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Tafere Mulaw Belete Department of Pharmacology, ngalaba nke ọgwụ na ahụike sayensị, Mahadum Gondar, Gondar, Ethiopia Nkwukọrịta ozi: Tafere Mulaw Belete Tel +251 918045943Email [email protected] Abstract: ịba bụ nnukwu nsogbu ahụike zuru ụwa ọnụ na-akpata nnukwu ọnwụ na ọrịa kwa afọ Ọnụego .Nhọrọ ọgwụgwọ dị ụkọ ma na-ama aka nke ukwuu site na mpụta nke nje nje na-eguzogide ọgwụ, bụ nke na-ebute ihe mgbochi dị ukwuu n'ịchịkwa ọrịa ịba.Iji gbochie ihe mberede ahụike ọha na eze, ọgwụ mgbochi ịba ọhụrụ nwere ọgwụgwọ otu dose, nnukwu ọgwụgwọ ike, na usoro ọhụrụ nke omume. A na-achọ ngwa ngwa ngwa ngwa. Mmepe ọgwụ antimalarial nwere ike ịgbaso ụzọ dịgasị iche iche, site na mgbanwe nke ọgwụ ndị dị ugbu a na nhazi nke ọgwụ ọhụrụ na-ezubere iche maka ebumnuche ọhụrụ. Ọganihu ọgbara ọhụrụ na bayoloji parasaiti na nnweta teknụzụ genomic dị iche iche na-enye ọtụtụ ebumnuche ọhụrụ. maka mmepe nke ọgwụgwọ ọhụrụ.Ọtụtụ na-ekwe nkwa targEkpughere ets maka itinye aka na ọgwụ ọjọọ n'afọ ndị na-adịbeghị anya. Ya mere, nyocha a na-elekwasị anya na ọganihu sayensị na nkà na ụzụ kachasị ọhụrụ na nchọpụta na mmepe nke ọgwụ antimalarial ọhụrụ. Ihe kachasị adọrọ mmasị ndị na-edozi ihe mgbochi ịba na-amụ ruo ugbu a gụnyere proteases, protein kinases, plasmodium sugar transporter inhibitors, aquaporin 3 inhibitors, choline transport inhibitors, dihydroorotate dehydrogenase inhibitors, pentadiene biosynthesis inhibitor, farnesyltransferase inhibitor na enzymes na-etinye aka na lipid metabolism na DNA replication. Nke a nyochaa na-achikota ọhụrụ molekụla lekwasịrị anya maka antimalarial ọgwụ mmepe na okwu ha na-egbochi ọgwụ: K. , ebumnobi ọhụrụ, ọgwụ mgbochi ịba, ụdị omume, nje ịba
Ọrịa ịba bụ ọrịa na-efe efe na-efe efe na-agbawa obi, ọkachasị na ndịda Sahara Africa, akụkụ nke Eshia na South America. N'agbanyeghị mbọ niile, taa, ọ bụ otu n'ime ihe na-ebute ọrịa na-anwụ anwụ ọkachasị ụmụ nwanyị dị ime na ụmụaka. Òtù (WHO) 2018 akụkọ, e nwere nde 228 ọrịa ịba na 405,000 na-anwụ n'ụwa nile. Ihe fọrọ nke nta ka ọ bụrụ ọkara nke ndị bi n'ụwa nọ n'ihe ize ndụ nke ịba, na ọtụtụ ikpe (93%) na ọnwụ (94%) na-eme na Africa. Ụmụ nwanyị dị ime nde 125 nọ n'ihe ize ndụ nke ịba kwa afọ, ụmụaka 272,000 na-erubeghị afọ ise na-anwụkwa n'ihi ịba. Plasmodium na-ebute ịba n'ime mmadụ bụ P. vivax, P. knowlesi, P. ovale, P. ịba na P. falciparum. N'ime ndị a, Plasmodium falciparum bụ ụdị Plasmodium kacha egbu egbu na nke juru ebe niile.3
Na enweghị ọgwụ mgbochi dị irè, ọgwụgwọ ọgwụgwọ nke ọgwụ ịba na-anọgide na-abụ nanị ụzọ isi jikwaa ma gbochie ọrịa ịba. Ọtụtụ nchọpụta egosiwo na irè nke ọtụtụ ọgwụ mgbochi ịba na-emebi site na mberede na Plasmodium spp.4 ọgwụ na-eguzogide ọgwụ. a kọwapụtala na ọ fọrọ nke nta ka ọ bụrụ ọgwụ mgbochi ịba niile dị, na-ewusi mmepe nke ọgwụ mgbochi ịba ọhụrụ megide ebumnuche ndị dị adị na nchọta usoro mgbasa ozi gametophytic nwekwara ike ime na mmụba asexual n'ime erythrocytes, karịsịa na ụdị parasaiti na-eguzogide ọgwụ.6 Ọtụtụ enzymes, ion. ọwa, ndị na-ebu njem, ụmụ irighiri ihe na-emekọrịta ihe Mwakpo mkpụrụ ndụ ọbara uhie (RBC), na ụmụ irighiri ihe na-akpata nrụgide oxidative parasite, metabolism lipid, na mmebi hemoglobin bụ isi ihe na-emepe emepe ọgwụ mgbochi ịba ọhụrụ megide ịba na-agbanwe ngwa ngwa na-ekwe nkwa ebumnuche ọhụrụ maka protozoa.7
A na-ekpebi ikike nke ọgwụ mgbochi ịba ọhụrụ site n'ọtụtụ ihe achọrọ: usoro omume ọhụrụ, enweghị mgbochi mgbochi ọgwụ mgbochi ịba ugbu a, ọgwụgwọ otu dose, ịdị irè megide ma ọkwa ọbara asexual na gametocytes na-ahụ maka nnyefe. Na mgbakwunye, ọhụrụ. ọgwụ mgbochi ịba kwesịrị ịdị irè n'igbochi ọrịa (chemoprotectants) na ikpochapụ imeju nke P. vivax hypnotics (ndị na-egbochi nlọghachi azụ).8
Nchọpụta ọgwụ ọdịnala na-eso ụzọ dị iche iche iji chọpụta ọgwụ mgbochi ịba ọhụrụ iji lụso ịba ọgụ. Ndị a na-emezi usoro na usoro ọgwụ ugbu a, na-agbanwe ọgwụ mgbochi ịba dị ugbu a, nyocha ngwaahịa sitere n'okike, ikewapụ ihe mgbochi na-agbanwe agbanwe, na-eji ụzọ chemotherapy jikọtara ọnụ, na imepụta ọgwụ. maka ihe ozo.8,9
Na mgbakwunye na ụzọ nchọpụta ọgwụ ọdịnala eji amata ọgwụ mgbochi ịba ọhụrụ, egosila na ịmara ihe ọmụmụ ihe ọmụmụ Plasmodium cell biology na genome bụ ngwá ọrụ siri ike maka ikpughe usoro mgbochi ọgwụ, ma nwee ikike imepụta ọgwụ nwere oke mgbochi ịba na mgbochi ịba.Ike dị ukwuu maka ọgwụ ọhụrụ.Ịlụso ọrịa ọrịa ịba ọgụ nwere ike ịkwụsị otu oge.10 Nyocha mkpụrụ ndụ ihe nketa nke Plasmodium falciparum chọpụtara 2680 genes dị mkpa maka uto nke ọbara asexual, si otú ahụ na-achọpụta usoro cellular isi nke dị oké mkpa maka ịmepụta ọgwụ ọhụrụ.10,11 New ọgwụ kwesịrị: (i) ibelata ọgwụ mgbochi ọrịa, (ii) ime ngwa ngwa, (iii) dị mma, ọkachasị ụmụaka na ụmụ nwanyị dị ime, na (iv) gwọọ ịba n'otu dose.12 Ihe ịma aka bụ ịchọta ọgwụ na-edozi ahụ. njirimara ndị a niile. Ebumnuche nke nyocha a bụ iji nye echiche nke ebumnuche ọhụrụ maka ọgwụgwọ ọrịa ịba, nke ọtụtụ ụlọ ọrụ na-amụ, ka ndị na-agụ akwụkwọ wee nwee ike ịgwa ndị na-agụ akwụkwọ banyere ọrụ gara aga.
Ka ọ dị ugbu a, ọtụtụ ọgwụ mgbochi ịba na-elekwasị anya n'ogo asexual nke ọrịa ịba nke na-ebute ọrịa mgbaàmà. Ogbo pre-erythrocytic (imeju) na-anọgide na-adọrọ mmasị n'ihi na ọ dịghị ihe mgbaàmà ọ bụla emepụtara. ngwaahịa eke, semi-synthetic na synthetic ogige mepụtara kemgbe 1940.13 ọgwụ mgbochi ịba dị adị na-adaba n'ụdị atọ sara mbara: ihe nrụpụta quinoline, antifolates na ihe nrụpụta artemisinin. Ọ nweghị otu ọgwụ ka achọpụtala ma ọ bụ mepụta nke nwere ike ikpochapụ ụdị nje nje ịba niile. Ya mere, ka ọ dị irè megide ọrịa ịba, a na-ejikarị ngwakọta ọgwụ eme ihe n'otu oge. Quinoline bụ ọgwụ mgbochi ịba na-ejikarị eme ihe maka ọgwụgwọ ịba. iji gwọọ ọrịa na narị afọ nke 17. Site n'etiti 1800s ruo 1940s, qui.itoolu bụ ọgwụgwọ ọkọlọtọ maka ịba.14 Na mgbakwunye na nsị, mpụta nke ụdị P. falciparum na-eguzogide ọgwụ na-egbochi ọgwụgwọ ọgwụgwọ nke quinine. Otú ọ dị, a ka na-eji quinine na-agwọ ọrịa ịba siri ike, na-ejikarị ya na ọrịa ịba. ọgwụ nke abụọ iji mee ka oge ọgwụgwọ dị mkpụmkpụ ma belata mmetụta.15,16
Ọgụgụ 1 Usoro ndụ nke Plasmodium n'ime mmadụ. Usoro na ụdị nje nje ndị dị iche iche nke ọgwụ mgbochi ịba na-eme.
Na 1925, ndị na-eme nchọpụta German chọtara ọgwụ antimalarial synthetic nke mbụ, pamaquin, site n'ịgbanwe methylene blue.Pamaquin nwere oke irè na nsi na-enweghị ike iji na-agwọ ọrịa ịba.Ma pamaquin na-enye ogige ndị ndu iji mepụta ọgwụ mgbochi ịba mma.Mepacrine (quinacrine) bụ ihe ọzọ. Mwepụta nke methylene blue eji agwọ ịba n'oge Agha Ụwa nke Abụọ.17
Emepụtara Chloroquine n'oge Agha Ụwa nke Abụọ iji gwọọ ọrịa ịba. Chloroquine bụ ọgwụ a na-ahọrọ maka ọgwụgwọ ịba n'ihi ịdị irè ya, nchekwa na ọnụ ala dị ala.Ma iji ya eme ihe n'enweghị isi n'oge na-adịghị anya mere ka ụdị P. falciparum na-eguzogide chloroquine. 18 Primaquine na-eji ọgwụgwọ ọgwụgwọ agwọ ọrịa Plasmodium vivax na-alọghachi azụ nke hypnosis kpatara. -P.Dịurnal ọrụ.19
Ejikọtara ihe mgbochi quinoline ọhụrụ, nke butere ọgwụ ọhụrụ dị ka piperaquine na amodiaquine. Mgbe mpụta nke nguzogide chloroquine, amodiaquine, analog nke chloroquine dochie anya phenyl, gosipụtara nrụpụta dị mma megide chloroquine na-eguzogide ụdị Plasmodium falciparondyrnid bụ Manni P. base antimalarial ọgwụ emepụtara na China na 1970. Ọ dị irè megide ụdị ọgwụ na-eguzogide ọgwụ nke P. falciparum, P. vivax, P. malaria na P. ovale. ọrịa ịba.21 Mefloquine e mepụtara n'etiti 1980s ma na-atụ aro ugbu a maka chemoprevention nke ịba nke ụdị nile kpatara, gụnyere ụdị na-eguzogide chloroquine. Otú ọ dị, ojiji ya na-ejikọta ya na ụfọdụ mmetụta na nkwụsị ọgwụ.22 Quinoline sitere na ọgwụ. na-eme ihe n'ụzọ bụ isi na ọkwa ọbara nke parasaiti, ma ụfọdụ ọgwụ mgbochi ịba na-eme n'ọkwa imeju. Ọgwụ ndị a na-egbochi site n'ịme compl.ex with heme in the parasite's food vacuoles.Ya mere, a na-egbochi heme polymerization.N'ihi ya, heme a tọhapụrụ n'oge nkwụsị nke hemoglobin na-akwakọba n'ọkwa nsị, na-egbu nje nje na-egbu egbu. iri abụọ na atọ.
Antifolates bụ ọgwụ mgbochi ịba nke na-egbochi njikọ nke folic acid, nke dị mkpa maka njikọ nke nucleotides na amino acids.Antifolates na-egbochi nkewa nuklia nke ụdị Plasmodium n'oge oge schizont na erythrocytes na hepatocytes.Sulfadoxine nwere usoro yiri nke para-aminobenzoic acid. (PABA), akụkụ nke folic acid. Ha na-egbochi njikọ dihydrofolate site na igbochi dihydrofolate synthase, bụ isi enzyme nucleic acid biosynthesis. iri abụọ na anọ
Pyrimethamine na proguanil bụ ọgwụ antimalarial schizont nke na-eme n'ụdị asexual nke ụdị Plasmodium. Ọgwụ ndị a na-egbochi enzyme dihydrofolate reductase (DHFR), nke na-egbochi mbelata dihydrofolate na tetrahydrofolate, nke dị mkpa maka biosynthesis nke amino acids na nucleic acid. Proguanil bụ prodrug metabolized na cyclic guanidine.Proguanil bụ ọgwụ antifolate mbụ e ji agwọ ọrịa ịba. Ihe kpatara ya bụ na ọ na-ebibi mkpụrụ ndụ ọbara uhie tupu parasaiti ahụ wakporo ha mgbe ha na-abanye n'ọbara. Ọzọkwa, proguanil bụ ihe nchebe. ọgwụ.Pyrimethamine na-ejikarị ọgwụ ndị ọzọ na-eme ngwa ngwa. Otú ọ dị, ojiji ya ebelatala n'ihi nkwụsị ọgwụ.24,25
Atovaquone bụ ọgwụ mgbochi ịba nke mbụ akwadoro na-elekwasị anya na mitochondria nke Plasmodium parasite.Atovaquone na-egbochi njem elektrọn site na ime ihe dị ka analog ubiquinone iji gbochie akụkụ cytochrome b nke cytochrome bc1 complex. Mgbe ejikọtara ya na proguanil, atovaquone dị mma ma dị irè maka ụmụ nwanyị dị ime. na ụmụaka.Atovaquone dị irè megide ọnọdụ mmekọahụ nke parasaiti nke onye ọbịa na anwụnta.Ya mere, ọ na-egbochi nnyefe nke ịba site na anwụnta na ụmụ mmadụ. Ngwakọta a kwadoro na proguanil mepụtara n'okpuru aha ahia ahụ Malarone.24,26
Artemisinin sitere na Artemisia annua na 1972. Artemisinin na ihe ndị sitere na ya gụnyere artemether, dihydroartemisinin, artemether na artesunate nwere nnukwu ọrụ dị iche iche. nke gametocytes sitere na ụmụ mmadụ ruo anwụnta.27 Artemisinin na ihe ndị na-emepụta ya dị irè megide chloroquine- na mefloquine na-eguzogide ọgwụ. Ha dị nchebe, dị irè ma na-eme ngwa ngwa ọbara schizonts megide ụdị Plasmodium niile. Otú ọ dị, artemisinin ekpochapụghị nkwụsị imeju nke imeju. Mgbochi ndị a nwere obere ndụ ọkara ndụ na adịghị ike bioavailability, na-eduga n'igbochi ọgwụ, na-eme ka ha ghara ịdị irè dị ka monotherapy.Ya mere, a na-atụ aro ọgwụ artemisinin na ọgwụ ndị ọzọ na-egbochi ịba.28
Mmetụta antimalarial nke artemisinin nwere ike ịbụ n'ihi ọgbọ nke free radicals nke na-esi na nkwụsị nke artemisinin endoperoxide bridges na parasite nri vesicles, si otú a na-egbochi parasaiti calcium ATPase na proteasome.29,30 Artemether na-eji dị ka monotherapy.Fast onu absorption.Bioavailability. okpukpu abụọ mgbe a na-enye ya n'ihu nri. N'otu oge na mgbasa ozi usoro, artemether na-agbanye hydrolyzed na dihydroartemisinin n'ime eriri afọ na imeju.
Artesunate bụ ihe mgbapụta nke ọkara sịntetik n'ihi mmetụta mgbochi ịba ya ngwa ngwa, enweghị nnukwu mgbochi ọgwụ na oke mmiri solubility. A na-akwado ya dị ka ọgwụ mbụ maka ịba siri ike.31
Tetracyclines na macrolides bụ ọgwụ mgbochi ịba na-eji nwayọ eme ihe dị ka ọgwụgwọ mgbakwunye na quinine na malaria falciparum.A na-ejikwa Doxycycline maka chemoprophylaxis na mpaghara ndị nwere nnukwu nguzogide.32 Usoro nke ugbu a eji alụso ọgụ ọgụ ọgwụ mgbochi ịba bụ ọgwụgwọ ọgwụgwọ nke ngwakọta ọgwụ. A na-eji atụmatụ eme ihe n'oge gara aga site n'iji njikọ dị iche iche eme ihe.WHO na-akwado artemisinin-based mix therapy (ACT) dịka ọgwụgwọ mbụ maka ịba falciparum na-enweghị mgbagwoju anya. Ihe kpatara ya bụ na nchikota ọgwụ na-ebelata nkwụsị ọgwụ na mmetụta.33
ACT nwere akụrụngwa artemisinin dị ike nke na-ekpochapụ nje nje ngwa ngwa, yana ọgwụ na-eme ogologo oge nke na-ewepụ nje ndị fọdụrụnụ ma na-ebelata ihe mgbochi artemisinin.ACT ndị WHO kwadoro bụ artesunate/amodiaquine, artemether/ benzfluorenol, artesunate/mefloquine, artesunate/pyrrolidine, dihydroartemisin. piperaquine, Artesunate/sulfadoxine/pyrimethamine, artemether/piperaquine na artemisinin/piperaquine/primaquine.Chloroquine gbakwunyere primaquine na-anọgide na-abụ ọgwụ mbụ maka ikpochapụ Plasmodium vivax.Quinine + tetracycline/doxycycline nwere nnukwu akụkụ, mana ọ nwere nnukwu cucure. mmetụta na contraindicated na ụmụaka na ndị inyom dị ime34.
A na-atụ aro Mefloquine, atovaquone / proguanil, ma ọ bụ doxycycline na usoro chemoprevention maka ndị njem si na-abụghị ndị na-adịghị agwụ agwụ na ebe ndị na-adịghị mma. .36 Halofantrine adịghị mma maka ọgwụgwọ ọgwụgwọ n'ihi cardiotoxicity ya. A napụrụ Dapsone, mepalyline, amodiaquine, na sulfonamides na ọgwụgwọ ọgwụgwọ n'ihi mmetụta ha. 1.
Ọgwụ mgbochi ịba dị ugbu a dabere na ọdịiche dị na ụzọ metabolic isi dị n'etiti ụdị Plasmodium na ndị ọbịa ha. Ụzọ ụzọ metabolic bụ isi nke parasaiti, gụnyere heme detoxification, fatty acid synthesis, nucleic acid synthesis, fatty acid synthesis, and oxidative stress, bụ ụfọdụ n'ime akwụkwọ akụkọ ahụ. saịtị maka imepụta ọgwụ.38,39 Ọ bụ ezie na a na-eji ọtụtụ ọgwụ mgbochi ịba kemgbe ọtụtụ afọ, ojiji ha na-ejedebe ugbu a n'ihi nguzogide ọgwụ. Dị ka akwụkwọ akụkọ si kwuo, ọ dịghị ọgwụ mgbochi ịba na-egbochi ọgwụ ndị a ma ama.7,40 Na N'ụzọ dị iche, a na-achọpụta ọtụtụ ọgwụ mgbochi ịba na anụmanụ in vivo ma ọ bụ ọmụmụ ihe nlereanya in vitro.Ya mere, usoro omume nke ọtụtụ ọgwụ mgbochi ịba ka na-ejighị n'aka.Ọzọkwa, usoro nke iguzogide ọtụtụ ọgwụ ịba amabeghị.39
Ịchịkwa ịba na-achọ usoro a haziri ahazi dị ka njikwa vector, ọgwụ mgbochi ịba dị irè ma dị mma, na ọgwụ mgbochi dị irè. N'ịtụle ọnụ ọgụgụ dị elu nke ọnwụ na ọrịa ịba, ihe mberede na mgbasa nke mgbochi ọgwụ, adịghị arụ ọrụ nke ọgwụ ịba dị ugbu a megide ndị na-abụghị erythrocyte na nke mmekọahụ. , ịmata ọgwụ mgbochi ịba ọhụrụ site n'ịghọta usoro ụzọ metabolic bụ isi nke ịba.Ọgwụ ịba dị oke mkpa.parasites.Iji nweta ebumnobi a, nchọcha ọgwụ kwesịrị ịtụba ebumnobi ọhụrụ akwadoro iji wepụta ogige ndu ọhụrụ.39,41
Enwere ọtụtụ ihe kpatara ọ dị mkpa iji chọpụta ihe mgbaru ọsọ metabolic ọhụrụ. Nke mbụ, ewezuga ọgwụ atovaquone na artemisinin sitere na ọgwụ, ọtụtụ ọgwụ mgbochi ịba anaghị adị iche iche nke kemịkalụ, nke nwere ike iduga nguzogide nbibi. Nke abụọ, n'ihi ụdị dịgasị iche iche nke putative chemotherapeutic targets, ọtụtụ ndị ka ekwenyebeghị. Ọ bụrụ na a kwadoro ya, ọ nwere ike ịmepụta ụfọdụ ogige ndị dị irè ma dị mma. Nchọpụta nke ihe mgbaru ọsọ ọgwụ ọhụrụ na nhazi nke ogige ọhụrụ nke na-eme ihe ọhụrụ a na-eji gburugburu ụwa taa iji lebara anya. nsogbu na-esite na mpụta nke iguzogide ọgwụ ndị dị ugbu a.40,41 Ya mere, a na-eji ihe ọmụmụ nke ndị na-emepụta ihe na-emepụta protein-kpọmkwem nke Plasmodium mee ihe maka nchọpụta ọgwụ ọjọọ. ọgwụ mgbochi ịba ndị a nwere ike ilekwasị anya na metabolite biosynthesis, mbufe akpụkpọ ahụ na usoro akara, yana usoro mmebi haemoglobin.40,42.
Plasmodium protease bụ ihe na-eme ka ahụ dị n'ebe nile ma na-achịkwa enzyme nke na-arụ ọrụ dị mkpa na ndụ nke nje nje protozoan na ọrịa ndị ha na-ebute. Ọ na-eme ka hydrolysis nke peptide bonds. mgbapụ, ịgbalite mbufụt, mbuso agha erythrocyte, ndakpọ nke hemoglobin na protein ndị ọzọ, autophagy, na mmepe nje.44.
Ọrịa ịba (glutamic aspartic acid, cysteine, metal, serine na threonine) bụ ebumnuche ọgwụgwọ na-ekwe nkwa n'ihi na mmebi nke mkpụrụ ndụ nje protease ịba na-egbochi mmebi nke hemoglobin na ọkwa erythrocyte nke nje nje.mmepe.45
Nkwụsị nke erythrocytes na mbuso agha nke merozoites na-achọ ịba proteases.A peptide synthetic (GlcA-Val-Leu-Gly-Lys-NHC2H5) na-egbochi Plasmodium falciparum schizont cysteine protease Pf 68. Ọ na-egbochi mmepe erythrocyte. na-atụ aro na protease na-ekere òkè dị mkpa na mbuso nje ndị nje na-awakpo mkpụrụ ndụ ọbara uhie.Ya mere, protease bụ ihe e ji ekwe nkwa ịmepụta ọgwụ mgbochi ịba.46
Na Plasmodium falciparum nri vacuoles, ọtụtụ aspartic proteases (plasma proteases I, II, III, IV) na cysteine proteases (falcipain-1, falcipain-2/, falcipain-3) kewapụrụ iche, Ejila hemoglobin belata, dị ka egosiri. na eserese 2.
Mmụba nke parasaiti P. falciparum omenala na ndị na-egbochi protease leupeptin na E-64 mere ka nchịkọta nke globin na-adịghị mma.Leupeptin na-egbochi cysteine na ụfọdụ serine proteases, ma E-64 kpọmkwem na-egbochi cysteine proteases.47,48 Mgbe a kwụsịrị ya. nke nje ndị nwere aspartate protease inhibitor pepstatin, globin anaghị agbakọba. Ọtụtụ nnyocha egosiwo na ndị na-egbochi cystatin abụghị nanị na-egbochi mmebi globin, kamakwa na-egbochi mmalite nke nkwụsị nke hemoglobin, dị ka hemoglobin denaturation, heme ntọhapụ na globin, na mmepụta heme. .49 Nsonaazụ ndị a na-egosi na a chọrọ cysteine proteases maka mmalite mbụ. Nzọụkwụ na mmebi nke hemoglobin site Plasmodium falciparum. Ma E-64 na pepstatin synergistically na-egbochi mmepe P. falciparum. Otú ọ dị, nanị E-64 gbochiri globin hydrolysis. 48,49 Ọtụtụ cysteine protease inhibitors, dị ka fluoromethyl ketone na vinyl sulfone, na-egbochi uto P. falciparum na hemoglobin degra.dation.Na ụdị anụmanụ nke ịba, fluoromethyl ketone na-egbochi ọrụ P. vickei protease ma na-agwọ 80% nke ọrịa ịba murine. Ya mere, ndị na-egbochi protease na-ekwe nkwa maka ọgwụ mgbochi ịba. Ọrụ sochirinụ achọpụtara ndị na-eme ihe na-eme falcipain na-arụ ọrụ biologically, gụnyere chalcone na phenothiazine. nke na-egbochi parasaiti metabolism na mmepe.50
Serine proteases na-etinye aka na schizont rupture na erythrocyte reinvasion n'oge Plasmodium falciparum ndụ cycle.Ọ nwere ike igbochi ya site na ọtụtụ serine protease inhibitors na bụ nhọrọ kasị mma ebe ọ bụ na ọ dịghị mmadụ enzyme homolog dị.The protease inhibitor LK3 dịpụrụ adịpụ na Streptomyces sp.na-eweda serine protease ịba.51 Maslinic acid bụ pentacyclic triterpenoid sitere n'okike nke na-egbochi ntozu nke nje nje site na mgbanaka mgbanaka ruo na schizont, si otú ahụ kwụsị ntọhapụ nke merozoites na mbuso agha ha. Usoro nke nwere ike 2-pyrimidine nitrile igbochi falcipain. -2 na falcipain-3.52 statins na mgbochi nke plasma proteases site allophenostatin dabeere inhibitors na-egbochi hemoglobin mebiri emebi ma na-egbu nje parasites. .
Phosphoinotide lipid kinases (PIKs) bụ enzymes ebe niile na phosphorylate lipids na-achịkwa mmụba, nlanarị, ịzụ ahịa, na nrịbama intracellular. Klas PIK nke a na-amụkarị na 53 parasites bụ phosphoinositide 3-kinase (PI3K) na phosphatid-PIK4kinase (PI3K) na phosphatid-kinase. Achọpụtara mgbochi nke enzymes ndị a dị ka ihe nwere ike ịmepụta ọgwụ mgbochi ịba na profaịlụ ọrụ na-achọsi ike maka mgbochi, ọgwụgwọ na mkpochapụ nke ịba. (4)K ma gbochie mmepe intracellular nke otutu ụdị Plasmodium n'oge ọ bụla nke ọrịa ndị ọbịa. Ya mere, ịchebe (PI3K) na PI (4) K nwere ike imeghe ụzọ ọhụrụ dabere na nchọpụta ọgwụ ezubere iche iji chọpụta ọgwụ mgbochi ịba ọhụrụ.KAF156 dị ugbu a. na Phase II clinical trials.55,56 MMV048 bụ onyinye nwere ezi na vivo prophylactic ọrụ megide P. cynomolgi na ike aọgwụ na-egbochi nnyefe.MMV048 na-aga ule ụlọ ọgwụ Phase IIa ugbu a na Etiopia.11
Maka uto ngwa ngwa na mkpụrụ ndụ ọbara uhie oria, ụdị Plasmodium chọrọ ihe mejupụtara nke ọma iji mee ka metabolism ha sie ike. Ya mere, nje na-akwadebe erythrocytes ọbịa site n'ime ka ndị na-ebugharị pụrụ iche nke dị iche na ndị na-ebugharị sel ndị ọbịa na nnabata na iwepụ metabolites. Ndị na-ebu protein na ọwa bụ ndị nwere ike lekwasịrị anya n'ihi ọrụ dị mkpa ha na-ebuga metabolites, electrolytes na nri.57 Ndị a bụ Plasmodium surface anion channel (PSAC) na parasitic vacuolar membrane (PVM), nke na-enye ụzọ mgbasa ozi na-aga n'ihu maka nri nri banye n’ime mpụta.58
PSAC bụ ebumnuche kacha ekwe nkwa n'ihi na a na-ahụ ya n'ụdị nri dị iche iche (hypoxanthine, cysteine, glutamine, glutamate, isoleucine, methionine, proline, tyrosine, pantothenic acid na choline) iji nweta ọrụ dị mkpa na nje nje intracellular.PSAC enweghị nkọwa doro anya. ka amara ọwa ọwa mkpụrụ ndụ ihe nketa.58,59 Phloridizin, dantrolene, furosemide, na niflunomide bụ ndị na-egbochi anion transporter blockers. Ọgwụ ndị dị ka glyburide, meglitinide, na tolbutamide na-egbochi ntinye nke choline n'ime mkpụrụ ndụ ọbara uhie nke nje nje.60,61.
Ụdị ọbara Plasmodium falciparum na-adabere kpamkpam na glycolysis maka mmepụta ume, na-enweghị nchekwa ike;Ọ na-adabere na nnabata glucose mgbe niile. Parasaiti na-atụgharị pyruvate ka ọ bụrụ lactate ka ọ mepụta ATP, nke a chọrọ maka imegharị n'ime mkpụrụ ndụ ọbara uhie. akpụkpọ ahụ erythrocyte na ihe nje na-akpata 'ụzọ ọhụrụ permeation ụzọ'.63 A na-ebufe glucose n'ime nje ndị na-ebugharị Plasmodium falciparum hexose Transporter (PFHT) .PFHT nwere ụfọdụ àgwà ndị na-ebu sugar. D-glucose na D-fructose. Ya mere, ọdịiche dị na GLUT1 na PFHT mmekọrịta na ihe ndị na-emepụta ihe na-atụ aro na nhọrọ nhọrọ nke PFHT bụ ebumnuche ọhụrụ na-ekwe nkwa maka ịmepụta ọgwụ mgbochi ịba. 3361) na-egbochi nnabata glucose na fructose site na PFHT, mana ọ naghị egbochi njem hexose site na nnukwu glucose mammalian na ndị na-ebu fructose (GLUT1 na 5) .Compound 3361 na-egbochikwa nnabata glucose site na P. vivax nke PFHT.N'ihe ọmụmụ gara aga, compound 3361 gburu P. falciparum na omenala ma belata mmepụta P. berghei na ụdị òké.65
Ịchịkọta ọbara Plasmodium na-adaberekarị na glycolysis anaerobic maka uto na mmepe.60 Mkpụrụ ndụ ọbara uhie na-ebute ọrịa parasite na-amịkọrọ glucose ugboro 100 ngwa ngwa karịa mkpụrụ ndụ ọbara uhie na-enweghị ọrịa. Parasaiti metabolizes glucose site na glycolysis na lactate, nke a na-ebupụ site na parasaiti site na lactate: usoro ihe ngosi H+ n'ime gburugburu ebe dịpụrụ adịpụ.66 Mbupụ nke lactate na nnabata glucose dị oke mkpa maka idobe ihe ike chọrọ, pH intracellular, na nkwụsi ike osmotic parasite.Lactate: H + symporter system inhibition bụ ihe ọhụrụ na-ekwe nkwa maka mmepe nke ọgwụ ọhụrụ. Ọtụtụ ogige, dị ka MMV007839 na MMV000972, na-egbu asexual ọbara-ogbo P. falciparum parasites site na igbochi lactate: H + transporter.67
Dị ka ụdị sel ndị ọzọ, mkpụrụ ndụ ọbara uhie na-eme ka ọkwa Na + dị n'ime ala dị ala. Otú ọ dị, nje nje na-eme ka permeability nke akpụkpọ ahụ erythrocyte dịkwuo mfe ma mee ka ntinye Na + dị mfe, na-eduga n'ịba ụba nke cytoplasmic Na + erythrocyte cytoplasmic Na + na ọkwa nke extracellular. chọta onwe ha na mgbasa ozi Na + dị elu na ha ga-achụpụ Na + ions na akpụkpọ ahụ plasma ha iji nọgide na-enwe ọkwa cytoplasmic Na+ dị ala iji dị ndụ n'agbanyeghị ọnụnọ ha na saịtị intracellular. N'okwu a, a na-achịkwa ntinye Na+ na parasaịt site na iji P-ụdị ATPase. Transporter (PfATP4), nke na-arụ ọrụ dị ka usoro mgbapụta Na +-efflux bụ isi nke parasaiti, dị ka egosiri na foto 3.68, na-egbochi onye na-ebufe ihe a Ọ ga-eduga n'ịba ụba nke Na+ n'ime nje ahụ, nke ga-emecha mee ka ọ nwụọ. Ọrịa ịba. Ọtụtụ ogige, gụnyere sipagamin na nkeji 2, (+) -SJ733 na nkeji 1, na KAE609 na nkeji 2, nwere usoro ọrụ nke na-elekwasị anya PfATP4.67,69
Ọgụgụ 3. Usoro a tụrụ aro nke PfATP4 na-akpata parasaiti na ụdị H +-ATPase na-ebute ọrịa erythrocyte ọrịa na-esote mgbochi cipargamin.
Ụdị Plasmodium na-achịkwa ọkwa Na+ ha site n'iji ụdị P-ụdị ATPase transporter.Ọ na-ebubatakwa H+ site n'ụzọ yiri nke ahụ. Iji dozie mmụba H+ na-abawanye ma nọgide na-enwe pH intracellular nke 7.3, nje ịba na-eji V-ụdị ATPase na-ebugharị. ịchụpụ H +.Ịmepụta ọgwụ ọhụrụ bụ ihe mgbaru ọsọ na-ekwe nkwa.MMV253 na-egbochi ụdị H+ ATPase V-dị ka usoro ya site na nhọpụta mgbanwe na usoro mkpụrụ ndụ dum.70,71
Aquaporin-3 (AQP3) bụ protein channel aquaglycerol nke na-eme ka mmegharị mmiri na glycerol dị na mkpụrụ ndụ anụ ahụ mammalian.AQP3 na-akpalite na hepatocytes mmadụ na nzaghachi nke ọrịa nje na-arụ ọrụ dị mkpa na parasite replication.AQP3 na-enye ohere ịnweta glycerol n'ime P. berghei ma na-eme ka njegharị parasaịt na-emegharị n'oge asexual erythrocyte.72 Mbelata nke mkpụrụ ndụ ihe nketa nke AQP3 na-ebelata ibu dị n'ime imeju nke P. berghei.Ọzọkwa, ọgwụgwọ na AQP3 inhibitor auphen belatara ibu arọ P. berghei parasitemia na hepatocytes na P. falciparum parasitemia na erythrocytes, na-atụ aro na protein ndị ọbịa na-arụ ọrụ dị egwu na usoro ndụ dị iche iche nke parasaiti .73 Ọtụtụ ihe na-akpali mmasị, nkwụsị nke AQP3 na ụmụ oke mkpụrụ ndụ ihe nketa adịghị egbu egbu, na-atụ aro na protein ndị ọbịa nwere ike ịchọta ọgwụgwọ ọhụrụ. Ọrụ a na-abawanye anyị. nghọta nke usoro imeju ndị ọbịa na-emetụta ọrịa Plasmodium ma gosipụta ikike nke pro ndị aakwụsị ka ọgwụ ịba n’ọdịnihu.71,72
Phospholipids na-arụ ọrụ dị mkpa n'ime usoro ndụ intra-erythrocyte nke Plasmodium falciparum, ma dị ka akụkụ nhazi nke membranes na dị ka usoro nchịkwa nke na-achịkwa ọrụ nke enzymes dị iche iche. Ụmụ irighiri ihe ndị a dị mkpa maka mmepụta parasite n'ime ọbara ọbara uhie. Mgbe mwakpo erythrocyte gasịrị, phospholipid etoju na-abawanye, nke phosphatidylcholine bụ isi lipid n'ime ha cell membrane components.Parasites synthesize phosphatidylcholine de novo iji choline dị ka precursor.Nke a de novo ụzọ dị oké mkpa maka parasaiti uto na nlanarị.Na-egbochi choline ibuga n'ime parasites ma na-egbochi phosphatidylcholine biosynthesis. na-akpata ọnwụ parasaiti.74 Albitiazolium, ọgwụ nke batara n'ule nke Abụọ, na-arụ ọrụ bụ isi site n'igbochi ibufe choline n'ime parasite. ọnọdụ.N'ụzọ doro anya, otu injections gwọrọ elu parasitemia ọkwa.75,76
Phosphocholine cytidyltransferase bụ ọnụego-njedebe nzọụkwụ na de novo biosynthesis nke phosphatidylcholine.77 The diquaternary ammonium compound G25 na dicationic compound T3 na-egbochi phosphatidylcholine synthesis na parasites.G25 bụ 1000-npịaji na-erughị egbu egbu ahịrị mkpụrụ ndụ mammalian. ogige na nchọpụta ọgwụ mgbochi ịba.78,79
Otu isi ihe dị mkpa n'ịgbasa ụdị Plasmodium n'ime ndị agha mmadụ bụ nkewa zuru oke na ngwa ngwa nke DNA parasaiti, nke dabere na nnweta metabolites dị mkpa dị ka pyrimidine. Na Plasmodium, pyrimidine nucleotides na-arụ ọrụ dị egwu na njikọ DNA, phospholipids na glycoproteins.Nkwekọrịta Nucleotide na-esote ụzọ abụọ bụ isi: ụzọ mgbapụta na ụzọ de novo. na-anọchite anya ebumnuche nwere ike ime maka mmepe ọgwụ mgbochi ịba.80 Mkpụrụ ndụ mmadụ na-enweta pyrimidines site n'ịnapụta pyrimidine emepụtalarị ma ọ bụ site na de novo synthesis. Agbanyeghị, igbochi de novo pyrimidine biosynthesis na nje nje na-ebute ọnwụ nke mkpụrụ ndụ ndị a n'ihi naỌrịa ịba enweghị ụzọ mgbapụta pyrimidine, nke na-eme ka nje ahụ ghara ịdaba na nkwụsị nke DHODH.81 DSM190 na DSM265 bụ ndị na-emechi emechi nke parasaiti DHODH enzyme, nke dị ugbu a na ule ụlọ ọgwụ nke Phase 2. P218 bụ DHODH inhibitor dị irè megide pyrimethamine niile. Ụdị na-eguzogide ọgwụ ugbu a na Phase 1.KAF156 (Ganaplacide) nọ ugbu a na nnwale ụlọ ọgwụ nke Phase 2b na phenylfluorenol.82
Isoprenoids na-achọrọ maka post-translational lipid mgbanwe nke protein na asexual replication nke Plasmodium falciparum.Isoprenoids na-synthesized si ise-carbon precursor isopentyl diphosphate (IPP) ma ọ bụ isomer ya, dimethylallyl diphosphate (DMAPP), site na otu n'ime abụọ onwe ụzọ.Mevalonate. ụzọ na ụzọ 2C-methyl-D-erythritol 4-phosphate (MEP) ụzọ.N'ọtụtụ microorganisms, ụzọ abụọ a na-ekewapụ onwe ya.Bacteria na Plasmodium falciparum na-adabere kpamkpam na ụzọ MEP, ebe ụmụ mmadụ na-adịghị.Ya mere, enzymes na ndị a. A na-enyocha ụzọ MEP dị ka ebumnuche ọgwụgwọ ọhụrụ nwere ike. .83,84 PfDXR inhibitors na-egbochi Plasmodium falciparum.Plasmodium falciparum na-eto eto ma bụrụ nke na-adịghị egbu egbu nye mkpụrụ ndụ mmadụ.PfDXR bụ ihe ọhụrụ nwere ike ime nammepe ọgwụ antimalarial.83 Fosmidomycin, MMV019313 na MMV008138 na-egbochi DOXP redutoisomerase, bụ isi enzyme nke ụzọ DOXP na-anọghị n'ime mmadụ.N'ihi na mgbochi nke protein prenylation na Plasmodium na-akpaghasị uto nke nje ndị na-edina ụdị onwe, nke a bụ ihe nwere ike ime antimalarial.
Protein prenylated na-arụ ọrụ dị oke mkpa n'ụdị usoro cellular dị iche iche gụnyere ịzụ ahịa vesicle, ntugharị mgbaàmà, nhazigharị DNA na nkewa sel. Mgbanwe ntụgharị ntụgharị a na-eme ka njikọ nke protein intracellular na akpụkpọ ahụ ma na-eme ka mmekọrịta protein-protein dị mfe.Farnesyltransferase na-akpalite mbufe nke otu farnesyl, otu 15-carbon isoprenoid lipid unit, site na farnesyl pyrophosphate na C-terminus nke protein nwere motif CaaX.Farnesyltransferase bu ihe ohuru ohuru maka mmepe nke ogwu ogwu n'ihi na mgbochi ya na-egbu nje.86
Na mbụ, evolushọn nke iguzogide nje nje site na farnesyltransferase inhibitor BMS-388,891 tetrahydroquinoline gosipụtara mmụgharị na protein nke mpaghara substrate peptide. Na nhọrọ nke tetrahydroquinoline ọzọ na BMS-339,941, a hụrụ ngbanwe na akpa nke farnesyl binding pyrophosphate. .N'ọmụmụ ihe ọzọ, a chọtara ngbanwe na farnesyltransferase beta subunit nke ụdị MMV019066 na-eguzogide ọgwụ nke P. falciparum. Nleba anya na-egosi na ngbanwe ahụ na-agbagọ isi mmekọrịta nke obere molekul na saịtị farnesylation na-arụ ọrụ, na-akpata nkwụsị ọgwụ. .87
Otu n'ime ihe mgbaru ọsọ na-ekwe nkwa maka ịmepụta ọgwụ ọhụrụ bụ igbochi P. falciparum ribosome, yana akụkụ ndị ọzọ nke nsụgharị nsụgharị nke na-ahụ maka njikọ protein. Ụdị Plasmodium nwere genomes atọ: nucleus, mitochondria, na acroplasts (site na chloroplasts residual). Ndị na-egbochi protein synthesis nwere nnukwu ihe ịga nke ọma na ụlọ ọgwụ dị ka ọgwụ nje dị irè. P. falciparum ribosome nọ n'etiti etiti evolushọn n'etiti prokaryotes na eukaryotes, na-akọwapụta ya nke ọma na ribosome mmadụ ma si otú a na-enye ebumnuche ọhụrụ dị mkpa na-ekwe nkwa. nke ribosomes tinyere ọgbagharaenger RNA ma dị mkpa maka njikọ protein na eukaryotes.PfEF2 dịpụrụ adịpụ dị ka ebumnuche ọhụrụ maka mmepe ọgwụ mgbochi ịba.87,89
Mgbochi nke njikọ protein Were nchọta nke sordarin, ngwaahịa sitere n'okike nke na-ahọrọ nke na-egbochi njikọ protein fungal site na igbochi yist eukaryotic elongation factor. 1 ọmụmụ, kwadoro ikike nke PfEF2 dị ka ihe mgbaru ọsọ dị irè maka ọgwụ mgbochi ịba.88,90
Akụkụ bụ isi nke ịba siri ike bụ nchikota nke erythrocytes na-ebute nje nje, mbufụt, na mgbochi nke microvasculature. Plasmodium falciparum na-eji heparan sulfate eme ihe ka ọ na-ejikọta ya na endothelium na mkpụrụ ndụ ọbara ndị ọzọ, na-eme ka ọ ghara ịmịnye ọbara. -mmekọrịta ọgwụ na-eweghachi oruru ọbara egbochiri ma na-emetụta uto parasite.91
Ọtụtụ nchọpụta egosila na sevuparin, polysaccharide anti-adhesion nke sitere na heparin, nwere mmetụta antithrombin na-ewepu. gaa na N-terminal extracellular heparan sulfate-binding structure nke Plasmodium falciparum erythrocyte membrane protein 1, Duffy-binding-like domain 1α (DBL1α), a na-eche na ọ bụ ihe dị mkpa n'ịchụpụ nje erythrocytes.92,93 Ụfọdụ Tebụl 2 na-achịkọta. ule ụlọ ọgwụ na ọkwa dị iche iche.
Oge nzipu: Mar-24-2022