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Tafere Mulaw Belete Department of Pharmacology, Faculty of Medicine and Health Sciences, Gondar University, Gondar, Ethiopia Correspondence: Tafere Mulaw Belete Tel +251 918045943Email [email protected] Abstract: ʻO ka maʻi malaria kahi pilikia olakino nui o ka honua e hoʻonui ai i ka make a me ka maʻi maʻi i kēlā me kēia makahiki. .He liʻiliʻi nā koho lapaʻau a paʻakikī nui ʻia e ka puka ʻana mai o nā maʻi parasite kūpaʻa, kahi mea e keakea nui ai i ka mālama ʻana i ka maʻi malaria. ʻO ka hoʻomohala ʻana i ka lāʻau antimalarial hiki ke hahai i nā ʻano ʻano like ʻole, mai ka hoʻololi ʻana i nā lāʻau lapaʻau e kū nei a hiki i ka hoʻolālā ʻana i nā lāʻau lapaʻau hou e huli ana i nā pahuhopu hou. no ka hoʻomohala ʻana i nā lāʻau lapaʻau houUa hōʻike ʻia nā ets no ka hana lāʻau lapaʻau i nā makahiki i hala iho nei. No laila, ke nānā nei kēia loiloi i nā holomua ʻepekema a me ka ʻenehana hou i ka ʻike ʻana a me ka hoʻomohala ʻana i nā lāʻau antimalarial hou. transporter inhibitors, aquaporin 3 inhibitors, choline transport inhibitors, dihydroorotate dehydrogenase inhibitors, pentadiene biosynthesis inhibitor, farnesyltransferase inhibitor a me nā enzymes i komo i ka lipid metabolism a me ka DNA replication. This review summarizes new molecular targets for antimalarial drug development and their inhibitors.Key words: drug resistance , nā pahuhopu hou, nā lāʻau antimalarial, ke ʻano o ka hana, malaria parasite
ʻO ka maʻi malaria kahi maʻi maʻi maʻi parasitic, ʻoi aku hoʻi ma ka sub-Saharan Africa, nā ʻāpana o Asia a me ʻAmelika Hema. ʻOiai kekahi mau hoʻoikaika ʻana, i kēia lā ʻo ia kekahi o nā kumu nui o ka morbidity a me ka make nui i nā wahine hāpai a me nā keiki. Wahi a ka World Health ʻO ka Organization (WHO) 2018 hōʻike, aia he 228 miliona mau maʻi malaria a me 405,000 mau make ma ka honua holoʻokoʻa. Kokoke ka hapalua o ka heluna o ka honua i ka maʻi malaria, me ka hapa nui o nā hihia (93%) a me nā make (94%) e kū nei ma ʻApelika. He 125 miliona mau wāhine hāpai i ka maʻi maʻi i kēlā me kēia makahiki, a he 272,000 mau keiki ma lalo o 5 mau makahiki i make i ka maʻi malaria. ʻO Plasmodium ka mea e hoʻoulu ai i ka maʻi maʻi i loko o ke kanaka, ʻo ia ka P. vivax, P. knowlesi, P. ovale, P. malaria a me P. falciparum. ʻO kēia mau mea, ʻo Plasmodium falciparum ka mea make a nui loa o Plasmodium.3
I ka loaʻa ʻole o ka lāʻau lapaʻau maikaʻi, ʻo ka hoʻohana ʻana i nā lāʻau antimalarial ke ala wale nō e mālama a pale i ka maʻi maʻi malaria. ua hōʻike ʻia me nā lāʻau lapaʻau antimalarial kokoke i loaʻa, e hoʻoikaika ana i ka hoʻomohala ʻana i nā lāʻau antimalarial hou e kūʻē i nā mea i hoʻopaʻa ʻia i kēia manawa a me ka ʻimi ʻana ʻO ka pae gametophytic o ka hoʻouna ʻana hiki ke hana i ka hoʻonui asexual i loko o nā erythrocytes, ʻoi aku hoʻi i nā ʻano parasite kū'ē.6 Several enzymes, ion nā awāwa, nā mea lawe, nā molekele pili ʻO ke koko ʻulaʻula (RBC) hoʻouka ʻia, a me nā moleke kuleana no ke koʻikoʻi o ka parasite oxidative stress, lipid metabolism, a me ka hoʻohaʻahaʻa hemoglobin he kī nui i ka hoʻomohala ʻana i nā lāʻau antimalarial hou e kūʻē i ka hoʻololi wikiwiki ʻana i ka malaria Ke hoʻohiki nei i nā pahuhopu hou no protozoa.7
Hoʻoholo ʻia ka hiki o nā lāʻau antimalarial hou e kekahi mau koi: kahi ʻano hana hou, ʻaʻohe kūʻē kūʻē i nā lāʻau antimalarial o kēia manawa, hoʻokahi-dose lapaʻau, efficacy e kūʻē i ka pae koko asexual a me nā gametocytes kuleana no ka hoʻouna ʻana. Pono nā lāʻau lapaʻau antimalarial i ka pale ʻana i ka maʻi (chemoprotectants) a me ka hoʻomaʻemaʻe ʻana i ke ake o ka P. vivax hypnotics (anti-relapse agents).8
ʻO ka loaʻa ʻana o ka lāʻau lapaʻau kuʻuna ma muli o kekahi mau ala e ʻike ai i kahi lāʻau antimalarial hou e hakakā ai i ka maʻi malaria. no na mea e ae.8,9
Ma waho aʻe o nā ʻano ʻike lāʻau kuʻuna i hoʻohana ʻia no ka ʻike ʻana i nā lāʻau antimalarial hou, ua hōʻike ʻia ka ʻike o ka Plasmodium cell biology a me ka genome he mea hana ikaika no ka wehe ʻana i nā mīkini kūʻē lāʻau, a hiki ke hoʻolālā i nā lāʻau me ka hana antimalarial kiʻekiʻe a me ka antimalarial.ʻO ka mana nui no nā lāʻau lapaʻau hou. E hakakā ana i ka maʻi malaria i hoʻokahi manawa a no nā mea a pau.10 ʻO ka nānā ʻana i ke ʻano o Plasmodium falciparum i ʻike ʻia he 2680 genes mea nui no ka ulu ʻana o ke koko asexual, a laila e ʻike ai i nā kaʻina hana kelepona nui e koʻikoʻi no ka hoʻomohala ʻana i nā lāʻau lapaʻau hou.10,11 New Pono nā lāʻau lapaʻau: (i) hoʻoponopono i ka kūʻē ʻana i ka lāʻau, (ii) hana wikiwiki, (iii) palekana, ʻoi aku ka nui o nā keiki a me nā wahine hāpai, a (iv) hoʻōla i ka maʻi malaria i hoʻokahi dosis. ʻO kēia mau hiʻohiʻona a pau. ʻO ke kumu o kēia loiloi e hāʻawi i kahi manaʻo o nā pahuhopu hou no ka mālama ʻana i nā maʻi malaria, ke aʻo ʻia nei e kekahi mau hui, i hiki i ka poʻe heluhelu ke hoʻomaopopo i ka hana mua.
I kēia manawa, ʻo ka hapa nui o nā lāʻau antimalarial e kuhikuhi ana i ka pae asexual o ka maʻi maʻi malaria e hoʻoulu ai i ka maʻi hōʻailona. nā huahana kūlohelohe, semi-synthetic a me synthetic pūhui i hoʻomohala ʻia mai ka makahiki 1940.13 Hāʻule nā lāʻau antimalarial e kū nei i ʻekolu mau ʻāpana ākea: nā quinoline derivatives, antifolates a me artemisinin derivative. No laila, no ka hoʻohana ʻana i ka maʻi maʻi malaria, hoʻohana pinepine ʻia nā hui pū ʻana o nā lāʻau lapaʻau i ka manawa like. e mālama i ka maʻi i ke kenekulia 17. Mai ka waena o 1800s a i ka 1940s, quiʻeiwa ka lāʻau lapaʻau maʻamau no ka maʻi maʻi.14 Ma waho aʻe o ka ʻawaʻawa, ʻo ka puka ʻana mai o nā ʻano lāʻau kūʻē o P. falciparum ua kaupalena ka hoʻohana ʻana i ka quinine. ʻO ka lāʻau lua e hoʻopōkole i ka manawa lapaʻau a hōʻemi i nā hopena ʻaoʻao.15,16
Kiʻi 1 ʻO ka pōʻai ola o Plasmodium i loko o ke kanaka. Nā pae a me nā ʻano o nā parasite e hana ai nā ʻano lāʻau antimalarial.
Ma 1925, ua ʻike nā mea noiʻi Kelemania i ka lāʻau antimalarial synthetic mua, pamaquin, ma ka hoʻololi ʻana i ka methylene blue. He palena palena ʻole a me ka ʻawaʻawa o Pamaquin a ʻaʻole hiki ke hoʻohana ʻia e mālama i ka maʻi maʻi. derivative o ka methylene blue i hoʻohana ʻia no ka mālama ʻana i ka maʻi malaria i ke Kaua Honua II.17
Ua hoʻomohala ʻia ʻo Chloroquine i ka wā o ke Kaua Honua II no ka mālama ʻana i ka maʻi maʻi. 18 Hoʻohana ʻia ka Primaquine i ka lāʻau lapaʻau no ka mālama ʻana i ka Plasmodium vivax ma muli o ka hypnosis. -P.Haina o na la.19
Hoʻohui ʻia nā derivatives quinoline hou, ka hopena i nā lāʻau lapaʻau hou e like me ka piperaquine a me ka amodiaquine. Ma hope o ka puka ʻana o ke kū'ē chloroquine, amodiaquine, kahi analog phenyl-substituted o chloroquine, hōʻike i ka maikaʻi maikaʻi loa e kūʻē i ka chloroquine-resistant strains o Plasmodium falciparonachrum. ʻO ka lāʻau lapaʻau antimalarial base i kūkulu ʻia ma Kina i ka makahiki 1970. He mea maikaʻi ia e kūʻē i nā lāʻau kūʻē i ka lāʻau o P. falciparum, P. vivax, P. malaria a me P. ovale. Loaʻa ʻia ʻo Pyronadrine ma ke ʻano he ACT me ka artesunate, ka mea i hōʻike i ka maikaʻi maikaʻi loa i nā mea āpau. malaria parasites.21 Ua hoʻomohala ʻia ʻo Mefloquine i ka waena o 1980s a ua ʻōlelo ʻia i kēia manawa no ka chemoprevention o ka maʻi malaria i hoʻokumu ʻia e nā ʻano āpau, e komo pū ana me nā maʻi chloroquine-resistant. hana nui ma ke koko o ka parasite, aka, ke hana nei kekahi mau laau antimalarial ma ke ake o ke ake.ex me ka heme i loko o nā vacuoles meaʻai a ka parasite. No laila, ua ālai ʻia ka heme polymerization. ʻO ka hopena, ʻo ka heme i hoʻokuʻu ʻia i ka wā o ka haki ʻana o ka hemoglobin e hōʻiliʻili i nā pae ʻawaʻawa, e pepehi ana i ka parasite me nā ʻōpala ʻawaʻawa.
ʻO nā antifolates nā lāʻau antimalarial e kāohi ana i ka synthesis o ka folic acid, he mea nui ia no ka synthesis o nā nucleotides a me nā amino acids.Antifolates block nuclear division of Plasmodium species i ka wā schizont phase in erythrocytes a me hepatocytes.Sulfadoxine he hana like me ka para-aminobenzoic acid (PABA), he ʻāpana o ka waikawa folic. Kāohi lākou i ka dihydrofolate synthesis ma ke kāohi ʻana i ka dihydrofolate synthase, kahi enzyme kī i ka biosynthesis nucleic acid. iwakāluakūmāhā
ʻO Pyrimethamine a me proguanil nā lāʻau antimalarial schizont e hana ana ma ke ʻano asexual o nā ʻano Plasmodium. Ke kāohi nei kēia mau lāʻau i ka enzyme dihydrofolate reductase (DHFR), ka mea e pale ai i ka hoʻemi ʻana o ka dihydrofolate i tetrahydrofolate, he mea nui ia no ka biosynthesis o nā waikawa amino a me nā waikawa nucleic. ʻO ka Proguanil kahi prodrug metabolized i ka cyclic guanidine.ʻO Proguanil ka lāʻau antifolate mua i hoʻohanaʻia i ka mālamaʻana i ka maʻi maʻi. Hoʻohana nui ʻia ka Pyrimethamine me nā lāʻau lapaʻau wikiwiki ʻē aʻe.
ʻO Atovaquone ka lāʻau antimalarial mua i'āponoʻia e huli ana i ka mitochondria o ka Plasmodium parasite.Atovaquone ke kāohi i ka lawe electron ma ka hanaʻana ma keʻano he analog ubiquinone e ālai i ka māhele cytochrome b o ka cytochrome bc1 complex. Ke hui pū me ka proguanil, palekana a maikaʻi ka atovaquone no nā wāhine hāpai. a me na keiki.Atovaquone mea pono e ku e i ka sexual stage of the parasite of the host and mosquito.No laila, ke kaohi ia i ka lawe ana o ka malaria mai na makika i kanaka.A paa hui me ka proguanil i kukuluia ma lalo o ke kalepa inoa Malarone.24,26
Ua unuhi ʻia ʻo Artemisinin mai Artemisia annua i ka makahiki 1972. ʻO Artemisinin a me kāna mau derivatives me ka artemether, dihydroartemisinin, artemether a me artesunate he hana ākea ākea. ʻO Artemisinin ke kāohi i nā pae parasite āpau i loko o nā ʻulaʻula ʻulaʻula, ʻoi loa i ka wā mua o ko lākou ulu ʻana. o ka gametocytes mai ke kanaka a hiki i na makika.27 He mea pono ka Artemisinin a me kona mau mea i loaa mai i ka chloroquine a me ka mefloquine-resistant strains. ʻO kēia mau lāʻau lapaʻau he mau hapalua ola pōkole a me ka bioavailability maikaʻi ʻole, e alakaʻi ana i ke kūʻē ʻana i ka lāʻau, e hoʻolilo iā lākou i mea ʻole e like me ka monotherapy.
ʻO ka hopena antimalarial o artemisinin ma muli paha o ka hoʻokumu ʻana o nā radical manuahi e hopena mai ka ʻoki ʻana o nā alahaka artemisinin endoperoxide i loko o nā vesicle meaʻai parasite, no laila ke kāohi nei i ka parasite calcium ATPase a me ka proteasome.29,30 Artemether i hoʻohana ʻia e like me ka monotherapy.Fast oral absorption.Bioavailability pāpālua ke lawelawe ʻia ma ke alo o ka meaʻai. I ka manawa i loko o ka ʻōnaehana systemic, ua hydrolyzed ka artemether i dihydroartemisinin i loko o ka ʻōpū a me ke ake.
ʻO Artesunate kahi mea hoʻoheheʻe semi-synthetic ma muli o kona hopena antimalarial wikiwiki, nele i ka nui o ka pale ʻana i ka lāʻau a me ka nui o ka wai.
ʻO nā Tetracyclines a me nā macrolides nā lāʻau antimalarial lohi i hoʻohana ʻia e like me ka adjunctive therapy i ka quinine in falciparum malaria.Hoʻohana pū ʻia ʻo Doxycycline no chemoprophylaxis ma nā wahi me ke kūpaʻa kiʻekiʻe. Ua hoʻohana ʻia ka hoʻolālā i ka wā ma mua ma o ka hoʻohana ʻana i nā hui paʻa. ʻO WHO ka manaʻo o ka artemisinin-based combination therapy (ACT) ma ke ʻano he lāʻau lapaʻau mua no ka maʻi malaria falciparum ʻole.
Loaʻa i ka ACT kahi mea artemisinin ikaika e hoʻomaʻemaʻe koke i nā parasites, a me kahi lāʻau lōʻihi e hoʻopau ai i ke koena parasites a hōʻemi i ke kūʻē artemisinin. ʻO nā ACT i ʻōlelo ʻia e WHO he artesunate/amodiaquine, artemether/benzfluorenol, artesunate/mefloquine, artesunate/pyrrolidine, dihydroartemisinin/ piperaquine, Artesunate / sulfadoxine / pyrimethamine, artemether / piperaquine a me artemisinin / piperaquine / primaquine. ʻO Chloroquine plus primaquine ka lāʻau lapaʻau mua no ka hoʻopau ʻana i ka Plasmodium vivax. ʻO Quinine + tetracycline / doxycycline he kiʻekiʻe koʻikoʻi o ka lāʻau lapaʻau. nā hopena a ua contraindicated i nā keiki a me nā wahine hāpai34.
ʻO ka Mefloquine, atovaquone/proguanil, a i ʻole doxycycline ka mea i paipai ʻia i ka chemoprevention regimens no ka poʻe huakaʻi mai ka non-endemic a hiki i nā wahi endemic. .36 ʻAʻole kūpono ʻo Halofantrine no ka hoʻohana therapeutic ma muli o kona cardiotoxicity. ʻO Dapsone, mepalyline, amodiaquine, a me sulfonamides i hoʻihoʻi ʻia mai ka hoʻohana lāʻau ma muli o ko lākou hopena ʻaoʻao. 1.
Loaʻa nā lāʻau antimalarial i kēia manawa e pili ana i nā ʻokoʻa o nā ala metabolic nui ma waena o nā ʻano Plasmodium a me kā lākou mau pūʻali. nā kahua no ka hoʻolālā lāʻau.38,39 ʻOiai ua hoʻohana ʻia ka hapa nui o nā lāʻau antimalarial no kekahi mau makahiki, ua kaupalena ʻia ko lākou hoʻohana ʻana ma muli o ke kūʻē ʻana i ka lāʻau. ʻO ka ʻokoʻa, ʻike ʻia ka hapa nui o nā lāʻau antimalarial i loko o nā holoholona in vivo a i ʻole in vitro model studies.
Pono ka mālama ʻana i ka maʻi malaria i nā hoʻolālā i hoʻonohonoho ʻia e like me ka hoʻokele vector, nā lāʻau antimalarial maikaʻi a palekana, a me nā lāʻau lapaʻau maikaʻi. , ka ʻike ʻana i nā lāʻau antimalarial hou ma o ka hoʻomaopopo ʻana i nā ala metabolic kumu o ka malaria.He mea koʻikoʻi nā lāʻau malaria.parasites. No ka hoʻokō ʻana i kēia pahuhopu, pono ka noiʻi lāʻau lapaʻau e hoʻopaʻa i nā pahuhopu hou i hoʻopaʻa ʻia e hoʻokaʻawale i nā pūhui kepau hou.39,41
Nui nā kumu no ka pono e ʻike i nā pahuhopu metabolic hou. ʻO ka mua, koe wale nā lāʻau atovaquone a me artemisinin i loaʻa, ʻo ka hapa nui o nā lāʻau lapaʻau antimalarial ʻaʻole kemika, hiki ke alakaʻi i ka cross-resistance. ʻO ka lua, ma muli o ka nui o nā ʻano like ʻole. ʻO nā pahuhopu chemotherapeutic putative, ʻaʻole i hoʻopaʻa ʻia. nā pilikia e puka mai ana mai ka puka ʻana mai o ke kūʻē ʻana i nā lāʻau lapaʻau e kū nei.40,41 No laila, ua hoʻohana ʻia ke aʻo ʻana o ka novel target protein-specific inhibitors o Plasmodium no ka ʻike ʻana i ka lāʻau. Ua puka mai ka hana. ʻO kēia mau lāʻau antimalarial hiki ke kuhikuhi i ka biosynthesis metabolite kī, ka lawe ʻana i ka membrane a me nā ʻōnaehana hōʻailona, a me nā kaʻina hoʻohaʻahaʻa hemoglobin.40,42
ʻO ka Plasmodium protease he catalytic a me ka enzyme regulatory e hana nui ana i ke ola ʻana o nā parasites protozoan a me nā maʻi i hoʻokumu ʻia e lākou. ka pale ʻana, ka hoʻoulu ʻana o ka mumū, ka hoʻouka ʻana o ka erythrocyte, ka haki ʻana o ka hemoglobin a me nā protein ʻē aʻe, autophagy, a me ka hoʻomohala ʻana o nā parasite.44
ʻO nā protease malaria (glutamic aspartic acid, cysteine, metala, serine a me threonine) ke hoʻohiki nei i nā pahuhopu therapeutic no ka mea ʻo ka hoʻohaunaele ʻana o ka maʻi malaria protease e pale ai i ka hōʻemi ʻana o ka hemoglobin a me ka pae erythrocyte o ka parasite.hooulu.45
ʻO ka haʻihaʻi ʻana o nā erythrocytes a me ka hoʻouka ʻana o nā merozoites e pono ai i nā proteases maʻi malaria. ʻO kahi peptide synthetic (GlcA-Val-Leu-Gly-Lys-NHC2H5) ke kāohi i ka Plasmodium falciparum schizont cysteine protease Pf 68. Ke kāohi nei ia i ka hoʻomohala ʻana i ka evaryth. ke manaʻo nei he hana nui ka proteases i ka hoʻouka ʻana o ka parasite i nā ʻulaʻula ʻulaʻula.
I loko o ka Plasmodium falciparum meaʻai vacuoles, ua hoʻokaʻawale ʻia kekahi mau aspartic proteases (plasma proteases I, II, III, IV) a me cysteine proteases (falcipain-1, falcipain-2/, falcipain-3) i hoʻokaʻawale ʻia, Hoʻohana ʻia e hoʻohaʻahaʻa i ka hemoglobin, e like me ka hōʻike ʻana. ma ke Kii 2.
Incubation o moʻomeheu P. falciparum parasites me ka protease inhibitors leupeptin a me E-64 hopena i ka hōʻiliʻili o undegraded globin.Leupeptin inhibits cysteine a me kekahi serine proteases, akā, E-64 kiko'ī inhibits cysteine proteases.47,48 Ma hope o incubation. ʻO nā parasite me ka aspartate protease inhibitor pepstatin, ʻaʻole i hōʻiliʻili ʻia ka globin. Ua hōʻike ʻia nā haʻawina he nui ʻaʻole kaohi ʻana o nā inhibitors cystatin ʻaʻole wale i ka hoʻohaʻahaʻa ʻana o ka globin, akā ke keʻakeʻa nei hoʻi i nā ʻanuʻu mua o ka hemo ʻana o ka hemoglobin, e like me ka hemoglobin denaturation, hoʻokuʻu heme mai globin, a me ka hana heme. .49 Hōʻike kēia mau hopena e koi ʻia nā cysteine proteases no ka pae mua. Nā ʻanuʻu i ka hoʻohaʻahaʻa ʻana o ka hemoglobin e Plasmodium falciparum. ʻO E-64 a me ka pepstatin synergistically block P. falciparum development. Akā naʻe, ʻo E-64 wale nō i kāohi i ka hydrolysis globin. 48,49 ʻO kekahi mau mea hoʻopiʻi cysteine protease, e like me ka fluoromethyl ketone a me ka vinyl sulfone, ke kāohi i ka ulu ʻana o P. falciparum a me ka hemoglobin degra.I loko o ka holoholona holoholona o ka malaria, fluoromethyl ketone inhibits P. vinckei protease hana a ho'ōla 80% o murine malaria maʻi.No laila, protease inhibitors ua olelo hoopomaikai i moho no antimalarial laau. Ma hope o ka hana i ikeia biologically active falcipain inhibitors, me ka chalcone a me ka phenothiazine, e ālai ana i ka metabolism a me ka hoʻomohala ʻana.50
Hoʻopili ʻia ka Serine proteases i ka schizont rupture a me ka erythrocyte reinvasion i ka wā o ka Plasmodium falciparum life cycle. Hiki ke pale ʻia e kekahi mau mea hoʻokaʻawale serine protease a ʻo ia ke koho maikaʻi loa mai ka loaʻa ʻole o ka homolog enzyme kanaka.hoʻohaʻahaʻa i ka malaria serine protease.51 ʻO ka waikawa Maslinic kahi triterpenoid pentacyclic maoli e kāohi ai i ka oʻo ʻana o nā parasite mai ka pae apo a hiki i ka pae schizont, a laila hoʻopau i ka hoʻokuʻu ʻana o nā merozoites a me kā lākou hoʻouka ʻana. ʻO -2 a me falcipain-3.52 statins a me ka pale ʻana i nā protease plasma e nā allophenostatin-based inhibitors e pale i ka hemoglobin degradation a pepehi i nā parasites. .
ʻO Phosphoinositide lipid kinases (PIKs) he mau enzymes e phosphorylate lipids e hoʻoponopono i ka hoʻonuiʻana, ke ola, ke kālepaʻana, a me ka hōʻailona intracellular. ʻO nā papa PIK i aʻo nuiʻia ma 53 parasite he phosphoinositide 3-kinase (PI3K) a me ka phosphatidylinositol 4-kinase (PI4K). ʻO ka pale ʻana i kēia mau enzyme i ʻike ʻia ma ke ʻano he pahuhopu kūpono no ka hoʻomohala ʻana i nā lāʻau antimalarial me nā ʻano hana i makemake ʻia no ka pale ʻana, mālama ʻana a me ka hoʻopau ʻana i ka maʻi maʻi. (4)K a keʻakeʻa i ka hoʻomohala intracellular o nā ʻano Plasmodium he nui i kēlā me kēia manawa o ka maʻi maʻi. i loko o ka Phase II hoʻokolohua hoʻokolohua.55,56 MMV048 mea he hui me ka maikai in vivo prophylactic hana ku e P. cynomolgi a me ka hiki as he lāʻau lapaʻau hoʻouna. Ke hele nei ʻo MMV048 i nā hoʻokolohua lapaʻau Phase IIa ma ʻAitiopa.11
No ka ulu wikiwiki ʻana i nā ʻāpana koko ʻulaʻula i hoʻopili ʻia, pono nā ʻano Plasmodium i ka nui o nā substrates e hoʻomaʻamaʻa i kā lākou metabolism ikaika. No laila, hoʻomākaukau nā parasites i nā erythrocytes host ma o ka hoʻoulu ʻana i nā transporters kūikawā e ʻokoʻa loa mai nā mea lawe pūnaewele host i ka lawe ʻana a me ka wehe ʻana i nā metabolites. ʻO nā protein a me nā alahele ka mea e hiki ke hoʻopaʻa ʻia ma muli o kā lākou kuleana nui i ka lawe ʻana i nā metabolites, electrolytes a me nā meaʻai. i loko o ka parasite intracellular.58
ʻO ka PSAC ka pahuhopu nui loa no ka mea loaʻa ia i nā ʻano meaʻai like ʻole (hypoxanthine, cysteine, glutamine, glutamate, isoleucine, methionine, proline, tyrosine, pantothenic acid a me choline) e loaʻa ai nā kuleana koʻikoʻi i ka intracellular parasites. i ike ia host channel genes.58,59 Phloridizin, dantrolene, furosemide, a me niflunomide mea potent anion transporter blockers.Drugs e like me glyburide, meglitinide, a me tolbutamide keakea i ka influx o choline i parasitic-infected koko 'ulaʻula cell.60,61
ʻO ke ʻano koko o Plasmodium falciparum e hilinaʻi kokoke loa i ka glycolysis no ka hana ʻana i ka ikehu, me ka mālama ʻole o ka ikehu;ke hilinaʻi nei i ka lawe mau ʻana o ka glucose. Hoʻololi ka parasite i ka pyruvate i lactate e hana ai i ka ATP, kahi i koi ʻia no ka hana hou ʻana i loko o nā ʻulaʻula ʻulaʻula. ka erythrocyte membrane a me ka parasite-induced 'new permeation ala'.63 Lawe 'ia ka glucose i loko o nā parasites e ka Plasmodium falciparum hexose transporter (PFHT). ʻO D-glucose a me D-fructose. No laila, ʻokoʻa ka pilina o GLUT1 a me PFHT me nā substrates e hōʻike ana i ka inhibition koho o PFHT kahi pahuhopu hou no ka hoʻomohala ʻana i nā lāʻau antimalarial novel.64 He kaulahao lōʻihi O-3-hexose derivative (compound. 3361) kaohi i ka glucose a me ka fructose uptake e ka PFHT, aka, aole ia e keakea i ka lawe hexose e ka nui o ka mammalian glucose a me ka fructose transporters (GLUT1 a me 5).Compound 3361 no hoi i keakea i ka glucose uptake e P. vivax o PFHT. Ma na a'o mua, hui 'ia 3361 pepehi P. falciparum ma ka mo'omeheu a hoemi P. berghei reproduction ma ka iole models.65
ʻO ka pūʻulu koko Plasmodium e hilinaʻi nui ana i ka glycolysis anaerobic no ka ulu ʻana a me ka ulu ʻana.60 ʻO nā keʻena koko ʻulaʻula i loaʻa i ka parasite e hoʻopaʻa i ka glucose 100 mau manawa ʻoi aku ka wikiwiki ma mua o ke koko ʻulaʻula ʻole. He mea nui ka hoʻokuʻu ʻana aku i ka lactate a me ka glucose uptake no ka mālama ʻana i nā koi ikehu, ka pH intracellular, a me ka paʻa osmotic parasite.Lactate:H + symporter system inhibition he mea hoʻohiki hou no ka hoʻomohala ʻana i nā lāʻau lapaʻau hou. ʻO kekahi mau pūhui, e like me MMV007839 a me MMV000972, pepehi i ke koko asexual P. falciparum parasites ma ke kāohi ʻana i ka lactate: H + transporter.67
E like me nā ʻano cell ʻē aʻe, mālama nā ʻulaʻula ʻulaʻula i nā pae haʻahaʻa o Na +. loaʻa iā lākou iho i loko o ka media Na + kiʻekiʻe a pono e kipaku aku i nā ion Na + mai ko lākou membrane plasma e mālama i nā pae cytoplasmic haʻahaʻa Na + i mea e ola ai ʻoiai ko lākou hele ʻana i nā pūnaewele intracellular. transporter (PfATP4), e hana ana ma ke ano o ka Na + -efflux pump mechanism o ka parasite, e like me ia i hoikeia ma ke Kii 3.68, e kaohi ana i keia transporter. malaria parasite.He nui nā pūhui, me ka sipagamin i ka māhele 2, (+)-SJ733 i ka māhele 1, a me ka KAE609 i ka māhele 2, loaʻa kahi hana o ka hana e kuhikuhi ana i ka PfATP4.67,69
Kiʻi 3. Manaʻo manaʻo o ka parasite-induced PfATP4 a me ka V-type H+-ATPase i ka make erythrocyte maʻi ma hope o ka hoʻopaʻa ʻana o cipargamin.
Hoʻoponopono nā ʻano Plasmodium i ko lākou mau pae Na + ma o ka hoʻohana ʻana i ka transporter ATPase P-type. Lawe pū ʻo ia i ka H + ma o ke ala like. Hoʻokuʻu aku i ka H +. ʻO ka hoʻomohala ʻana i kahi lāʻau hou he pahuhopu hoʻohiki. Hoʻopaʻa ʻo MMV253 i ka V-type H + ATPase ma ke ʻano o kāna hana ma ke koho ʻana i ka mutation a me ka sequencing genome holoʻokoʻa.70,71
ʻO ka Aquaporin-3 (AQP3) he protein aquaglycerol channel e hoʻoikaika i ka neʻe ʻana o ka wai a me ka glycerol i loko o nā pūnana mammalian. Hoʻokomo ʻia ʻo AQP3 i loko o nā hepatocytes kanaka i ka pane ʻana i ka maʻi parasite a he kuleana koʻikoʻi i ka replication parasite. Hāʻawi ʻo AQP3 i ka glycerol i P berghei a hoʻoikaika i ka hana hou ʻana o ka parasite ma ke ʻano erythrocyte asexual.72 ʻO ka hoʻemi ʻana o ka genetic o AQP3 i hoʻopau nui i ka haʻahaʻa parasite ma ka pae ate o P. berghei. falciparum parasitemia i loko o nā erythrocytes, e hōʻike ana e pāʻani koʻikoʻi nā protein host i nā kūlana ola like ʻole o ka parasite. ka hoʻomaopopo ʻana i nā kaʻina hana o ka ate i hoʻopilikia ʻia e ka maʻi Plasmodium a hōʻike i ka hiki o kēia mau processes like me nā lāʻau antimalarial e hiki mai ana.71,72
He kuleana koʻikoʻi ka Phospholipids i ka pōʻai ola intra-erythrocyte o Plasmodium falciparum, ma ke ʻano he ʻāpana o nā membranes a me nā molekele hoʻoponopono e hoʻoponopono i nā hana o nā enzymes like ʻole. Piʻi ka pae phospholipid, ʻo ia ka phosphatidylcholine ka lipid nui i loko o kā lākou mau membrane cell. ka hopena o ka parasite make.74 Albitiazolium, he lāʻau i komo i ka Phase II ho'āʻo, hana nui ma ke keakea ana i ka lawe ana o choline i loko o ka parasite.Albitiazolium hoahu a hiki i ka 1000-fold ma Plasmodium a keakea parasite ulu me ka relapse. kūlana.Notably, hoʻokahi injection hoola kiʻekiʻe parasitemia pae.75,76
ʻO ka Phosphocholine cytidyltransferase ka pae palena palena i ka biosynthesis de novo o phosphatidylcholine.77 ʻO ka diquaternary ammonium compound G25 a me ka pūhui dicationic T3 ke kāohi nei i ka phosphatidylcholine synthesis i nā parasites. ʻO G25 he 1000-fold ka liʻiliʻi o nā meaʻawaʻawa i nā lāʻau lapaʻau nui. pūhui i ka ʻike a me ka hoʻomohala ʻana i ka lāʻau antimalarial.78,79
ʻO kahi hana koʻikoʻi i ka hoʻolaha ʻana o nā ʻano Plasmodium i loko o nā pūʻali kanaka ʻo ia ka māhele ākea a wikiwiki o ka DNA parasite, e hilinaʻi ana i ka loaʻa ʻana o nā metabolites pono e like me pyrimidines. ʻO ka glycoproteins.Nucleotide synthesis e hahai ana i ʻelua mau ala nui: ke ala hoʻopakele a me ke ala de novo.Dihydroorotate dehydrogenase (DHODH) he enzyme koʻikoʻi e hoʻopiʻi i ka oxidation o dihydroorotate i orotate, ka pae palena palena i ka de novo pyrimidine synthesis. No laila, DHODH ʻO ia ka pahuhopu e hiki ke hoʻohiki ʻia no ka hoʻomohala ʻana i ka lāʻau antimalarial.80 Loaʻa i nā pūnaewele kanaka nā pyrimidines ma o ka hoʻopakele ʻana i nā pyrimidines i hana mua ʻia a i ʻole ma ka synthesis de novo. Eia nō naʻe, ʻo ka hoʻopaʻa ʻana i ka biosynthesis de novo pyrimidine i loko o nā parasites ka hopena i ka make o kēia mau cell no ka meaʻAʻole i loaʻa i ka malaria parasite kahi ala hoʻopakele pyrimidine, kahi e hoʻonāwaliwali ai ka parasite i ke kāohi ʻana e DHODH.81 DSM190 a me DSM265 nā mea paʻa koho o ka enzyme DHODH parasite, aia i kēia manawa i ka Phase 2 clinical trials. ʻO P218 he mea hoʻopaneʻe DHODH e kū pono ana i nā pyrimethamine- a pau. i kēia manawa ma ka Phase 1. KAF156 (Ganaplacide) i kēia manawa i kahi hoʻokolohua lapaʻau Phase 2b me phenylfluorenol.82
Pono nā Isoprenoids no ka hoʻololi ʻana o ka lipid post-translational o nā protein a me ka replication asexual o Plasmodium falciparum. Hoʻohui ʻia nā Isoprenoids mai ka ʻelima-carbon precursor isopentyl diphosphate (IPP) a i ʻole kona isomer, dimethylallyl diphosphate (DMAPP), e kekahi o nā ala kūʻokoʻa ʻelua.Mevalonate alahele a me 2C-methyl-D-erythritol 4-phosphate (MEP) alahele. I ka nui o nā microorganisms, ʻo kēia mau ala ʻelua e pili pū ana. ʻImi ʻia ke ala MEP ma ke ʻano he mau pahuhopu therapeutic hou. .83,84 PfDXR inhibitors inhibit Plasmodium falciparum.Plasmodium falciparum ulu a nontoxic i ke kanaka.ka hoʻomohala ʻana i ka lāʻau antimalarial.83 Fosmidomycin, MMV019313 a me MMV008138 kaohi i ka DOXP reductoisomerase, kahi enzyme kī o ke ala DOXP i ʻike ʻole ʻia i loko o ke kanaka.
He kuleana koʻikoʻi nā protein prenylated i nā ʻano hana kelepona e like me ke kālepa vesicle, ka hoʻololi ʻana i ka hōʻailona, ka hoʻoponopono ʻana i ka replication DNA, a me ka māhele cell. ka hoʻoili ʻana o ka pūʻulu farnesyl, he 15-carbon isoprenoid lipid unit, mai farnesyl pyrophosphate a i ka C-terminus o nā protein i loaʻa i ka motif CaaX. ʻO Farnesyltransferase kahi pahuhopu hou no ka hoʻomohala ʻana i nā lāʻau antimalarial no ka mea ua hoʻopau kāna inhibition i ka parasite.86
Ma mua, ua hōʻike ka evolution o ke kū'ē i nā parasites e ka farnesyltransferase inhibitor BMS-388,891 tetrahydroquinoline i ka hoʻololi ʻana i ka protein o ka peptide substrate-binding domain. .Ma kekahi noiʻi ʻē aʻe, ua ʻike ʻia nā hoʻololi ʻana i loko o ka farnesyltransferase beta subunit o kahi MMV019066-resistant strain o P. falciparum.Ua hōʻike nā haʻawina hoʻohālike i ka hoʻololi ʻana o ka mutation i ke kahua pānaʻi koʻikoʻi o ka mole liʻiliʻi me ka farnesylation active site, ka hopena i ka lāʻau kūʻē. .87
ʻO kekahi o nā pahuhopu hoʻohiki no ka hoʻomohala ʻana i nā lāʻau hou, ʻo ia ka pale ʻana i ka ribosome P. falciparum, a me nā ʻāpana ʻē aʻe o ka mīkini unuhi kuleana no ka synthesis protein. ʻO nā ʻano Plasmodium he ʻekolu genomes: nucleus, mitochondria, a me nā acroplas (mai ke koena chloroplasts). Pono nā genomes a pau i nā mīkini unuhi e hana. Loaʻa i nā mea hoʻopiʻi synthesis protein ka lanakila nui ma ke ʻano he lāʻau antibiotics. Noho ʻo P. falciparum ribosome i kahi evolutionary waena waena ma waena o nā prokaryotes a me nā eukaryotes, e hoʻokaʻawale iā ia mai ka ribosome kanaka a no laila e hāʻawi ai i kahi pahuhopu hou koʻikoʻi. o nā ribosomes ma ka ʻōpalaenger RNA a he mea nui ia no ka synthesis protein i nā eukaryotes. Ua hoʻokaʻawale ʻia ʻo PfEF2 ma ke ʻano he pahuhopu hou no ka hoʻomohala ʻana i ka lāʻau antimalarial.87,89
Ka hoʻopaʻa ʻana o ka protein synthesis E lawe i ka loaʻa ʻana o ka sodarin, kahi huahana kūlohelohe e poloka i ka synthesis protein fungal ma ke kāohi ʻana i ka hū eukaryotic elongation factor 2. Pēlā nō, M5717 (DDD107498 ma mua), he mea hoʻopale koho o ka 80S ribosome-interacting PfEF2 i kēia manawa 1 mau haʻawina, e hōʻoia ana i ka hiki o PfEF2 ma ke ʻano he pahuhopu kūpono no nā lāʻau antimalarial.88,90
ʻO nā hiʻohiʻona nui o ka malaria koʻikoʻi ka hoʻopaʻa ʻana o nā erythrocytes i hoʻopili ʻia e ka parasite, ka mumū, a me ka blockage o microvasculature. Hoʻohana ʻo Plasmodium falciparum i ka heparan sulfate e pili ana i ka endothelium a me nā ʻāpana koko ʻē aʻe, e keakea ana i ke kahe o ke koko. -e hoʻihoʻi ka pilina o ka lāʻau i ke kahe koko i ālai ʻia a pili i ka ulu ʻana o ka parasite.91
Ua hōʻike ʻia kekahi mau noiʻi ʻo sevuparin, kahi polysaccharide anti-adhesion i hana ʻia mai ka heparin, he hopena antithrombin-eliminating. Hoʻopaʻa ʻo Sevuparin i ka komo ʻana o merozoite i loko o nā erythrocytes, ka hoʻopaʻa ʻana o nā erythrocytes i hoʻopili ʻia i nā erythrocytes i hoʻopaʻa ʻole ʻia, a hoʻopaʻa ʻia i nā cell endothelial vascular. i ka N-terminal extracellular heparan sulfate-binding structure o Plasmodium falciparum erythrocyte membrane protein 1, Duffy-binding-like domain 1α (DBL1α), a ua manaʻo ʻia he mea nui ia i ka hoʻokaʻawale ʻana i nā erythrocytes maʻi. nā hoʻokolohua lapaʻau ma nā pae like ʻole.
Ka manawa hoʻouna: Mar-24-2022