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Ngokuthuthuka okuqhubekayo kobuchwepheshe bebhayoloji yamangqamuzana, ubudlelwano phakathi kokuguqulwa kwezakhi zofuzo kanye nokukhubazeka nezifo buye bazuza ukuqonda okujulile.Ama-Nucleic acid adonse ukunaka okukhulu ngenxa yamandla awo amakhulu okusetshenziswa ekuxilongeni nasekwelapheni izifo.Izidakamizwa ze-Nucleic acid zibhekisela ezingxenyeni zokwenziwa ze-DNA noma ze-RNA ezinemisebenzi yokwelapha izifo.Izidakamizwa ezinjalo zingasebenza ngokuqondile kuzakhi zofuzo ezihlosiwe ezibangela izifo noma ama-mRNA ahlosiwe abangela izifo, futhi abambe iqhaza ekwelapheni izifo ezingeni lofuzo.Uma kuqhathaniswa nezidakamizwa ze-molecule ezincane zendabuko kanye nezidakamizwa ze-antibody, izidakamizwa ze-nucleic acid zingalawula ukubonakaliswa kwezakhi zofuzo ezibangela izifo ezivela empandeni, futhi zibe nezici "zokwelapha izimpawu nokwelapha imbangela".Izidakamizwa ze-Nucleic acid nazo zinezinzuzo ezisobala ezifana nokusebenza kahle okuphezulu, ubuthi obuphansi, nokucaciswa okuphezulu.Kusukela umuthi wokuqala we-nucleic acid i-fomivirsen sodium yethulwa ngo-1998, izidakamizwa eziningi ze-nucleic acid sezigunyazwe ukwelashwa komtholampilo.

Izidakamizwa ze-nucleic acid njengamanje ezimakethe emhlabeni jikelele ikakhulukazi zifaka i-antisense nucleic acid (ASO), i-RNA encane ephazamisayo (siRNA), kanye nama-nucleic acid aptamers.Ngaphandle kwama-nucleic acid aptamers (angase adlule ama-nucleotide angu-30), izidakamizwa ze-nucleic acid ngokuvamile ama-oligonucleotides akhiwa ama-nucleotide angu-12 kuya kwangu-30, aziwa nangokuthi izidakamizwa ze-oligonucleotide.Ngaphezu kwalokho, ama-miRNA, ama-ribozyme kanye nama-deoxyribozyme nawo abonise ukubaluleka okukhulu kwentuthuko ekwelapheni izifo ezihlukahlukene.Izidakamizwa ze-Nucleic acid seziphenduke enye yezinkambu ezithembisa kakhulu ocwaningweni nasekuthuthukisweni kwe-biomedicine namuhla.

Izibonelo zemithi egunyaziwe ye-nucleic acid

asdsada

I-Antisense nucleic acid

Ubuchwepheshe be-Antisense ubuchwepheshe obusha bokuthuthukiswa kwezidakamizwa obususelwe kumgomo wokuphelelisa isisekelo se-Watson-Crick, kusetshenziswa izingcezu ezithile ze-DNA noma ze-RNA ezihlanganiswe ngokuzenzakalelayo noma ezihlanganiswe umzimba ukuze kulawulwe ngokukhethekile ukuvezwa kofuzo oluqondiwe.I-antisense nucleic acid inokulandelana kwesisekelo okuhambisana ne-RNA eqondiwe futhi ingabophezela kuyo ngokuqondile.Ama-nucleic acid e-Antisense ngokuvamile ahlanganisa i-antisense DNA, i-antisense RNA nama-ribozymes.Phakathi kwazo, ngenxa yezimpawu zokuzinza okuphezulu kanye nezindleko eziphansi ze-antisense DNA, i-antisense DNA ithatha isikhundla esiphezulu ocwaningweni lwamanje nasekusetshenzisweni kwezidakamizwa ze-antisense nucleic acid.

I-Fomivirsen sodium (igama lokuhweba i-Vitravene) yasungulwa ngu-Ionis Novartis.Ngo-August 1998, i-FDA yasigunyaza ukuba selashwe i-cytomegalovirus retinitis ezigulini ezingenawo amandla omzimba (ikakhulukazi iziguli ze-AIDS), kwaba umuthi wokuqala we-nucleic acid okumele udayiswe.I-Fomivirsen ivimbela ukubonakaliswa kwengxenye yephrotheni ye-CMV ngokubophezela ku-mRNA ethile (IE2), ngaleyo ndlela ilawule ukuvezwa kwezakhi zofuzo zegciwane ukuze kuzuzwe imiphumela yokwelapha.Kodwa-ke, ngenxa yokuvela kokwelashwa ngezidambisigciwane ezisebenza kahle kakhulu, okunciphise kakhulu isibalo seziguli, ngo-2002 nango-2006, uNovartis wakhansela ukugunyazwa kwemakethe kwezidakamizwa ze-Fomivirsen eYurophu nase-United States ngokulandelana, futhi umkhiqizo umisiwe emakethe.

I-Mipomersen sodium (igama lokuhweba i-Kynamro) umuthi we-ASO owakhiwa inkampani yaseFrance i-Genzyme.NgoJanuwari 2013, i-FDA yagunyaza ukwelashwa kwe-homozygous family hypercholesterolemia.I-Mipomersen ivimbela ukuvezwa kweprotheyini ye-ApoB-100 (apolipoprotein) ngokubophezela ku-ApoB-100mRNA, ngaleyo ndlela yehlise ngokuphawulekayo i-cholesterol yomuntu ephansi-density lipoprotein, low-density lipoprotein nezinye izinkomba, kodwa ngenxa yemiphumela engemihle efana nobuthi besibindi, Disemba 13, 2012 isicelo sokuthengiswa kwezidakamizwa kwe-EMA futhi ngosuku olufanayo lwenqaba isicelo.

NgoSepthemba 2016, i-Eteplirsen (igama lokuhweba i-Exon 51) eyakhiwe yi-Sarepta yokwelapha i-Duchenne muscular dystrophy (DMD) yagunyazwa yi-FDA.Iziguli ze-DMD ngokuvamile azikwazi ukuveza amaprotheni asebenzayo e-anti-atrophic ngenxa yokuguqulwa kwezakhi zofuzo ze-DMD emzimbeni.I-Eteplirsen ibophezela ngokuqondile ku-exon 51 ye-pre-messenger RNA (Pre-mRNA) yephrotheni, ikhipha i-exon 51, futhi ibuyisela ezinye izakhi zofuzo ezansi nomfula Isisho esivamile se-, ukuloba nokuhumusha ukuze kutholwe ingxenye ye-dystrophin, ukuze kuzuzwe umphumela wokwelapha.

I-Nusinersen iyisidakamizwa se-ASO esakhiwe yi-Spinraza ukuze zokwelapha i-spinal muscular atrophy futhi yagunyazwa yi-FDA ngo-December 23, 2016. Ngo-2018, i-Inotesen eyakhiwe ngu-Tegsedi yokwelashwa kwe-hereditary transthyretin amyloidosis yabantu abadala yagunyazwa yi-FDA.Ngo-2019, iGolodirsen, eyakhiwe ngabakwaSarepta yokwelapha i-Duchenne muscular dystrophy, yagunyazwa yi-FDA.Inendlela yokusebenza efana ne-Eteplirsen, futhi indawo yayo yokusebenza iba yi-exon 53. Ngawo lowo nyaka, iVolanesorsen, ithuthukiswe ngokuhlanganyela yi-Ionisand Akcea yokwelapha i-hyperchylomicronemia yomndeni, yagunyazwa yi-European Medicines Agency (EMA).I-Volanesorsen ilawula i-triglyceride metabolism ngokuvimbela ukukhiqizwa kwe-apolipoprotein C-Ⅲ, kodwa futhi inomphumela oseceleni wokwehlisa amazinga e-platelet.

 

I-Defibrotide iyingxube ye-oligonucleotide enezakhiwo ze-plasmin ezakhiwe yi-Jazz.Iqukethe u-90% we-DNA enomucu owodwa kanye ne-10% ye-DNA ephindwe kabili.Yagunyazwa yi-EMA ngo-2013 futhi yavunyelwa yi-FDA yokwelashwa kwemithambo ye-hepatic enzima.Isifo se-Oclusive.I-Defibrotide ingakhuphula umsebenzi we-plasmin, ikhulise i-activator ye-plasminogen, ikhuthaze ukulawulwa okuphezulu kwe-thrombomodulin, futhi yehlise ukubonakaliswa kwe-von Willebrand factor kanye ne-plasminogen activator inhibitors ukuze kuzuzwe imiphumela yokwelapha.

siRNA     

I-siRNA iwucezu oluncane lwe-RNA olunobude obuthile nokulandelana okukhiqizwe ngokusika i-RNA eqondiwe.Lawa ma-siRNA angaheha ngokuqondile ukucekelwa phansi kwethagethi ye-mRNA futhi azuze imiphumela yokuthulisa izakhi zofuzo.Uma kuqhathaniswa nezidakamizwa ze-molecule encane yamakhemikhali, umphumela wokuthulisa ufuzo wezidakamizwa ze-siRNA unokucaciswa okuphezulu nokusebenza kahle.

Ngo-Agasti 11, 2018, umuthi wokuqala we-siRNA patisiran (igama lokuhweba elithi Onpattro) wagunyazwa yi-FDA futhi wethulwa ngokusemthethweni.Lesi esinye sezigigaba ezinkulu emlandweni wokuthuthukiswa kobuchwepheshe bokuphazamiseka kwe-RNA.I-Patsiran yasungulwa ngokuhlanganyela yi-Alnylam kanye ne-Genzyme, inkampani ephethwe yi-Sanofi.Kuwumuthi we-siRNA wokwelapha i-thyroxine-mediated amyloidosis yofuzo.Ngo-2019, i-givosiran (igama lokuhweba elithi Givlaari) yagunyazwa yi-FDA njengomuthi wesibili we-siRNA wokwelapha i-acute hepatic porphyria kubantu abadala.Ngo-2020, i-Alnylam yasungula umuthi oyinhloko wohlobo I wokwelapha izingane kanye nabantu abadala.I-Lumasiran ene-oxaluria ephezulu ivunywe yi-FDA.NgoDisemba 2020, i-Inclisiran, eyakhiwe ngokuhlanganyela i-Novartis kanye ne-Alnylam yokwelapha i-hypercholesterolemia yabantu abadala noma i-dyslipidemia exubile, yagunyazwa yi-EMA.

I-Aptamer

Ama-aptamers e-Nucleic acid angama-oligonucleotide angabophezela ezinhlobonhlobo zama-molecule aqondiwe njengama-molecule amancane e-organic, i-DNA, i-RNA, i-polypeptides noma amaprotheni anobungane obuphezulu kanye nokucaciswa okuthile.Uma kuqhathaniswa nama-antibodies, ama-nucleic acid aptamers anezici zokuhlanganisa okulula, izindleko eziphansi kanye nohlu olubanzi lwezinhloso, futhi anamandla abanzi okusetshenziswa kwezidakamizwa ekuxilongweni kwezifo, ekwelapheni nasekuvimbeleni.

I-Pegaptanib umuthi wokuqala we-nucleic acid aptamer owakhiwe yi-Valeant ukuze welaphe ukuwohloka kwe-macular emanzi ehlobene neminyaka futhi yavunywa yi-FDA ngo-2004. Ngokulandelayo, yagunyazwa yi-EMA kanye ne-PMDA ngoJanuwari 2006 kanye noJulayi 2008 futhi yangena emakethe.I-Pegaptanib ivimbela i-angiogenesis ngokuhlanganiswa kwesakhiwo sendawo kanye ne-vascular endothelial growth factor ukuze kuzuzwe imiphumela yokwelapha.Kusukela lapho, ihlangabezane nokuncintisana kwezidakamizwa ezifanayo i-Lucentis, futhi isabelo sayo semakethe sehle kakhulu.

Izidakamizwa ze-Nucleic acid seziphenduke indawo eshisayo emithini yomtholampilo kanye nemakethe yezidakamizwa emisha ngenxa yomphumela wazo omangalisayo wokwelapha kanye nomjikelezo wokuthuthuka omfushane.Njengesidakamizwa esisafufusa, sibhekana nezinselelo ngenkathi sibhekene namathuba.Ngenxa yezici zayo zangaphandle, ukucaciswa, ukuzinza kanye nokulethwa okusebenzayo kwama-nucleic acid sekube yimibandela eyinhloko yokwahlulela ukuthi i-oligonucleotides ingaba izidakamizwa ezisebenza kahle kakhulu ze-nucleic acid.Imiphumela engekho ekuhlosweni ibilokhu iyiphuzu eliyinhloko lezidakamizwa ze-nucleic acid ezingenakunakwa.Kodwa-ke, izidakamizwa ze-nucleic acid zingathinta ukubonakaliswa kwezakhi zofuzo ezibangela izifo ezivela empandeni, futhi zingafinyelela ukucaciswa kokulandelana ezingeni elilodwa lesisekelo, elinezici "zokwelapha imbangela nokwelapha izimpawu".Ngenxa yokuhlukahluka kwezifo eziningi, ukwelashwa kwezakhi zofuzo kuphela kungafinyelela imiphumela ehlala njalo.Ngokuthuthuka okuqhubekayo, ukuphelela nokuthuthuka kobuchwepheshe obuhlobene, izidakamizwa ze-nucleic acid ezimelwe ama-antisense nucleic acids, i-siRNA, nama-nucleic acid aptamers ngokuqinisekile azosusa igagasi elisha ekwelapheni izifo nasembonini yezemithi.

Rizinkomba:

[1] Liu Shaojin, Feng Xuejiao, Wang Junshu, Xiao Zhengqiang, Cheng Pingsheng.Ukuhlaziywa kwemakethe kwezidakamizwa ze-nucleic acid ezweni lami kanye nezinyathelo zokuphikisa[J].I-Chinese Journal of Biological Engineering, 2021, 41(07): 99-109.

[2] Chen Wenfei, Wu Fuhua, Zhang Zhirong, Sun Xun.Inqubekelaphambili yocwaningo ku-pharmacology yezidakamizwa ze-nucleic acid[J].Ijenali yesiShayina Yemithi, 2020, 51(12): 1487-1496.

[3] Wang Jun, Wang Lan, Lu Jiazhen, Huang Zhen.Ukuhlaziywa kokusebenza kahle nenqubekelaphambili yocwaningo lwezidakamizwa ezimakethwayo ze-nucleic acid[J].Ijenali yesiShayina Yezidakamizwa Ezintsha, 2019, 28(18): 2217-2224.

Mayelana nombhali: U-Sha Luo, isisebenzi socwaningo lwemithi yaseShayina kanye nentuthuko, njengamanje usebenzela inkampani enkulu yasekhaya yocwaningo nentuthuko yezidakamizwa, futhi uzibophezele ocwaningweni nasekuthuthukisweni kwemithi emisha yamaShayina.

Imikhiqizo ehlobene:

Ikhithi ye-Cell Direct RT-qPCR


Isikhathi sokuthumela: Nov-19-2021