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Yi rijista tare da takamaiman bayanan ku da takamaiman magungunan sha'awa kuma za mu dace da bayanan da kuka bayar tare da labarai a cikin babban ma'ajin mu kuma da sauri yi muku imel ɗin kwafin PDF.
Tafere Mulaw Belete Sashen Nazarin Magungunan Magunguna, Makarantar Magunguna da Kimiyyar Lafiya, Jami'ar Gondar, Gondar, Habasha, Tafere Mulaw Belete Tel +251 918045943Email [email protected] Abstract: Cutar zazzabin cizon sauro babbar matsala ce ta duniya da ke haifar da mace-mace da cututtuka a kowace shekara Rate Zaɓuɓɓukan magani sun yi karanci kuma suna fuskantar ƙalubale sosai sakamakon bullowar nau'ikan ƙwayoyin cuta masu juriya, waɗanda ke haifar da babbar cikas ga shawo kan cutar zazzabin cizon sauro.Don hana yiwuwar gaggawar lafiyar jama'a, sabbin magungunan zazzabin cizon sauro tare da jiyya guda ɗaya, fa'idodin warkewa, da sabbin hanyoyin aiwatar da aiki. Ana buƙatar gaggawa.Ci gaban magungunan antimalarial na iya bin hanyoyi daban-daban, kama daga gyare-gyaren magungunan da ake amfani da su zuwa ƙirar magungunan litattafan da ke da sababbin manufofi. Ci gaban zamani a cikin ilimin halitta na parasite da samuwa na fasaha daban-daban na kwayoyin halitta suna ba da dama ga sababbin manufofi. don haɓaka sabbin hanyoyin kwantar da hankali.Targe da yawa masu albarkaets don maganin miyagun ƙwayoyi an bayyana a cikin 'yan shekarun nan.Saboda haka, wannan bita ya mayar da hankali ga sababbin ci gaban kimiyya da fasaha a cikin bincike da ci gaba da sababbin magungunan antimalarial.Mafi yawan ban sha'awa maganin rigakafi da aka yi nazari ya zuwa yanzu sun hada da proteases, protein kinases, plasmodium sugar. masu hana sufuri, masu hanawa aquaporin 3, masu hana safarar choline, dihydroorotate dehydrogenase inhibitors, pentadiene biosynthesis inhibitor, farnesyltransferase inhibitor da enzymes da ke shiga cikin metabolism na lipid da DNA replication.Wannan bita ya taƙaita sabbin maƙasudin ƙwayoyin cuta don ci gaban magungunan zazzabin cizon sauro da kalmomin su: masu hana magunguna.Key. , Sabbin hari, magungunan zazzabin cizon sauro, yanayin aiki, cutar zazzabin cizon sauro
Zazzabin cizon sauro cuta ce mai saurin kamuwa da cututtuka, musamman a yankin kudu da hamadar Sahara, da wasu sassan Asiya da Kudancin Amurka.Duk da kokarin da ake yi, a yau yana daya daga cikin abubuwan da ke haifar da cututtuka da mace-mace musamman mata masu juna biyu da kananan yara.A cewar hukumar lafiya ta duniya. Rahoton Hukumar (WHO) na 2018, an sami bullar cutar zazzabin cizon sauro miliyan 228 da kuma mutuwar mutane 405,000 a duniya. Kusan rabin al’ummar duniya na cikin hadarin kamuwa da cutar zazzabin cizon sauro, inda akasarin wadanda suka kamu da cutar (93%) da kuma mace-mace (94%) na faruwa a Afirka. Mata masu juna biyu miliyan 125 na fuskantar barazanar kamuwa da cutar zazzabin cizon sauro a kowace shekara, kuma yara 272,000 ‘yan kasa da shekaru 5 ne ke mutuwa sakamakon zazzabin cizon sauro. Plasmodium da ke haifar da zazzabin cizon sauro a jikin dan adam sun hada da P. vivax, P. knowlesi, P. ovale, P. malaria da P. falciparum.Daga cikin wadannan, Plasmodium falciparum shi ne mafi kisa da kuma yawan jinsunan Plasmodium.3
Idan babu ingantaccen maganin alurar riga kafi, yin amfani da magunguna na maganin zazzabin cizon sauro ya kasance hanya ɗaya tilo don sarrafawa da rigakafin cutar zazzabin cizon sauro.Bincike da yawa sun nuna cewa tasirin mafi yawan magungunan zazzabin cizon sauro yana raguwa ta hanyar gaggawa a cikin Plasmodium spp.4 Mai jurewar ƙwayoyi. An ba da rahoto tare da kusan dukkanin magungunan rigakafin zazzabin cizon sauro, yana ƙarfafa haɓakar sabbin magungunan zazzabin cizon sauro a kan ingantattun maƙasudai da kuma neman Tsarin gametophytic na watsawa yana iya yin aiki akan haɓakar jima'i a cikin erythrocytes, musamman a cikin nau'ikan ƙwayoyin cuta masu juriya.6 Yawancin enzymes, ion. tashoshi, masu jigilar kaya, masu mu'amala da kwayoyin cutar Red blood cell (RBC) mamayewa, da kwayoyin da ke haifar da danniya mai saurin kamuwa da cuta, metabolism na lipid, da lalata haemoglobin sune mabuɗin don haɓaka sabbin magungunan zazzabin cizon sauro kan cutar cizon sauro da sauri.
Ana yin la'akari da yuwuwar sabbin magungunan zazzabin cizon sauro ta hanyar buƙatu da yawa: sabon yanayin aiki, babu juriya ga magungunan zazzabin cizon sauro na yanzu, jiyya guda ɗaya, inganci akan duka matakin jinin asexual da kuma gametocytes da ke da alhakin watsawa. magungunan zazzabin cizon sauro yakamata suyi tasiri wajen hana kamuwa da cuta (chemoprotectants) da share hanta na P. vivax hypnotics (maganin sake dawowa).8
Binciken magungunan gargajiya ya biyo bayan hanyoyi da yawa don gano sabon maganin zazzabin cizon sauro don yaƙar zazzabin cizon sauro.Wadannan suna inganta tsarin magunguna na yau da kullun, da gyare-gyaren magungunan zazzabin cizon sauro, tantance samfuran halitta, keɓance magungunan juriya, yin amfani da hanyoyin haɗin gwiwar chemotherapy, da haɓaka magunguna. don sauran amfani.8,9
Baya ga hanyoyin gano magungunan gargajiya da ake amfani da su wajen gano sabbin magungunan zazzabin cizon sauro, an nuna ilimin kimiyyar halittar kwayar cutar ta Plasmodium da kwayoyin halittar jini a matsayin kayan aiki mai karfi na fallasa hanyoyin jure magunguna, kuma yana da damar kera magungunan da ke da yawan maganin zazzabin cizon sauro da na zazzabin cizon sauro.Babban yuwuwar samun sabbin magunguna.Yaki da yiwuwar katsewar cutar malaria sau ɗaya kuma gabaɗaya.10 Binciken kwayoyin halitta na Plasmodium falciparum ya gano kwayoyin halitta 2680 masu mahimmanci don haɓakar matakin jini na jima'i, ta haka ne ke gano mahimman hanyoyin salula waɗanda ke da mahimmanci don haɓaka sabbin magunguna.10,11 Sabon. kwayoyi yakamata: (i) magance juriya na miyagun ƙwayoyi, (ii) yin sauri, (iii) a kiyaye lafiya, musamman ga yara da mata masu juna biyu, da (iv) maganin zazzabin cizon sauro a kashi ɗaya.12 Kalubalen shine a sami maganin da zai magance matsalar. duk waɗannan halayen. Manufar wannan bita shine don ba da ra'ayi game da sababbin abubuwan da za a yi amfani da su don magance cututtuka na zazzabin cizon sauro, wanda kamfanoni da yawa ke nazarin su, don a iya sanar da masu karatu game da ayyukan da suka gabata.
A halin yanzu, yawancin magungunan zazzabin cizon sauro suna kaiwa matakin kamuwa da cutar zazzabin cizon sauro wanda ke haifar da alamun bayyanar cututtuka. Matsayin pre-erythrocytic (hanta) ya kasance mara kyau saboda ba a samar da alamun asibiti ba. kayayyakin halitta, Semi-Synthetic da synthetic mahadi da aka samu tun daga shekarun 1940.13 Magungunan rigakafin zazzabin cizon sauro na wanzuwa sun kasu kashi uku: abubuwan da ake samu na quinoline, antifolates da artemisinin. Don haka, don yin tasiri a kan kamuwa da cutar zazzabin cizon sauro, ana amfani da haɗin magunguna a lokaci ɗaya. don magance cututtuka a karni na 17. Daga tsakiyar 1800s zuwa 1940s, qui.tara shine daidaitaccen maganin zazzabin cizon sauro.14 Baya ga guba, bullar nau'ikan nau'ikan P. falciparum masu jure wa magunguna sun iyakance amfani da quinine. Duk da haka, har yanzu ana amfani da quinine don maganin zazzabin cizon sauro, galibi a hade tare da magani na biyu don rage lokacin jiyya da rage illa.15,16
Hoto 1 Halin rayuwa na Plasmodium a cikin mutane.Mataki da nau'ikan ƙwayoyin cuta waɗanda nau'ikan magungunan zazzabin cizon sauro daban-daban ke aiki.
A cikin 1925, masu bincike na Jamus sun gano maganin rigakafin cutar zazzabin cizon sauro na farko, pamaquin, ta hanyar gyaggyara methylene blue.Pamaquin yana da iyakacin inganci da guba kuma ba za a iya amfani da shi don magance cutar malaria ba. wanda aka samu na methylene blue da aka yi amfani da shi don magance zazzabin cizon sauro a lokacin yakin duniya na biyu.17
An samar da Chloroquine a lokacin yakin duniya na biyu don maganin zazzabin cizon sauro.Chloroquine maganin zazzabin cizon sauro ne da aka zaba saboda ingancinsa, aminci da tsadarsa.Amma amfani da shi ba da dadewa ba ya haifar da fitowar nau'in P. falciparum mai jure wa chloroquine. 18 Primaquine da ake amfani da therapeutically don magance relapsing Plasmodium vivax lalacewa ta hanyar hypnosis.Primaquine ne m gameticidal da Plasmodium falciparum.Primaquine yana sa hemolytic anemia a marasa lafiya da glucose-6-phosphate dehydrogenase (G6PD) rashi. -P.Aikin Rana.19
Sabbin abubuwan da suka samo asali na quinoline an haɗa su, wanda ya haifar da sababbin magunguna irin su piperaquine da amodiaquine.Bayan fitowar juriya na chloroquine, amodiaquine, analog mai maye gurbin phenyl na chloroquine, ya nuna tasiri mai kyau a kan chloroquine-resistant nau'in Plasmodium falciparonchrine a Manni P. tushen maganin zazzabin cizon sauro da aka samar a kasar Sin a shekarar 1970. Yana da tasiri a kan nau'ikan P. falciparum, P. vivax, P. malaria da P. ovale.Pyronadrine yana samuwa a matsayin ACT tare da artesunate, wanda ya nuna kyakkyawan inganci ga kowa da kowa. Cutar zazzabin cizon sauro.21 An samar da Mefloquine a tsakiyar shekarun 1980 kuma a halin yanzu ana ba da shawarar don rigakafin cutar zazzabin cizon sauro da kowane nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in halitta (Maleria) ke haifar da yin rigakafin cutar zazzabin cizon sauro (malaria) da ake kira "Mefloquine" don yin rigakafin cutar zazzabin cizon sauro. suna aiki da farko akan matakin jini na parasite, amma wasu magungunan zazzabin cizon sauro suna aiki akan matakin hanta.Ex with heme in parasite's food vacuoles.Saboda haka, heme polymerization ya toshe.Saboda haka, heme da aka saki a lokacin rushewar haemoglobin ya taru zuwa matakan guba, ya kashe kwayoyin cutar tare da guba mai guba. ashirin da uku
Antifolates su ne magungunan zazzabin cizon sauro waɗanda ke hana haɗin folic acid, wanda ke da mahimmanci don haɗakar nucleotides da amino acid.Antifolates suna toshe rarraba makaman nukiliya na nau'in Plasmodium a lokacin lokacin schizont a cikin erythrocytes da hepatocytes.Sulfadoxine yana da tsari mai kama da para-aminobenzoic acid. (PABA), wani bangare na folic acid.Suna hana haɗin dihydrofolate ta hanyar hana dihydrofolate synthase, wani mahimmin enzyme a cikin nucleic acid biosynthesis. ashirin da hudu.
Pyrimethamine da proguanil su ne schizont antimalarial kwayoyi da aiki a kan asexual nau'i na Plasmodium jinsin.Wadannan kwayoyi hana enzyme dihydrofolate reductase (DHFR), wanda ya hana rage dihydrofolate zuwa tetrahydrofolate, wanda yake da muhimmanci ga biosynthesis na amino acid da nucleic acid. Proguanil ne prodrug metabolized zuwa cyclic guanidine.Proguanil shi ne na farko antifolate magani amfani da maganin zazzabin cizon sauro.Dalili kuwa shi ne cewa yana lalata jajayen kwayoyin halitta kafin parasite ya mamaye su a lokacin da suke shiga cikin jini. miyagun ƙwayoyi.Pyrimethamine an fi amfani da shi tare da wasu magunguna masu saurin aiki.Duk da haka, amfani da shi ya ragu saboda juriya na miyagun ƙwayoyi.24,25
Atovaquone shine na farko da aka amince da maganin zazzabin cizon sauro wanda ke niyya da mitochondria na Plasmodium parasite.Atovaquone ya hana jigilar lantarki ta hanyar yin aiki azaman analog na ubiquinone don toshe ɓangaren cytochrome b na cytochrome bc1 complex. Lokacin da aka haɗa shi da proguanil, atovaquone yana da aminci da tasiri ga mata masu juna biyu. da yara.Atovaquone yana da tasiri a kan matakin jima'i na parasite na mai gida da kuma sauro.Saboda haka, yana hana yaduwar cutar zazzabin cizon sauro zuwa ga mutane.Haɗin haɗin gwiwa tare da proguanil da aka haɓaka a ƙarƙashin sunan kasuwanci Malarone.24,26
Artemisinin an cire shi daga Artemisia annua a cikin 1972. Artemisinin da abubuwan da suka samo asali ciki har da artemether, dihydroartemisinin, artemether da artesunate suna da aikin bakan gizo. na gametocytes daga mutane zuwa sauro.27 Artemisinin da abubuwan da suka samo asali suna da tasiri a kan nau'in chloroquine- da mefloquine. parasites.Wadannan magungunan suna da ɗan gajeren rabin rayuwa da ƙarancin rayuwa, suna haifar da juriya na ƙwayoyi, suna sa su zama marasa tasiri a matsayin monotherapy.Saboda haka, ana ba da shawarar abubuwan artemisinin tare da sauran magungunan zazzabin cizon sauro.28
Sakamakon antimalarial na artemisinin na iya zama saboda samar da radicals kyauta wanda ke haifar da raguwar gadoji na artemisinin endoperoxide a cikin vesicles na abinci na parasites, wanda ke hana ƙwayoyin cuta na calcium ATPase da proteasome.29,30 Artemether ana amfani dashi azaman monotherapy.Fast baki sha.Bioavailability. ninki biyu lokacin da aka gudanar da shi a gaban abinci.Da zarar a cikin tsarin kewayawa, artemether yana hydrolyzed zuwa dihydroartemisinin a cikin gut da hanta.
Artesunate wani nau'in sinadari ne na wucin gadi saboda saurin maganin zazzabin cizon sauro, rashin juriya ga magunguna da kuma mafi yawan ruwa.
Tetracyclines da macrolides suna jinkirin yin maganin zazzabin cizon sauro da aka yi amfani da su azaman ƙarin magani ga quinine a cikin malaria malaria.Doxycycline kuma ana amfani dashi don chemoprophylaxis a wuraren da ke da juriya. An yi amfani da dabarun da aka yi amfani da su a baya ta hanyar yin amfani da tsayayyen haɗuwa.WHO ta ba da shawarar maganin haɗin gwiwa na artemisinin (ACT) a matsayin magani na farko don maganin malaria maras rikitarwa.
ACT yana ƙunshe da wani ɓangaren artemisinin mai ƙarfi wanda ke kawar da ƙwayoyin cuta da sauri, da kuma magani mai tsawo wanda ke kawar da ragowar ƙwayoyin cuta kuma yana rage juriya na artemisinin.ACTs da WHO ta ba da shawarar su ne artesunate / amodiaquine, artemether / benzfluorenol, artesunate / mefloquine, artesunate / pyrrolidine, dihydroartemisine. piperaquine, Artesunate/sulfadoxine/pyrimethamine, artemether/piperaquine da artemisinin/piperaquine/primaquine.Chloroquine da primaquine ya kasance magani na farko-farko don kawar da Plasmodium vivax.Quinine + tetracycline/doxycycline, amma yana da babban tasiri. illa kuma an hana shi a cikin yara da mata masu juna biyu34.
Ana ba da shawarar Mefloquine, atovaquone / proguanil, ko doxycycline a cikin tsarin chemoprevention ga matafiya daga wuraren da ba su da ƙarfi zuwa wuraren da ba su da ƙarfi. .36 Halofantrine bai dace da amfani da magani ba saboda cututtukan zuciya.Dapsone, mepalyline, amodiaquine, da sulfonamides an cire su daga maganin warkewa saboda tasirin su. 1.
A halin yanzu ana samun magungunan rigakafin zazzabin cizon sauro akan bambance-bambance a cikin manyan hanyoyin rayuwa tsakanin nau'ikan Plasmodium da rundunoninsu. Manyan hanyoyin rayuwa na parasites, gami da detoxification na heme, haɓakar fatty acid, haɓakar acid nucleic, haɓakar fatty acid, da damuwa na oxidative, wasu ne daga cikin littafin. wuraren tsara magunguna.38,39 Ko da yake yawancin magungunan zazzabin cizon sauro an yi amfani da su tsawon shekaru da yawa, amfani da su a halin yanzu yana da iyaka saboda juriya na miyagun ƙwayoyi.A cewar wallafe-wallafen, ba a sami magungunan rigakafin da ke hana wuraren da aka sani ba.7,40 A Sabanin haka, yawancin magungunan zazzabin cizon sauro ana gano su a cikin dabbobi a cikin vivo ko nazarin samfurin in vitro.Saboda haka, yanayin aikin mafi yawan magungunan zazzabin cizon sauro ba shi da tabbas.Bugu da ƙari, hanyoyin jure wa mafi yawan magungunan zazzabin cizon sauro ba su da tabbas.39
Magance zazzabin cizon sauro yana buƙatar haɗaɗɗun dabaru irin su sarrafa ƙwayoyin cuta, ingantattun magungunan rigakafin cutar maleriya masu inganci, da ingantattun alluran rigakafi.La'akari da yawan mace-mace da cututtukan zazzabin cizon sauro, gaggawa da yaduwar juriya na ƙwayoyi, rashin tasirin magungunan rigakafin da ake samu a kan marasa erythrocyte da matakan jima'i. , gano sabbin magungunan zazzabin cizon sauro ta hanyar fahimtar ainihin hanyoyin rayuwa na zazzabin cizon sauro.Magungunan zazzabin cizon sauro suna da mahimmanci.Don cimma wannan buri, ya kamata bincike-binciken miyagun ƙwayoyi ya yi nisa da sababbi, ingantattun maƙasudai don ware sabbin mahaɗan gubar.39,41
Akwai dalilai da yawa don buƙatar gano sababbin maƙasudin rayuwa. Na farko, ban da magungunan atovaquone da artemisinin, yawancin magungunan zazzabin cizon sauro ba su bambanta da sinadarai ba, wanda zai iya haifar da juriya. putative chemotherapeutic hari, da yawa har yanzu ba a tabbatar da su.Idan ingantacciyar hanya, zai iya samar da wasu mahadi masu tasiri da aminci.Gano sababbin magungunan miyagun ƙwayoyi da kuma ƙirar sababbin mahadi waɗanda ke aiki akan sababbin maƙasudin ana amfani da su sosai a duniya a yau don magancewa. matsalolin da suka taso daga bayyanar juriya ga magungunan da ake da su.40,41 Saboda haka, an yi amfani da nazarin abubuwan da aka yi amfani da su na musamman na masu hana furotin na Plasmodium don gano magungunan miyagun ƙwayoyi. An sami shiga tsakani.Wadannan yuwuwar magungunan zazzabin cizon sauro sun yi niyya ga mahimman hanyoyin biosynthesis na metabolite, jigilar membrane da tsarin sigina, da hanyoyin lalata haemoglobin.40,42
Plasmodium protease wani nau'in sinadari ne mai kayyadewa a ko'ina kuma yana taka muhimmiyar rawa a rayuwar protozoan parasites da cututtukan da suke haifarwa.Yana haifar da hydrolysis na peptide bond. gujewa, kunna kumburi, erythrocyte mamayewa, rushewar haemoglobin da sauran sunadarai, autophagy, da ci gaban parasites.44
Maganin cutar zazzabin cizon sauro (glutamic aspartic acid, cysteine, karfe, serine da threonine) sune maƙasudin maganin warkewa saboda rushewar kwayar cutar zazzabin cizon sauro yana hana lalacewar haemoglobin da matakin erythrocyte na parasite.ci gaba.45
Rushewar erythrocytes da mamayewar merozoites na gaba yana buƙatar proteases na malaria.A peptide na roba (GlcA-Val-Leu-Gly-Lys-NHC2H5) yana hana Plasmodium falciparum schizont cysteine protease Pf 68. Yana hana ci gaba da erythrocyte. ya nuna cewa proteases na taka muhimmiyar rawa wajen mamayewar kwayoyin cutar jajayen jini.Saboda haka, proteases wata manufa ce mai ban sha'awa don bunkasa magungunan zazzabin cizon sauro.46
A cikin Plasmodium falciparum abinci vacuoles, da yawa aspartic proteases (plasma proteases I, II, III, IV) da cysteineproteases (falcipain-1, falcipain-2/, falcipain-3) an ware, An yi amfani da su rage haemoglobin, kamar yadda aka nuna. a cikin Hoto 2.
Ƙunƙarar al'adar P. falciparum parasites tare da masu hana protease leupeptin da E-64 ya haifar da tarawar globin da ba ta da kyau.Leupeptin yana hana cysteine da wasu ƙwayoyin cuta na serine, amma E-64 musamman yana hana cysteine proteases.47,48 Bayan an gama. na parasites tare da aspartate protease inhibitor pepstatin, globin bai tara ba. Yawancin bincike sun nuna cewa masu hana cystatin ba wai kawai hana lalatawar globin ba, har ma suna hana matakan farko na rushewar haemoglobin, irin su haemoglobin denaturation, sakin heme daga globin, da kuma samar da heme. .49 Wadannan sakamakon sun nuna cewa ana buƙatar proteases na cysteine don mataki na farko. Matakai a cikin lalata haemoglobin ta hanyar Plasmodium falciparum. Dukansu E-64 da pepstatin synergistically sun hana ci gaban P. falciparum. Duk da haka, kawai E-64 ya katange globin hydrolysis. 48,49 da dama cysteine protease inhibitors, irin su fluoromethyl ketone da vinyl sulfone, hana P. falciparum girma da hemoglobin degra.dation.A cikin samfurin dabba na zazzabin cizon sauro, fluoromethyl ketone yana hana ayyukan P. vickei protease kuma yana warkar da kashi 80% na cututtukan zazzabin cizon sauro.Saboda haka, protease inhibitors suna yin alkawalin 'yan takara don maganin maleriya. Ayyukan da suka biyo baya sun gano masu hana falcipain masu amfani da kwayoyin halitta, ciki har da chalcone da phenothiazine. wanda ke toshe magudanar ruwa da ci gaba.50
Serine proteases suna da hannu a cikin schizont rupture da erythrocyte reinvasion a lokacin da Plasmodium falciparum rayuwa cycle.Za a iya katange da dama serine protease inhibitors kuma shi ne mafi kyau zabi tun da babu wani ɗan adam enzyme homolog.The protease inhibitor LK3 ware daga Streptomyces sp.yana kaskantar da cutar malaria serine protease.51 Maslinic acid wani nau'in pentacyclic triterpenoid ne na halitta wanda ke hana maturation na parasites daga matakin zobe zuwa matakin schizont, wanda hakan ya kawo karshen sakin merozoites da mamayewarsu.Jirgin 2-pyrimidine nitrile mai ƙarfi na hana falcipain. -2 da falcipain-3.52 statins da kuma hana ƙwayoyin plasma proteases ta allphenostatin-based inhibitors hana haemoglobin lalata da kuma kashe parasites.Yawancin cysteine protease blockers suna samuwa, ciki har da Epoxomicin, lactacystin, MG132, WEHI-842, 6statin da WEHI-91 .
Phosphoinositide lipid kinases (PIKs) su ne enzymes na ko'ina waɗanda phosphorylate lipids don daidaita haɓakawa, rayuwa, fataucin, da siginar salula.Mafi yawan karatun PIK azuzuwan a cikin 53 parasites sune phosphoinositide 3-kinase (PI3K) da phosphatid-PIK4kinase. An gano hana waɗannan enzymes a matsayin maƙasudin maƙasudin ci gaba da magungunan antimalarial tare da bayanan ayyukan da ake so don rigakafin, jiyya da kuma kawar da cutar malaria.54 UCT943, imidazopyrazine (KAF156) da aminopyridines wani sabon nau'i ne na mahadi na antimalarial wanda ke kaiwa ga PI. (4)K da kuma hana haɓakar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar cuta (KAF156) ta kasance a halin yanzu. a cikin gwaji na asibiti na Phase II.55,56 MMV048 wani fili ne mai kyau a cikin vivo prophylactic aiki a kan P. cynomolgi da m as a watsa toshe miyagun ƙwayoyi.MMV048 a halin yanzu yana fuskantar gwajin asibiti na Phase IIa a Habasha.11
Don saurin girma a cikin ƙwayoyin jajayen jini masu kamuwa da cuta, nau'in Plasmodium suna buƙatar isassun abubuwa masu ƙarfi don sauƙaƙe ƙarfin kuzarin su. Don haka, parasites suna shirya erythrocytes mai masaukin baki ta hanyar haifar da masu jigilar kayayyaki na musamman waɗanda suka bambanta sosai da masu jigilar ƙwayoyin cuta a cikin ɗauka da kawar da metabolites. Masu gina jiki da kuma tashoshi suna da yuwuwar hari saboda muhimmiyar rawar da suke takawa a cikin jigilar metabolites, electrolytes da abinci mai gina jiki.57 Waɗannan su ne tashar tashar Plasmodium surface anion (PSAC) da kuma ƙwayar ƙwayar ƙwayar ƙwayar cuta (PVM), waɗanda ke ba da hanyar ci gaba da yaduwa don abubuwan gina jiki. cikin kwayar cutar ta cikin salula.58
PSAC ita ce manufa mafi cika alkawari saboda ana samun ta a cikin nau'ikan abubuwan gina jiki (hypoxanthine, cysteine, glutamine, glutamate, isoleucine, methionine, proline, tyrosine, pantothenic acid da choline) don samun manyan ayyuka a cikin ƙwayoyin cuta na cikin salula. zuwa sanannun tashar tashoshi masu watsa shirye-shirye.58,59 Phloridizin, dantrolene, furosemide, da niflunomide sune masu hana jigilar jigilar anion masu ƙarfi.Magunguna irin su glyburide, meglitinide, da tolbutamide suna hana kwararar choline cikin ƙwayoyin jajayen jini masu kamuwa da cuta.60,61
Tsarin jini na Plasmodium falciparum ya dogara kusan gaba ɗaya akan glycolysis don samar da makamashi, ba tare da ajiyar makamashi ba;Yana dogara ne akan yawan shan glucose akai-akai. Kwayoyin cuta suna canza pyruvate zuwa lactate don samar da ATP, wanda ake buƙata don yin kwafi a cikin jajayen ƙwayoyin jini. membrane erythrocyte da kuma 'sabuwar hanyar wucewa'.63 Ana jigilar glucose zuwa parasites ta hanyar Plasmodium falciparum hexose transporter (PFHT) PFHT yana da wasu halaye na jigilar sukari. D-glucose da D-fructose. Don haka, bambance-bambance a cikin hulɗar GLUT1 da PFHT tare da substrates suna nuna cewa zaɓin zaɓi na PFHT shine sabon manufa mai ban sha'awa don haɓaka magungunan antimalarial novel.64 A doguwar sarkar O-3-hexose. 3361) yana hana glucose da fructose ta hanyar PFHT, amma baya hana jigilar hexose ta manyan glucose na dabbobi masu shayarwa da masu jigilar fructose (GLUT1 da 5) .Compound 3361 kuma ya hana shan glucose ta hanyar P. vivax na PFHT. A cikin binciken da ya gabata, fili 3361 ya kashe P. falciparum a al'ada kuma ya rage haɓakar P. berghei a cikin ƙirar linzamin kwamfuta.65
Rukunin jini na Plasmodium ya dogara ne akan anaerobic glycolysis don girma da haɓaka.60 Kwayoyin jajayen jini masu kamuwa da cuta suna sha glucose sau 100 da sauri fiye da jajayen jinin da ba su kamu da cutar ba. Kwayoyin cuta suna metabolizes glucose ta hanyar glycolysis zuwa lactate, wanda ake fitarwa daga parasite ta hanyar lactate: hanyar H + mai nuna alama a cikin yanayi na waje.66 Lactate fitarwa da kuma ɗaukar glucose yana da mahimmanci don kiyaye bukatun makamashi, pH na ciki, da kwanciyar hankali na osmotic parasite.Lactate:H + symporter tsarin hanawa shine sabon manufa mai ban sha'awa don bunkasa sababbin kwayoyi.Da yawa mahadi, irin su MMV007839 da MMV000972, kashe asexual jini-matakin P. falciparum parasites ta hana lactate: H + transporter.67
Kamar sauran nau'in tantanin halitta, ƙwayoyin jini na jini suna kula da ƙananan matakan Na + na ciki. Duk da haka, ƙwayoyin cuta suna ƙara haɓakar ƙwayar erythrocyte kuma suna sauƙaƙe shigarwar Na +, wanda ke haifar da karuwa a cikin erythrocyte cytoplasmic Na + maida hankali zuwa matakin matsakaicin matsakaici. Saboda haka, parasites. sun sami kansu a cikin manyan kafofin watsa labarai na Na + kuma dole ne su fitar da Na + ions daga membrane na plasma don kula da ƙananan matakan cytoplasmic Na + don tsira duk da kasancewarsu a cikin rukunin intracellular. transporter (PfATP4), wanda ke aiki a matsayin tsarin farko na Na + -efflux famfo na parasites, kamar yadda aka nuna a hoto 3.68, hana wannan jigilar zai haifar da karuwar adadin Na+ a cikin kwayar cutar, wanda zai haifar da mutuwar kwayar cutar. Maleriya parasite.Da yawa mahadi, ciki har da sipagamin a cikin lokaci 2, (+) -SJ733 a cikin lokaci 1, da KAE609 a cikin lokaci 2, suna da tsarin aiki wanda ke kaiwa PfATP4.67,69
Hoto 3. Tsarin da aka ba da shawarar na PfATP4 da nau'in V-type H +-ATPase a cikin mutuwar erythrocyte mai kamuwa da cuta bayan hana cipargamin.
Nau'in Plasmodium suna sarrafa matakan Na+ ta hanyar amfani da nau'in P-type ATPase. Yana kuma shigo da H+ ta hanya iri ɗaya. Don daidaita yawan adadin H+ da kuma kula da pH na cikin salula na 7.3, ƙwayar cutar cizon sauro tana amfani da wani nau'in V-type ATPase transporter zuwa fitar da H +. Samar da sabon magani shine manufa mai ban sha'awa.MMV253 yana hana nau'in H+ ATPase na V-a matsayin tsarin aikinta ta hanyar maye gurbin maye gurbin da tsarin kwayoyin halitta gaba daya.70,71
Aquaporin-3 (AQP3) shine furotin tashar aquaglycerol wanda ke sauƙaƙe motsi na ruwa da glycerol a cikin ƙwayoyin mammalian.AQP3 yana haifar da shi a cikin hepatocytes na mutum don amsawa ga kamuwa da cutar parasite kuma yana da muhimmiyar rawa a cikin kwafin parasite.AQP3 yana ba da damar yin amfani da glycerol zuwa P. berghei kuma yana sauƙaƙa kwafi na parasites a cikin matakin erythrocyte na asexual.72 Ragewar kwayoyin halitta na AQP3 yana rage nauyin hanta a matakin hanta na P. berghei.Bugu da ƙari, jiyya tare da mai hana AQP3 auphen yana rage nauyin P. berghei parasitemia a cikin hepatocytes da P. falciparum parasitemia a cikin erythrocytes, yana nuna cewa sunadaran sunadaran suna taka muhimmiyar rawa a cikin matakai daban-daban na rayuwa na parasite .73 Mafi yawan abin ban sha'awa, rushewar AQP3 a cikin berayen kwayoyin halitta ba mai mutuwa ba ne, yana nuna cewa furotin mai masaukin yana da wani sabon manufa na warkewa.Wannan aikin yana ƙaruwa da mu. fahimtar hanyoyin hanta mai masaukin baki da cutar Plasmodium ta shafa kuma yana nuna yuwuwar waɗannan prodaina zama magungunan zazzabin cizon sauro na gaba.71,72
Phospholipids suna taka muhimmiyar rawa a cikin sake zagayowar rayuwa ta intra-erythrocyte na Plasmodium falciparum, duka a matsayin tsarin tsarin membranes da kuma tsarin kwayoyin halitta waɗanda ke daidaita ayyukan enzymes daban-daban.Waɗannan ƙwayoyin suna da mahimmanci don haifuwa parasite a cikin ƙwayoyin jini.Bayan mamayewar erythrocyte, Matakan phospholipid suna karuwa, wanda phosphatidylcholine shine babban lipid a cikin sassan cell membranes.Parasites suna hada phosphatidylcholine de novo ta amfani da choline a matsayin precursor.Wannan hanyar de novo yana da mahimmanci ga ci gaban parasites da rayuwa.Hana jigilar choline cikin parasites kuma yana hana phosphatidylcholine biosynthesis. yana haifar da mutuwar parasite.74 Albitiazolium, maganin da ya shiga gwaji na Phase II, yana aiki da farko ta hanyar hana jigilar choline zuwa cikin parasite. yanayi.Musamman, allura daya warke high pmatakan arasitemia.75,76
Phosphocholine cytidyltransferase shine matakin iyakacin iyaka a cikin de novo biosynthesis na phosphatidylcholine.77 Diquaternary ammonium fili G25 da dicationic fili T3 sun hana phosphatidylcholine kira a cikin parasites.G25 shine 1000-ninki ƙasa da layukan guba ga mammalian kwayoyi. mahadi a cikin gano magungunan rigakafin zazzabin cizon sauro da haɓakawa.78,79
Babban mataki a cikin yaduwar nau'in Plasmodium a cikin rundunonin ɗan adam shine rarrabuwa da sauri na DNA parasites, wanda ya dogara da samuwar mahimman metabolites irin su pyrimidine. glycoproteins.Nucleotide kira ya bi manyan hanyoyi guda biyu: hanyar ceto da kuma hanyar de novo.Dihydroorotate dehydrogenase (DHODH) wani muhimmin enzyme ne wanda ke haifar da oxidation na dihydroorotate zuwa orotate, mataki mai iyakancewa a cikin de novo pyrimidine kira. HODHrefore, yana wakiltar maƙasudi mai yuwuwar ci gaban magungunan zazzabin cizon sauro.80 Kwayoyin ɗan adam suna samun pyrimidine ta hanyar ceton pyrimidine da aka riga aka kafa ko ta hanyar de novo. Duk da haka, hana de novo pyrimidine biosynthesis a cikin parasites yana haifar da mutuwar waɗannan kwayoyin halitta sabodacutar zazzabin cizon sauro ba ta da hanyar ceton pyrimidine, wanda ke sa ƙwayar cuta ta zama mai rauni ga hanawa ta DHODH.81 DSM190 da DSM265 sune masu hana masu hana ƙwayoyin cuta DHODH enzyme, wanda a halin yanzu yake cikin gwajin gwaji na asibiti na Phase 2. P218 shine mai hana DHODH mai tasiri akan duk-pyrimethamine. Juriya a halin yanzu a cikin Mataki na 1.KAF156 (Ganaplacide) a halin yanzu yana cikin gwaji na asibiti na Phase 2b tare da phenylfluorenol.82
Ana buƙatar isoprenoid don gyare-gyaren lipid bayan fassarar sunadaran da kuma maimaita asexual na Plasmodium falciparum.Isoprenoids an haɗa su daga isoprenoids na farko na isopentyl diphosphate (IPP) ko isomer na dimethylallyl diphosphate (DMAPP), ta ɗayan hanyoyi masu zaman kansu guda biyu.Mevalonate. hanya da 2C-methyl-D-erythritol 4-phosphate (MEP) hanya.A mafi yawan ƙananan ƙwayoyin cuta, waɗannan hanyoyi guda biyu sun bambanta da juna. Ana binciko hanyar MEP azaman yuwuwar sabbin maƙasudin warkewa. .83,84 PfDXR inhibitors suna hana Plasmodium falciparum.Plasmodium falciparum yana girma kuma ba mai guba bane ga ƙwayoyin ɗan adam.PfDXR shine yuwuwar sabuwar manufa a cikinCi gaban maganin zazzabin cizon sauro.83 Fosmidomycin, MMV019313 da MMV008138 sun hana DOXP redutoisomerase, wani mahimmin enzyme na hanyar DOXP wanda ba ya cikin mutane.Saboda hana shigar da furotin a cikin Plasmodium yana rushe haɓakar ƙwayoyin cuta na jima'i, wannan shine yiwuwar anti.5malarial.
Pronylated sunadaran suna taka muhimmiyar rawa a cikin matakai daban-daban na salon salula da suka haɗa da fataucin vesicle, watsa sigina, tsarin kwafin DNA, da rarrabawar tantanin halitta.Wannan gyare-gyaren bayan fassarorin yana sauƙaƙe ɗaurin sunadaran cikin salula zuwa membranes kuma yana sauƙaƙe hulɗar furotin-protein.Farnesyltransferase yana haɓakar canja wurin rukunin farnesyl, rukunin 15-carbon isoprenoid lipid, daga farnesyl pyrophosphate zuwa C-terminus na sunadaran da ke ɗauke da motif CaaX.Farnesyltransferase sabon alƙawari ne don haɓaka magungunan zazzabin cizon sauro saboda hana shi yana kashe ƙwayoyin cuta.86
A baya can, juyin halitta na juriya ga parasites ta farnesyltransferase inhibitor BMS-388,891 tetrahydroquinoline ya nuna maye gurbi a cikin furotin na peptide substrate-daure yankin. .A cikin wani binciken, an samo maye gurbi a cikin farnesyltransferase beta subunit na MMV019066-resistant nau'i na P. falciparum. Nazarin samfurin ya nuna cewa maye gurbi yana karkatar da mahimmin ma'amala na ƙananan ƙwayoyin cuta tare da wurin aiki na farnesylation, wanda ya haifar da juriya na miyagun ƙwayoyi. .87
Ɗaya daga cikin maƙasudai masu ban sha'awa don haɓaka sababbin magunguna shine toshe P. falciparum ribosome, da kuma sauran sassan na'urorin fassarar da ke da alhakin gina jiki. Duk kwayoyin halittar suna buƙatar injinan fassara don yin aiki.Masu hana haɓakar furotin suna da gagarumar nasarar asibiti a matsayin ingantaccen maganin rigakafi. P. falciparum ribosome ya mamaye tsakiyar tsakiyar juyin halitta tsakanin prokaryotes da eukaryotes, yana bambanta shi da kyau daga ribosome ɗan adam kuma don haka yana ba da muhimmiyar sabuwar manufa. ribosomes tare da rikicienger RNA kuma yana da mahimmanci don haɗin furotin a cikin eukaryotes.PfEF2 an keɓe shi a matsayin sabon manufa don ci gaban magungunan zazzabin cizon sauro.87,89
Hana haɗakar furotin Ɗauki binciken sordarin, wani samfurin halitta wanda ya zaɓa ya toshe haɗin furotin na fungal ta hanyar hana yisti eukaryotic elongation factor 2. Hakazalika, M5717 (tsohon DDD107498), mai zaɓin zaɓi na 80S ribosome-mu'amala a halin yanzu yana cikin lokaci PfEF2. 1 karatu, tabbatar da yuwuwar PfEF2 a matsayin ingantacciyar manufa don magungunan zazzabin cizon sauro.88,90
Babban fasali na zazzabin cizon sauro mai tsanani shine rarrabuwar erythrocytes masu kamuwa da cuta, kumburi, da toshewar ƙwayoyin cuta. -Hadarin magunguna yana dawo da toshewar jini da kuma shafar ci gaban kwayoyin cuta.91
Yawancin karatu sun nuna cewa sevuparin, polysaccharide anti-adhesion da aka yi daga heparin, yana da tasirin kawar da antithrombin.Sevuparin yana hana mamayewar merozoite a cikin erythrocytes, ɗaure erythrocytes masu kamuwa da cuta zuwa erythrocytes marasa kamuwa da cuta, da kuma ɗaure ga ƙwayoyin endothelial na jijiyoyin jini, sevuurpathermore. zuwa tsarin N-terminal extracellular heparan sulfate-binding tsarin na Plasmodium falciparum erythrocyte membrane protein 1, Duffy-binding-like domain 1α (DBL1α), kuma ana tunanin ya zama muhimmiyar mahimmanci wajen gano cutar erythrocytes.92,93 Wasu Tebura 2 sun taƙaita. gwaji na asibiti a matakai daban-daban.
Lokacin aikawa: Maris 24-2022