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Tafere Mulaw Belete Department of Pharmacology, Kulliyadda Caafimaadka iyo Sayniska Caafimaadka, Jaamacadda Gondar, Gonder, Itoobiya, Warbixinta: Tafere Mulaw Belete Tel +251 918045943Email [email protected] Abstract: Duumadu waa dhibaato caafimaad oo wayn oo caalami ah oo keenta dhimasho iyo xanuun badan sanad walba .Ikhtiyaarada daawaynta ayaa ah kuwo aad u yar oo aad loola loolamayo marka ay soo baxaan noocyada dulinka u adkaysta,kuwaaso caqabad wayn ku ah xakamaynta duumada Si degdeg ah ayaa loogu baahan yahay. Horumarinta daawada antimalarial waxay raaci kartaa habab kala duwan, oo u dhexeeya wax ka beddelka daawooyinka jira ilaa naqshadaynta dawooyinka cusub ee bartilmaameedka cusub. horumarinta dawooyinka cusubets for faragelinta daroogada ayaa shaaca laga qaaday sannadihii la soo dhaafay. Sidaa darteed, dib u eegistani waxay diiradda saaraysaa horumarinta sayniska iyo tignoolajiyada ugu dambeeyay ee helitaanka iyo horumarinta daawooyinka cusub ee ka hortagga duumada. Xakameeyaha xadiidka, aquaporin 3 inhibitors, choline transport inhibitors, dihydroorotate dehydrogenase inhibitors, pentadiene biosynthesis inhibitor, farnesyltransferase inhibitor iyo ensaymes oo ku lug leh dheef-shiid kiimikaadka iyo DNA-da dib-u-eegista. , bartilmaameedyo cusub, dawooyinka ka hortagga duumada, qaabka ficilka, dulinka duumada
Duumadu waa cudur faafa oo aad u xun, gaar ahaan Afrikada Saxaraha ka hooseeya, qaybo ka mid ah Aasiya iyo Koonfurta Ameerika.In kasta oo ay jiraan dadaallo dhowr ah, haddana maanta waa mid ka mid ah sababaha ugu horreeya ee cudurrada iyo dhimashada inta badan haweenka uurka leh iyo carruurta. Sida laga soo xigtay Caafimaadka Adduunka Ururka (WHO) Warbixin 2018, waxaa jiray 228 milyan oo kiis oo duumada ah iyo 405,000 oo dhimasho ah adduunka oo dhan. Ku dhawaad kala badh dadka adduunka ayaa halis ugu jira duumada, iyadoo inta badan kiisaska (93%) iyo dhimashada (94%) ay ka dhaceen Afrika. 125 milyan oo haween uur leh ayaa halis ugu jira cudurka duumada sannad kasta, 272,000 oo carruur da'doodu ka yar tahay 5 sano ayaa u dhinta duumada. Plasmodium ee dadka duumada u horseeda waxaa ka mid ah P. vivax, P. Knowlesi, P. ovale, P. Malaria iyo P. falciparum. Kuwaas oo ka mid ah, Plasmodium falciparum waa nooca ugu badan ee dilaaga ah uguna badan ee Plasmodium.3
Maqnaanshaha tallaal wax ku ool ah, isticmaalka daawaynta ee dawooyinka ka hortagga duumada ayaa ah habka kaliya ee lagu maareeyo loogana hortago cudurka duumada. Daraasado dhowr ah ayaa muujiyay in waxtarka inta badan daawooyinka ka hortagga duumada ay waxyeello u geystaan xaaladaha degdegga ah ee daawada u adkeysata Plasmodium spp.4 ayaa lagu soo warramey in ku dhawaad dhammaan dawooyinka ka hortagga duumada ee la heli karo, xoojinta horumarinta dawooyinka cusub ee ka hortagga duumada ee ka dhanka ah bartilmaameedyada la ansixiyey ee hadda jira iyo raadinta Heerka gametophytic ee gudbinta waxay sidoo kale u dhaqmi kartaa kororka asexual ee gudaha erythrocytes, gaar ahaan noocyada dulinka u adkaysta.6 Dhowr enzymes, ion kanaalada, gaadiidleyda, molecules is dhexgal ee duulaanka unugyada dhiigga cas (RBC), iyo molecules ka mas'uulka ah dulin oksidative stress, dheef-shiid kiimikaad, iyo xaalufka haemoglobin ayaa fure u ah horumarinta dawooyinka ka hortagga duumada ee cusub
Awoodda dawooyinka ka hortagga duumada cusub waxaa lagu qiimeeyaa shuruudo dhowr ah: qaab cusub oo ficil ah, iska caabin la'aan dawooyinka ka hortagga duumada ee hadda jira, daawaynta hal-door ah, waxtarka labadaba heerka dhiigga asexual iyo gametocytes ee mas'uulka ka ah gudbinta. Daawooyinka ka hortagga duumada waa in ay wax ku ool u yeeshaan ka hortagga caabuqa (chemoprotectants) iyo ka nadiifinta beerka ee P. vivax hypnotics ( wakiilada dib u soo noqoshada).8
Daah-furka daawada dhaqameed waxa ay raacdaa dhowr habab oo lagu aqoonsanayo dawo cusub oo lagula dagaalamo duumada wax kale loo isticmaalo.8,9
Marka laga soo tago hababka daahfurka dawooyinka dhaqameed ee loo isticmaalo in lagu aqoonsado dawooyinka cusub ee ka hortagga duumada, aqoonta bayoolajiga unugyada Plasmodium iyo genome ayaa la muujiyay in ay yihiin qalab awood badan oo lagu daah-furo hababka iska caabbinta daroogada, waxana ay awood u leedahay in ay qaabeeyaan dawooyinka leh firfircoonida ka hortagga duumada iyo kaneecada.Awood weyn oo loogu talagalay dawooyinka cusub Daawooyinka waa in: (i) wax ka qabtaan caabbinta daroogada, (ii) si degdeg ah u dhaqmaan, (iii) badbaado leh, gaar ahaan carruurta iyo haweenka uurka leh, iyo (iv) ku daaweeyaan duumada hal dose.12 caqabada waa in la helo daawo wax ka qabanaysa Dhammaan sifooyinkaas. Ujeedada dib u eegistani waa in la siiyo fikrad ah bartilmaameedyo cusub oo loogu talagalay daawaynta dulinnada duumada, kuwaas oo ay baranayaan shirkado dhowr ah, si akhristayaasha loo ogeysiiyo shaqadii hore.
Waqtigan xaadirka ah, inta badan daawooyinka ka hortagga duumada ayaa bartilmaameedsada heerka jinsiga ah ee caabuqa duumada ee keena cudurrada calaamadaha. Heerka erythrocytic (beerka) ka hor ayaa weli ah mid aan soo jiidasho lahayn sababtoo ah wax calaamado caafimaad ah lama soo saarin. Alaabooyinka dabiiciga ah, isku-dhafka-synthetic-ka iyo isku-dhafka isku-dhafka ah ee la sameeyay ilaa 1940-yadii.13 Daawooyinka ka hortagga duumada ee jira waxay u qaybsan yihiin saddex qaybood oo waaweyn: derivatives quinoline, antifolates iyo derivatives artemisinin. Weli lama helin ama la sameeyay hal dawo oo baabi'in karta dhammaan noocyada dulinnada duumada. Sidaa darteed, si ay waxtar ugu yeelato infekshanka duumada, isku-darka dawooyinka ayaa inta badan la bixiyaa si isku mid ah. si loo daweeyo cudurrada qarnigii 17aad. Laga soo bilaabo bartamihii 1800-yadii ilaa 1940-meeyadii, quisagaal waxa ay ahayd daawaynta caadiga ah ee duumada daawada labaad si loo gaabiyo wakhtiga daawaynta oo loo yareeyo waxyeelada.15,16
Jaantuska 1-aad ee wareegga nolosha ee Plasmodium ee bini-aadmiga. Marxaladaha iyo noocyada dulinnada oo ay ku dhaqmaan noocyada kala duwan ee daawooyinka ka hortagga duumada.
1925-kii, cilmi-baarayaasha Jarmalku waxay heleen daawadii ugu horreysay ee antimalarial synthetic, pamaquin, iyada oo wax ka beddelaysa methylene blue. derivative of methylene blue loo isticmaalo daawaynta duumada intii lagu jiray dagaalkii labaad ee aduunka.17
Chloroquine waxaa la sameeyay intii lagu jiray dagaalkii labaad ee aduunka si loogu daweeyo duumada 18 Primaquine waxa loo isticmaalaa daawayn si loogu daweeyo soo noqoshada Plasmodium vivax oo ay keento hypnosis. -P.Hawl-maalmeedka.19
Ka dib markii ay soo baxday iska caabbinta chloroquine, amodiaquine, oo ah phenyl-lagu beddelay analogga chloroquine, ayaa muujisay waxtarka ugu fiican ee ka hortagga chloroquine-u-adkeysiga noocyada Plasmodium falciparonchrine. Daawooyinka ka hortagga duumada oo saldhig u ah oo lagu sameeyay Shiinaha 1970. Waxay wax ku ool u tahay noocyada daawooyinka u adkaysta ee P. falciparum, P. vivax, P. malaria iyo P. ovale. dulinka duumada ugu horreyntii waxay ku dhaqmaan heerka dhiigga ee dulin, laakiin qaar ka mid ah dawooyinka ka hortagga duumada ayaa ka shaqeeya marxaladda beerka.Sidaa darteed, heme polymerization waa xannibmay. Natiijo ahaan, heme-ka la sii daayo inta lagu jiro burburka haemoglobin wuxuu ku ururaa heerar sun ah, wuxuu dilay dulinkii qashinka sunta ah. labaatan iyo saddex
Antifolates waa dawooyinka ka hortagga duumada oo joojiya isku-dhafka folic acid, taas oo lagama maarmaan u ah isku-dhafka nucleotides iyo amino acids. Antifolates waxay xannibaan qaybta nukliyeerka ee noocyada Plasmodium inta lagu jiro marxaladda schizont ee erythrocytes iyo hepatocytes. Sulfadoxine waxay leedahay qaab-dhismeed la mid ah para-aminobenzoic acid. (PABA), qayb ka mid ah folic acid.Waxay joojiyaan isku-dhafka dihydrofolate iyaga oo joojinaya dihydrofolate synthase, enzym muhiimka ah ee nucleic acid biosynthesis. labaatan iyo afar
Pyrimethamine iyo proguanil waa dawooyinka ka hortagga duumada ee schizont kuwaas oo u dhaqma qaabka jinsiga ah ee noocyada Plasmodium. Daawooyinkani waxay joojiyaan enzyme dihydrofolate reductase (DHFR), taas oo joojisa dhimista dihydrofolate ilaa tetrahydrofolate, taas oo lagama maarmaan u ah biosynthesis ee amino acids iyo acids nucleic. Proguanil waa dawada la dheefshiido si guanidine cyclic ah. daawo.
Atovaquone waa dawada ka hortagga duumada ee ugu horreysa ee la ansixiyo oo lagu beegsanayo mitochondria ee dulinka Plasmodium.Atovaquone waxay joojisaa gaadiidka elektaroonigga ah iyada oo u dhaqmaysa sidii analoogga ubiquinone si loo xannibo qaybta cytochrome b ee dhismaha cytochrome bc1. Marka lagu daro proguanil, atovaquone waa ammaan iyo waxtar u leh haweenka uurka leh. iyo carruurta.Atovaquone waxay wax ku ool u tahay heerka galmada ee dulin ee martida loo yahay iyo kaneecada.Sidaas darteed, waxay joojisaa gudbinta kaneecada ee kaneecada dadka.
Artemisinin waxaa laga soo saaray Artemisia annua ee 1972. Artemisinin iyo waxyaabaha ay ka mid yihiin artemether, dihydroartemisinin, artemether iyo artesunate waxay leeyihiin hawl ballaaran spectrum. of gametocytes ee bini'aadamka ilaa kaneecada Daawooyinkani waxay leeyihiin nolol badhkeed oo gaaban iyo bioavailability liidata, taasoo keenta caabbinta daawada, taasoo ka dhigaysa mid aan waxtar lahayn sida monotherapy. Sidaa darteed, derivatives artemisinin ayaa lagula talinayaa in lagu daro daawooyinka kale ee ka hortagga duumada.28
Saamaynta ka hortagga duumada ee artemisinin waxaa laga yaabaa inay sabab u tahay jiilka xagjirnimada xorta ah ee ka dhasha dillaaca buundooyinka artemisinin endoperoxide ee marinnada cuntada dulinka, taas oo joojinaysa dulinka calcium ATPase iyo proteasome.29,30 Artemether waxaa loo isticmaalaa monotherapy. nuugista afka degdega ah. labanlaabantay marka la maamulo iyadoo ay jirto cunto. Marka wareegga nidaamka, artemether waxaa lagu shubaa dihydroartemisinin ee mindhicirka iyo beerka.
Artesunate waa derivative semi-synthetic sababtoo ah saameynteeda degdega ah ee ka hortagga duumada, la'aanta caabbinta daawada ee muhiimka ah iyo milanka biyaha oo weyn. Waxaa lagu taliyay inay noqoto daawada safka hore ee duumada daran.31
Tetracyclines iyo macrolides waa dawooyin ka hortag ah oo gaabis ah oo loo isticmaalo daawaynta isku dhafan ee quinine ee duumada falciparum.Doxycycline sidoo kale waxaa loo isticmaalaa chemoprophylaxis ee meelaha leh caabbinta sare leh. Istaraatiijiyad hore ayaa loo isticmaalay iyadoo la adeegsanayo isku-dhafan go'an.WHO waxay ku talinaysaa daaweynta isku-dhafka ah ee artemisinin-based (ACT) inay tahay daawaynta safka kowaad ee duumada falciparum aan murugsanayn.Sababta ayaa ah in isku darka dawooyinku ay yareeyaan caabbinta daroogada iyo waxyeellooyinka.33
ACT waxay ka kooban tahay qayb artemisinin ah oo awood leh oo si dhakhso ah u nadiifisa dulinnada, iyo daawada muddada dheer ee baabi'isa dulinnada haraaga ah waxayna yareysaa iska caabbinta artemisinin. piperaquine, Artesunate/sulfadoxine/pyrimethamine, artemether/piperaquine iyo artemisinin/piperaquine/primaquine. Saamaynta iyo ka-hortagga carruurta iyo haweenka uurka leh34.
Mefloquine, atovaquone/proguanil, ama doxycycline ayaa lagu talinayaa in chemoprevention regimens ee socotada ka soo non-endemic in endemic. .36 Halofantrine kuma habboona isticmaalka daweynta sababtoo ah wadnaha wadnaha.Dapsone, mepalyline, amodiaquine, iyo sulfonamides ayaa laga saaray isticmaalka daaweynta sababtoo ah saameyntooda. 1.
Daawooyinka ka hortagga duumada ee hadda la heli karo waxay ku saleysan yihiin kala duwanaanshaha dariiqyada dheef-shiid kiimikaad ee u dhexeeya noocyada Plasmodium iyo martigeliyahooda. Dariiqyada dheef-shiid kiimikaadka ugu weyn ee dulinku, oo ay ku jiraan detoxification heme, fatty acid synthesis, synthesis nucleic acid, fatty acid synthesis, iyo stress oxidative, ayaa ah qaar ka mid ah sheekada cusub. sites for drug design.38,39 Inkasta oo inta badan dawooyinka ka hortagga duumada la isticmaalo dhowr sano, isticmaalkoodu hadda waa xaddidan yahay sababtoo ah caabbinta daroogada. Sida laga soo xigtay suugaanta, lama helin dawooyinka ka hortagga duumada oo joojiya bartilmaameedyada daroogada ee la yaqaan.7,40 In Taas bedelkeeda, inta badan daawooyinka ka hortagga duumada ayaa laga helay xayawaanka in vivo ama daraasadaha model vitro. Sidaa darteed, qaabka ficilka inta badan daawooyinka ka hortagga duumada ayaa weli ah mid aan la hubin.
Xakamaynta duumadu waxay u baahan tahay xeelado isku xidhan sida xakamaynta xididada, dawooyinka ka hortagga duumada ee waxtarka iyo badbaadada leh, iyo tallaalo wax ku ool ah.Marka la tixgeliyo dhimashada sare iyo cudurrada duumada, xaaladaha degdegga ah iyo fiditaanka dawooyinka caabbinta, waxtar la'aanta daawooyinka ka hortagga duumada ee hadda jira ee ka dhanka ah non-erythrocyte iyo heerarka galmada , aqoonsiga dawooyinka cusub ee ka hortagga duumada iyadoo la fahmayo dariiqyada dheef-shiid kiimikaadka aasaasiga ah ee duumada.Daawooyinka duumada waa kuwo muhiim ah. dulin.Si loo gaadho yoolkan, cilmi-baadhista maandooriyuhu waa in ay bartilmaantaa bartilmaameedyo cusub oo la ansaxiyey si loo go'doomiyo isku-dhisyada rasaasta cusub.39,41
Waxaa jira dhowr sababood oo loogu baahan yahay in la aqoonsado bartilmaameedyada cusub ee dheef-shiid kiimikaadka. Marka hore, marka laga reebo daawooyinka atovaquone iyo artemisinin, inta badan daawooyinka ka hortagga duumada maaha kuwo kiimiko ah oo kala duwan, taas oo keeni karta iska-caabbin.Labaad, sababtoo ah noocyada kala duwan ee kala duwan Haddi la ansixiyo, waxaa laga yaabaa inay soo saarto qaar ka mid ah xeryahooda waxtarka leh oo badbaado leh. dhibaatooyinka ka dhasha soo bixitaanka caabbinta daawooyinka jira Daawooyinkan suurtagalka ah ee ka hortagga duumada ayaa bartilmaameedsanaya biosynthesis-shiid kiimikaad ee muhiimka ah, gaadiidka xuubka iyo hababka calaamadaynta, iyo hababka xaalufka haemoglobin.40,42
Plasmodium protease waa katalytic iyo nidaamin enzyme ah oo kaalin muhiim ah ka ciyaara badbaadada dulinnada protozoan iyo cudurrada ay keenaan.Waxay kicisaa hydrolysis of peptide bonds. baxsiga, firfircoonida caabuqa, duulaanka erythrocyte, burburka hemoglobin iyo borotiinada kale, autophagy, iyo horumarinta dulin.44
Proteases-ka duumada (glutamic aspartic acid, cysteine, birta, serine iyo threonine) ayaa ah bartilmaameedyo daweyn oo rajo leh sababtoo ah carqaladeynta hidda-wadaha borotiinka duumada waxay horjoogsataa hoos u dhaca hemoglobin iyo heerka dulinku ee erythrocyte.horumarinta.45
Burburinta erythrocytes iyo duulaanka xiga ee merozoites waxay u baahan yihiin borotiinka duumada. peptide synthetic (GlcA-Val-Leu-Gly-Lys-NHC2H5) waxay joojisaa Plasmodium falciparum schizont cysteine protease Pf 68. Waxay joojisaa horumarka erythrocyte waxay soo jeedinaysaa in proteases ay door muhiim ah ka ciyaaraan duulaanka dulinku ku hayo unugyada dhiigga cas.Sidaa darteed, proteases waa bartilmaameed rajo leh oo loogu talagalay horumarinta daawada ka hortagga duumada.46
Plasmodium falciparum vacuoles cuntada, dhowr proteases aspartic (plasma proteases I, II, III, IV) iyo cysteine proteases (falcipain-1, falcipain-2/, falcipain-3) ayaa la go'doomiyay, Loo isticmaalo hoos u dhigista hemoglobin, sida lagu muujiyay. sawirka 2aad.
Ku-soo-noqoshada dulinnada P. falciparum ee dhaqanka leh oo leh protease inhibitors leupeptin iyo E-64 waxay keentay ururinta globin aan hoos u dhicin.Leupeptin waxay joojisaa cysteine iyo qaar ka mid ah proteases serine, laakiin E-64 waxay si gaar ah u xakameysaa cysteine proteases.47,48 Ka dib marka la xiro. ee dulin leh aspartate protease inhibitor pepstatin, globin ma ururin. Daraasado dhowr ah ayaa muujiyay in cystatin inhibitors kaliya ma joojinayaan xaalufka globin, laakiin sidoo kale waxay joojiyaan talaabooyinka hore ee burburka hemoglobin, sida denaturation hemoglobin, heme sii deynta globin, iyo wax soo saarka heme. .49 Natiijooyinkani waxay soo jeedinayaan in cysteine proteases looga baahan yahay marxaladda bilowga ah Tallaabooyinka hoos u dhaca hemoglobin ee Plasmodium falciparum.Labada E-64 iyo pepstatin synergistically xannibay horumarinta P. falciparum. Si kastaba ha ahaatee, kaliya E-64 ayaa xannibay globin hydrolysis. 48,49 Dhowr cysteine protease inhibitors, sida fluoromethyl ketone iyo vinyl sulfone, waxay joojiyaan koritaanka P. falciparum iyo hemoglobin degraQaabka xayawaanka duumada, fluoromethyl ketone wuxuu joojiyaa dhaqdhaqaaqa P. vickei protease wuxuuna daaweeyaa 80% caabuqa duumada murine. Sidaa darteed, protease inhibitors ayaa u ballan qaadaya musharixiinta daawooyinka ka hortagga duumada. Shaqada soo socota ayaa lagu aqoonsaday inhibitors falcipain biologically firfircoon, oo ay ku jiraan chalcone iyo phenothiazine. kaas oo xannibaya dheef-shiid kiimikaadka iyo horumarka dulin.50
Serine proteases waxay ku lug leeyihiin dillaaca schizont iyo dib u soo noqoshada erythrocyte inta lagu jiro wareegga nolosha ee Plasmodium falciparum. Waxaa xannibi kara dhowr serine protease inhibitors waana doorashada ugu fiican tan iyo ma jiro enzyme homolog aadanaha.waxay hoos u dhigtaa duumada serine protease.51 Maslinic acid waa triterpenoid pentacyclic dabiici ah oo joojisa korriinka dulinnada laga soo bilaabo heerka giraanta ilaa heerka schizont, taas oo meesha ka saaraysa sii daynta merozoites iyo duulaankooda. -2 iyo falcipain-3.52 statins iyo xakamaynta borotiinka plasma by allophenostatin-ku salaysan inhibitors waxay ka hortagtaa hoos u dhaca hemoglobin waxayna dilaan dulinnada. .
Phosphoinotide lipid kinases (PIKs) waa enzymes meel kasta oo phosphorylate lipids si loo xakameeyo faafinta, badbaadada, ka ganacsiga, iyo calaamadaynta intracellular. Fasalada PIK ee ugu ballaadhan ee 53 dulin waa phosphoinositide 3-kinase (PI3K) iyo phosphatid-kinase (PI3K) iyo phosphatidyl4. Joojinta enzymes-yadan ayaa loo aqoonsaday inay tahay bartilmaameedka suurtagalka ah ee horumarinta dawooyinka ka hortagga duumada oo leh astaamo firfircoon oo la taaban karo oo loogu talagalay ka hortagga, daaweynta iyo baabi'inta duumada. (4)K iyo in ay joojiyaan horumarinta intracellular noocyada kala duwan ee Plasmodium marxalad kasta oo caabuqa martida loo yahay.Sidaa darteed, beegsiga (PI3K) iyo PI (4) K laga yaabaa in ay furto waddooyin cusub oo ku salaysan daawaynta bartilmaameedka daroogada si loo ogaado daawooyinka cusub ee ka hortagga duumada.KAF156 hadda waa in Wajiga II ee tijaabooyinka bukaan-socodyada.55,56 MMV048 waa isku-darka wanaagsan ee firfircoonida ka hortagga P. cynomolgi iyo suurtagalnimada as a gudbinta daawada xannibaysa.MMV048 waxay hadda ku socotaa Wajiga IIa tijaabooyin caafimaad gudaha Itoobiya.11
Si loo kobciyo degdega ah ee unugyada dhiigga cas ee caabuqa, noocyada Plasmodium waxay u baahan yihiin xaddi ku filan oo substrates si ay u fududeeyaan dheef-shiid kiimikaadkooda xoogga leh. Sidaa darteed, dulinku waxay diyaariyaan erythrocytes martigeliyaha iyaga oo keenaya gaadiidley khaas ah oo si weyn uga duwan gaadiidleyda unugyada martida loo yahay qaadashada iyo ka saarista dheef-shiid kiimikaadka. borotiinada xanbaarsan iyo kanaalada ayaa ah bartilmaameedyo suurtagal ah sababtoo ah doorkooda muhiimka ah ee qaadista dheef-shiid kiimikaadka, electrolytes iyo nafaqooyinka. galay dulinka unugyada gudaha.58
PSAC waa bartilmaameedka ugu rajo-gelinta badan sababtoo ah waxaa laga helaa noocyo kala duwan oo nafaqooyin ah (hypoxanthine, cysteine, glutamine, glutamate, isoleucine, methionine, proline, tyrosine, pantothenic acid iyo choline) si ay u helaan door muhiim ah dulinka unugyada gudaha. to known host channel genes.58,59 Phloridizin, dantrolene, furosemide, and niflunomide are potent anion transporter blockers.Daroogooyinka sida glyburide, meglitinide, iyo tolbutamide waxay xakameyaan qulqulka choline ee unugyada dhiiga cas ee dulin-faray.60,61
Nooca dhiigga ee Plasmodium falciparum wuxuu ku tiirsan yahay gebi ahaanba glycolysis wax soo saarka tamarta, iyada oo aan lahayn kayd tamar;Waxay ku tiirsan tahay qaadashada joogtada ah ee sonkorta. xuubka erythrocyte iyo dulin ay keentay 'dariiqa marin cusub'.63 Glucose waxa lagu qaadaa dulinnada Plasmodium falciparum hexose transporter (PFHT) D-glucose iyo D-fructose. Sidaa darteed, kala duwanaanshaha GLUT1 iyo PFHT isdhexgalka ee substrates waxay soo jeedinayaan in xannibaadda xulashada ee PFHT ay tahay bartilmaameed cusub oo rajo leh oo loogu talagalay horumarinta dawooyinka ka hortagga duumada.64 silsilad dheer oo O-3-hexose ah (isku dhafan 3361) waxay joojisaa qaadashada gulukooska iyo fructose ee PFHT, laakiin ma joojinayso gaadiidka hexose ee gulukooska naasleyda ee waaweyn iyo gaadiidka fructose (GLUT1 iyo 5) .Compound 3361 ayaa sidoo kale joojisay qaadashada gulukooska ee P. vivax of PFHT. Daraasadihii hore, 3361 waxay ku dileen P. falciparum dhaqanka waxayna hoos u dhigtay taranka P. berghei ee moodooyinka jiirka.65
Unugyada dhiigga ee Plasmodium-ku waxay inta badan ku xidhan yihiin glycolysis anaerobic ee koritaanka iyo horumarka.60 Unugyada dhiigga ee Parasite-ku ku dhacay waxay 100 jeer ka dhaqso badan yihiin unugyada dhiigga cas ee aan la qabin. habka calaamadaha H+ ee deegaanka dibadda.66 dhoofinta caanaha iyo qaadashada gulukooska ayaa muhiim u ah ilaalinta shuruudaha tamarta, pH intracellular, iyo xasilloonida osmotic dulin.Lactate:H + system symporter inhibition waa bartilmaameed cusub oo rajo ah oo loogu talagalay horumarinta dawooyinka cusub. Dhowr xeryo, sida MMV007839 iyo MMV000972, waxay dilaan dulinnada heerka dhiigga galciparum ee P. falciparum iyagoo joojinaya nuujinta: H+ gaadiidka.67
Sida noocyada kale ee unugyada, unugyada dhiigga cas ayaa ilaaliya heerarka hoose ee gudaha Na + si kastaba ha ahaatee, dulinku waxay kordhiyaan qulqulka xuubabka erythrocyte waxayna fududeeyaan gelitaanka Na +, taasoo keenta kororka cytoplasmic erythrocyte cytoplasmic Na + heerka dhexdhexaadinta unugyada ka baxsan. Sidaa darteed, dulinnada. Waxay isku arkaan warbaahinta sare ee Na+ waana inay ka saaraan Na+ ions xuubka balaasmaha si ay u ilaaliyaan heerarka cytoplasmic Na+ hooseeya si ay u noolaadaan inkastoo ay joogaan goobaha unugyada gudaha. Xaaladdan, Na+ qulqulka dulinka waxaa lagu maamulaa iyadoo la adeegsanayo nooca P-ATPase Transporter (PfATP4), kaas oo u shaqeeya sidii dulinka asaasiga ah ee Na+-eflux bamamka, sida ku cad Jaantuska 3.68, joojinta gaadiidkan Waxay horseedi doontaa korodhka qadarka Na+ ee gudaha dulin, taas oo ugu dambeyntii horseedi doonta dhimashada Duumada duumada. Dhowr xeryo, oo ay ku jiraan sipagamin ee wajiga 2, (+) -SJ733 ee wejiga 1, iyo KAE609 ee wejiga 2, waxay leeyihiin hab ficil oo bartilmaameedsanaya PfATP4.67,69
Jaantuska 3. Habka la soo jeediyay ee dulin-ku-noolayaasha PfATP4 iyo V-nooca H+-ATPase ee dhimashada erythrocyte ee cudurka qaba ka dib joojinta cipargamin.
Noocyada Plasmodium waxay xakameeyaan heerarkooda Na+ iyagoo isticmaalaya gaadiidka nooca P-ga ATPase.Waxay sidoo kale soo dejisaa H+ iyada oo loo marayo dariiq la mid ah. eryi H+. Samaynta dawo cusub waa yool rajo leh.MMV253 waxay joojisaa nooca V-H+ ATPase oo ah habkeeda ficilka ee xulashada beddelka iyo isku xigxiga-genome-ga dhan.70,71
Aquaporin-3 (AQP3) waa borotiinka kanaalka aquaglycerol kaas oo fududeeya dhaqdhaqaaqa biyaha iyo glycerol ee unugyada naasaha.AQP3 waxay ku dhacdaa hepatocytes ee bini'aadamka si ay uga jawaabto caabuqa dulin waxayna door muhiim ah ku leedahay dib-u-celinta dulin. berghei oo sahlaysa ku-noqoshada dulinka ee marxaladda asexual erythrocytes. falciparum parasitemia ee erythrocytes, oo soo jeedinaysa in borotiinka martida loo yahay ay door muhiim ah ka ciyaaraan marxaladaha nolosha ee kala duwan ee dulin .73 Inta badan, carqaladaynta AQP3 ee jiirarka hidde-socodka maaha mid halis ah, taas oo soo jeedinaysa in borotiinka martida loo yahay uu leeyahay bartilmaameed cusub oo daaweyn ah. fahamka hababka beerka martida loo yahay ee uu saameeyay caabuqa Plasmodium waxayna muujinaysaa kartida pro- kuwanjoojiya sidii dawooyinka ka hortagga duumada mustaqbalka.71,72
Phospholipids waxay door muhiim ah ka ciyaaraan wareegga nolosha intra-erythrocyte ee Plasmodium falciparum, labadaba sida qaybaha qaab dhismeedka ee xuubabka iyo sida molecule regulatory ee nidaamiya hawlaha enzymes kala duwan. Unugyadan ayaa lagama maarmaan u ah taranka dulin gudaha unugyada dhiigga cas.Ka dib duulaanka erythrocyte, Heerarka phospholipid ayaa kordha, kaas oo phosphatidylcholine uu yahay dufanka ugu weyn qaybaha xuubka unugga taasoo keentay dhimashada dulinka.74 Albitiazolium, oo ah daawo soo gashay marxaladaha labaad ee tijaabada ah, waxay u shaqaysaa ugu horrayn iyada oo la joojinayo gaadiidka choline ee dulinnada. Xaalado. Waxaa xusid mudan, hal cirbad oo keliya ayaa bogsatay parasitemia heerarka.75,76
Phosphocholine cytidyltransferase waa heerka-xaddidaadda tallaabada de novo biosynthesis of phosphatidylcholine.77 The diquaternary ammonium compound G25 iyo xarunta tilmaanta T3 inhibit phosphatidylcholine synthesis in dulin.G25 waa 1000-laab ka yar yihiin khadadka sunta ah ee mammalian daawooyinka. xeryahooda ku jira daahfurka iyo horumarinta daawada ka hortagga duumada.78,79
Tillaabada muhiimka ah ee faafinta noocyada Plasmodium ee dadka martida loo yahay waa qaybinta ballaaran oo degdegga ah ee DNA-da dulin, taas oo ku xidhan helitaanka dheef-shiid kiimikaadka muhiimka ah sida pyrimidine. glycoproteins. Nucleotide synthesis waxay raacdaa laba dariiqo oo waaweyn: waddada badbaadada iyo waddada de novo. Waxay ka dhigan tahay bartilmaameed rajo leh oo loogu talagalay horumarinta daawada ka hortagga duumada.80 Unugyada bini'aadamka waxay helayaan pyrimidines iyagoo badbaadinaya pyrimidine hore loo sameeyay ama de novo synthesis. Haddii jidka de novo biosynthetic la xannibo, unuggu wuxuu ku tiirsan yahay waddada badbaadada unuguna ma dhiman doono. Si kastaba ha ahaatee, joojinta de novo pyrimidine biosynthesis ee dulinnada waxay keentaa dhimashada unugyadaas sababtoo ahDulmiga duumada ayaa ka maqan dariiqa badbaadada ee pyrimidine, taas oo ka dhigaysa dulin u nugul in la xakameeyo DHODH.81 DSM190 iyo DSM265 waa horjoogayaasha xulashada ee dulin DHODH enzyme, taas oo hadda ku jirta marxaladda 2 ee tijaabooyinka bukaan-socodka.P218 waa DHODH inhibitor wax ku ool ah dhammaan pyrimethamine. Noocyada adkeysi leh ee hadda ku jira Wajiga 1.KAF156 (Ganaplacide) ayaa hadda ku jira tijaabada caafimaad ee Wajiga 2b ee phenylfluorenol.82
Isoprenoids waxaa looga baahan yahay beddelka dufanka dambe ee borotiinka iyo taranka galmada ee Plasmodium falciparum. Jidka iyo 2C-methyl-D-erythritol 4-phosphate (MEP) dariiqa. Inta badan microorganisms, labadan dariiqo waa kuwo iska soo horjeeda. Dariiqa MEP waxaa loo sahamiyaa sidii bartilmaameedyo daweyn oo cusub oo suurtagal ah. .83,84 PfDXR inhibitors waxay joojisaa Plasmodium falciparum. Plasmodium falciparum way koraan waana wax aan sun ahayn unugyada aadanaha.PfDXR waa bartilmaameed cusub oo suurtagal ahhorumarinta daawada ka hortagga duumada.83 Fosmidomycin, MMV019313 iyo MMV008138 waxay joojiyaan DOXP reductoisomerase, oo ah enzyme muhiimka ah ee waddada DOXP ee ka maqan aadanaha
Borotiinnada prenylated ayaa door muhiim ah ka ciyaara hababka kala duwan ee unugyada oo ay ku jiraan ka ganacsiga vesicle, beddelka calaamadaha, habaynta DNA-da, iyo qaybinta unugyada. wareejinta kooxda farnesyl, 15-carbon isoprenoid lipid unit, laga bilaabo farnesyl pyrophosphate ilaa C-terminus ee borotiinada ka kooban motif CaaX.Farnesyltransferase waa bartilmaameed cusub oo loogu talagalay horumarinta dawooyinka ka hortagga duumada sababtoo ah ka hortagga waxay dishaa dulin.86
Markii hore, kobcinta iska caabinta dulin ee farnesyltransferase inhibitor BMS-388,891 tetrahydroquinoline waxay muujisay isbeddel ku yimaada borotiinka substrate-ka-xukunka peptide. Doorashada tetrahydroquinoline kale oo leh BMS-339,941, isbeddel ayaa laga helay farnesyl binding pyrophosphate Daraasad kale, isbeddellada ayaa laga helay qaybta farnesyltransferase beta subunit ee MMV019066-adkeysiga u adkaysta ee P. falciparum. Daraasadaha qaabaynta ayaa muujiyay in isbeddelku uu leexiyo goobta muhiimka ah ee isdhexgalka molecule yar yar oo leh goobta firfircoon ee farnesylation, taasoo keentay iska caabbinta daroogada. .87
Mid ka mid ah yoolalka rajo-gelinta ah ee horumarinta dawooyinka cusub waa in la xannibo P. falciparum ribosome, iyo sidoo kale qaybaha kale ee mishiinka tarjumaadda ee mas'uulka ka ah isku-darka borotiinka. Noocyada Plasmodium waxay leeyihiin saddex genomes: nucleus, mitochondria, iyo acroplasts (laga bilaabo chloroplasts haraaga). Dhammaan genome-yada waxay u baahan yihiin mashiinnada tarjumaadda si ay u shaqeeyaan. P. falciparum ribosome waxay ku jirtaa meel dhexe oo horumarsan oo u dhaxaysa prokaryotes iyo eukaryotes, taasoo si muuqata uga soocanaysa ribosomeka bini'aadamka sidaas darteedna waxay siinaysaa bartilmaameed cusub oo rajo leh. ee ribosomes weheliso qasanenger RNA waxayna lagama maarmaan u tahay isku dhafka borotiinka ee eukaryotes.
Joojinta isku-dhafka borotiinka Qaado helitaanka sordarin, badeecad dabiici ah oo si xushmad leh u xannibaysa isku-darka borotiinka fangas iyada oo la xakameynayo khamiirka eukaryotic elongation factor 2. Similarly, M5717 (oo hore u ahaa DDD107498), xakameynta xulashada ee 80S ribosome-isdhexgalka PfEF2 ayaa hadda ah. 1 daraasado, ansaxiyay awoodda PfEF2 oo ah bartilmaameed wax ku ool ah oo loogu talagalay dawooyinka ka hortagga duumada.88,90
Astaamaha ugu muhiimsan ee duumada ba'an waa kala-soocidda erythrocytes ee dulin-ku-takoorka, caabuqa, iyo xannibaadda microvasculature. Plasmodium falciparum waxay isticmaashaa heparan sulfate sida ay ugu dhejiso endothelium iyo unugyada kale ee dhiigga, taasoo keenta xannibaadda socodka dhiigga. Joojinta unugyadan aan caadiga ahayn iyo pathogene -Isdhexgalka dawadu waxa ay soo celisaa socodka dhiiga ee xidhmay waxana ay saamaysaa korriinka dulinka.91
Daraasado dhowr ah ayaa muujiyay in sevuparin, polysaccharide anti-adhesion oo laga sameeyay heparin, ay leedahay saameynaha baabi'inta antithrombin.Sevuparin waxay joojisaa duulaanka merozoite ee erythrocytes, xidhitaanka erythrocytes ee caabuqa ee erythrocytes ee aan caabuqa lahayn iyo caabuqa, iyo isku xidhka unugyada endothelial ee xididdada dhiigga. ilaa N-terminal extracellular heparan sulfate-binding dhismeedka Plasmodium falciparum erythrocyte xuubka borotiinka 1, Duffy-binding-like domain 1α (DBL1α), waxaana loo maleynayaa inay tahay arrin muhiim u ah soo saarista erythrocytes cudurka qaba.92,93 Shaxda 2 ayaa soo koobaysa. tijaabooyin caafimaad oo heerar kala duwan ah.
Waqtiga boostada: Mar-24-2022