni e-intracellular ku-membrane futhi kusize ukusebenzisana kwamaprotheni-amaprotheni.I-Farnesyltransferase ikhuthaza ukudluliswa kweqembu le-farnesyl, i-15-carbon isoprenoid lipid unit, kusukela ku-farnesyl pyrophosphate kuya ku-C-terminus yamaprotheni aqukethe i-CaaX motif.I-Farnesyltransferase iyinhloso entsha ethembisayo yokuthuthukiswa kwezidakamizwa ze-antimalarial ngoba ukuvimbela kwayo kubulala i-parasite.86
Ngaphambilini, ukuvela kokumelana nama-parasites yi-farnesyltransferase inhibitor BMS-388,891 tetrahydroquinoline kubonise ukuguqulwa kwephrotheni yesizinda se-peptide substrate-binding.Ekukhethweni kwenye i-tetrahydroquinoline ene-BMS-339,941, ukuguqulwa kwatholakala ku-farnesyl binding pyrophosphate. .Kolunye ucwaningo, ukuguqulwa kwatholakala ku-farnesyltransferase beta subunit yohlobo olumelana ne-MMV019066 lwe-P. falciparum.Izifundo zokumodela zibonise ukuthi ukuguqulwa kuhlanekezela isayithi lokusebenzisana elibalulekile le-molecule encane nesayithi elisebenzayo le-farnesylation, okuholela ekuphikisweni kwezidakamizwa. .87
Enye yezinhloso ezithembisayo zokwakhiwa kwemithi emisha ukuvimba i-P. falciparum ribosome, kanye nezinye izingxenye zemishini yokuhumusha ebhekele ukuhlanganiswa kwamaprotheni.Izinhlobo zePlasmodium zinama-genome amathathu: i-nucleus, i-mitochondria, nama-acroplasts (kusuka kuma-chloroplast asele). Wonke ama-genomes adinga umshini wokuhumusha ukuze asebenze.Ama-protein synthesis inhibitors anempumelelo ebalulekile yomtholampilo njengama-antibiotic asebenzayo.I-Doxycycline, clindamycin, ne-azithromycin awusizo olukhulu lwe-antimalarial therapy ngoba avimbela ama-ribosomes ku-parasite mitochondria nama-aplastoplast, okwenza lawa ma-organelles angasebenzi.88 I-P. falciparum ribosome ithatha indawo emaphakathi yokuguquguquka phakathi kwe-prokaryote ne-eukaryote, iyihlukanisa ngokuphawulekayo ne-ribosome yomuntu futhi ngaleyo ndlela inikeze ithagethi entsha ethembisayo ebalulekile.I-Plasmodium falciparum elongation factor 2 (pfEF2) iyingxenye ye-ribosome eyenza i-GTP-dependence ama-ribosomes eduze kokungcolafaka i-RNA futhi ibalulekile ekuhlanganiseni amaprotheni kuma-eukaryotes.I-PfEF2 yahlukaniswa njengenhloso entsha yokuthuthukiswa kwezidakamizwa ezilwa nomalaleveva.87,89
Ukuvinjelwa kokuhlanganiswa kwamaprotheni Thatha ukutholwa kwe-sordarin, umkhiqizo wemvelo ovimba ngokukhetha ukwakheka kwamaprotheni esikhunta ngokuvimbela imvubelo ye-eukaryotic elongation factor 2. Ngokufanayo, i-M5717 (ngaphambilini eyayiyi-DDD107498), inhibitor ekhethiwe ye-80S ribosome-interacting, i-P okwamanje Ucwaningo lwe-1, oluqinisekisa amandla e-PfEF2 njengento ehlosiwe ephumelelayo yemithi elwa nomalaleveva.88,90
Izici eziyinhloko zikamalaleveva onzima ukuthunjwa kwama-erythrocyte anegciwane lesandulela ngculazi, ukuvuvukala, nokuvaleka kwe-microvasculature.I-Plasmodium falciparum isebenzisa i-heparan sulfate njengoba inamathela endothelium namanye amangqamuzana egazi, okubangela ukuvinjelwa kokugeleza kwegazi.Ukuvimbela lawa maseli angavamile kanye ne-pathogen. -ukusebenzelana kwezidakamizwa kubuyisela ukugeleza kwegazi elivinjiwe futhi kuthinte ukukhula kwezimuncagazi.91
Ucwaningo oluningana luye lwabonisa ukuthi i-sevuparin, i-polysaccharide elwa nokunamathela eyenziwe nge-heparin, inemiphumela yokuqeda i-antithrombin.I-Sevuparin ivimbela ukuhlasela kwe-merozoite kuma-erythrocytes, ibophezela ama-erythrocyte anegciwane kuma-erythrocyte angatheleleki namagciwane, futhi abophe kumaseli e-vascular endotherind endothermoreal. ku-N-terminal extracellular heparan sulfate-binding structure ye-Plasmodium falciparum erythrocyte membrane protein 1, i-Duffy-binding-like domain 1α (DBL1α), futhi kucatshangwa ukuthi iyisici esibalulekile ekutholeni ama-erythrocyte anegciwane.92,93 Ezinye Ithebula 2 lifingqa ukuhlolwa kwemitholampilo ezigabeni ezihlukahlukene.
Isikhathi sokuthumela: Mar-24-2022