Umthombo: Medical Micro
Emva kokuqhambuka kwe-COVID-19, izitofu ezimbini ze-mRNA zamkelwa ngokukhawuleza ukuba zithengiswe, nto leyo ithe yatsala ingqalelo engakumbi kuphuhliso lwamachiza e-nucleic acid.Kwiminyaka yakutshanje, inani leziyobisi ze-nucleic acid ezinokuthi zibe ngamachiza e-blockbuster ziye zapapasha idatha yeklinikhi, egubungela intliziyo kunye nezifo ze-metabolic, izifo zesibindi, kunye neentlobo zezifo ezinqabileyo.Amachiza e-Nucleic acid alindeleke ukuba abe ngamachiza alandelayo emolekyuli encinci kunye namachiza e-antibody.Uhlobo lwesithathu ngobukhulu lwechiza.
Udidi lweziyobisi zeNucleic acid
I-Nucleic acid yi-biological macromolecular compound eyenziwe yi-polymerization yee-nucleotides ezininzi, kwaye yenye yezona zinto zisisiseko zobomi.Izidakamizwa ze-Nucleic acid ziyi-oligoribonucleotides (RNA) okanye i-oligodeoxyribonucleotides (i-DNA) enemisebenzi eyahlukeneyo, enokuthi isebenze ngokuthe ngqo kwiijene ezijoliswe kuzo ezibangelwa izifo okanye zijolise kwi-mRNAs ukunyanga izifo kwinqanaba le-gene Indima ye.
▲ Inkqubo yokudibanisa ukusuka kwi-DNA ukuya kwi-RNA ukuya kwiprotheni (Umthombo womfanekiso: bing)
Okwangoku, iziyobisi eziphambili ze-nucleic acid ziquka i-antisense nucleic acid (ASO), i-RNA encinci ephazamisayo (i-siRNA), i-microRNA (i-miRNA), i-RNA encinci (i-saRNA), i-RNA yesithunywa (i-mRNA), i-aptamer, kunye ne-ribozyme., Antibody nucleic acid conjugated drugs (ARC), njl.
Ukongeza kwi-mRNA, uphando kunye nophuhliso lwamanye amachiza e-nucleic acid nawo afumene ingqalelo engakumbi kwiminyaka yakutshanje.Kwi-2018, iyeza lokuqala lehlabathi le-siRNA (i-Patisiran) livunyiwe, kwaye yayiyi-nucleic acid yokuqala yeziyobisi ukusebenzisa inkqubo yokuhanjiswa kwe-LNP.Kwiminyaka yakutshanje, isantya semarike samachiza e-nucleic acid siye sakhula.Kwi-2018-2020 kuphela, kukho i-4 siRNA iziyobisi, amachiza amathathu e-ASO avunyiwe (i-FDA kunye ne-EMA).Ukongeza, i-Aptamer, i-miRNA kunye nezinye iindawo nazo zinamachiza amaninzi kwinqanaba lekliniki.
Izinto eziluncedo kunye nemingeni yeziyobisi ze-nucleic acid
Ukusukela ngeminyaka yoo-1980, uphando kunye nophuhliso lwamachiza amatsha asekelwe ekujoliswe kuwo luye lwanda ngokuthe ngcembe, kwaye inani elikhulu lamachiza amatsha afunyenwe;Amachiza ekhemikhali amancinci emveli kunye namachiza e-antibody omabini enza iziphumo zekhemesti ngokubophelela kwiiproteni ezijoliswe kuzo.Iiprotheni ezijoliswe kuzo zinokuba yi-Enzymes, i-receptors, iziteshi ze-ion, njl.
Nangona iziyobisi ezincinci ze-molecule zineenzuzo zokuvelisa lula, ukulawulwa komlomo, iipropati ezingcono ze-pharmacokinetic, kunye nokuhamba ngokulula kwiimbumba zeseli, uphuhliso lwazo luchatshazelwa yi- druggability yethagethi (kunye nokuba iprotheni ekujoliswe kuyo inesakhiwo esifanelekileyo sepokotho kunye nobukhulu)., Ubunzulu, i-polarity, njl.);ngokwenqaku kwi-Nature2018, kuphela i-3,000 ye- ~ 20,000 iiprotheyini ezifakwe kwi-genome yomntu ingaba ngamayeza, kwaye kuphela i-700 inamachiza ahambelanayo aphuhlisiwe (kwi-Ikakhulu i-molecules ezincinci).
Inzuzo enkulu yeziyobisi ze-nucleic acid kukuba amachiza ahlukeneyo anokuphuhliswa kuphela ngokutshintsha ukulandelelana kwesiseko se-nucleic acid.Xa kuthelekiswa neziyobisi ezisebenza kwinqanaba leprotheyini yemveli, inkqubo yophuhliso lwayo ilula, iyasebenza, kwaye igxile kwibhayoloji;xa kuthelekiswa ne-genomic DNA-level treatment, iziyobisi ze-nucleic acid azikho umngcipheko wokuhlanganiswa kwe-gene kwaye ziguquguquka ngakumbi ngexesha lonyango.Iyeza linokuyekwa xa kungekho nyango lufunekayo.
Amachiza e-Nucleic acid aneenzuzo ezicacileyo ezifana nokucaciswa okuphezulu, ukusebenza kakuhle kunye nomphumo wexesha elide.Nangona kunjalo, ngeenzuzo ezininzi kunye nophuhliso olukhawulezileyo, iziyobisi ze-nucleic acid nazo zijongene nemingeni eyahlukeneyo.
Enye kukuguqulwa kwe-RNA ukunyusa ukuzinza kweziyobisi ze-nucleic acid kunye nokunciphisa i-immunogenicity.
Okwesibini kukuphuhliswa kwabathwali ukuqinisekisa ukuzinza kwe-RNA ngexesha lenkqubo yokudlulisa i-nucleic acid kunye neziyobisi ze-nucleic acid ukufikelela kwiiseli ezijoliswe kuzo / izitho ekujoliswe kuzo;
Eyesithathu kukuphuculwa kwenkqubo yokuhanjiswa kweziyobisi.Indlela yokuphucula inkqubo yokuhanjiswa kweziyobisi ukufezekisa umphumo ofanayo kunye needosi eziphantsi.
Ukuguqulwa kweekhemikhali zamachiza e-nucleic acid
Amachiza e-nucleic acid angaphandle kufuneka anqobe imiqobo emininzi ukuze angene emzimbeni ukuze adlale indima.Le miqobo ibangele ubunzima ekuphuhliseni amachiza e-nucleic acid.Nangona kunjalo, ngokuphuhliswa kobuchwepheshe obutsha, ezinye zeengxaki sele zisonjululwe ngokuguqulwa kweekhemikhali.Kwaye impumelelo kwitekhnoloji yenkqubo yonikezelo idlale indima ebalulekileyo ekuphuhliseni amachiza e-nucleic acid.
Ukuguqulwa kweekhemikhali kunokuphucula amandla amachiza e-RNA ukuxhathisa ukuthotywa yi-endonucleases engapheliyo kunye ne-exonucleases, kunye nokuphucula kakhulu ukusebenza kwamachiza.Kumachiza e-siRNA, ukuguqulwa kweekhemikhali kunokuphucula ukukhethwa kwemicu yabo ye-antisense ukunciphisa umsebenzi we-RNAi ekujoliswe kuyo, kunye nokutshintsha iipropati zomzimba kunye neekhemikhali ukwandisa amandla okuhambisa.
1. Ukuguqulwa kweekhemikhali zeswekile
Kwinqanaba lokuqala lophuhliso lweziyobisi ze-nucleic acid, iikhompawundi ezininzi ze-nucleic acid zibonise umsebenzi olungileyo webhayoloji kwi-vitro, kodwa umsebenzi wabo kwi-vivo wancitshiswa kakhulu okanye walahleka ngokupheleleyo.Isizathu esiphambili kukuba i-nucleic acids engatshintshiyo ichithwa ngokulula ngama-enzymes okanye ezinye izinto ezingapheliyo emzimbeni.Ukuguqulwa kweekhemikhali zeswekile ikakhulu kubandakanya ukuguqulwa kwe-2-position hydroxyl (2'OH) yeswekile kwi-methoxy (2'OMe), i-fluorine (F) okanye (2'MOE).Olu hlengahlengiso lunokwandisa ngempumelelo umsebenzi kunye nokukhetha, ukunciphisa imiphumo ekujoliswe kuyo, kunye nokunciphisa imiphumo emibi.
▲ Ukuguqulwa kweekhemikhali zeswekile (umthombo womfanekiso: isalathisi 4)
2. Ukuguqulwa kwamathambo e-Phosphoric acid
Eyona nto isetyenziswa ngokuqhelekileyo ukuguqulwa kweekhemikhali ze-phosphate backbone yi-phosphorothioate, oko kukuthi, i-oksijini engekho i-bridging kwi-phosphate backbone ye-nucleotide ithathelwe indawo yesulfure (ukuguqulwa kwe-PS).Ukuguqulwa kwe-PS kunokumelana nokuthotywa kwe-nucleases kunye nokuphucula ukusebenzisana kweziyobisi ze-nucleic acid kunye neeprotheni ze-plasma.Umthamo wokubopha, ukunciphisa izinga lokucocwa kwezintso kunye nokunyusa isiqingatha sobomi.
▲ Ukuguqulwa kwe-phosphorothioate (umthombo womfanekiso: isalathisi 4)
Nangona i-PS inokunciphisa ukudibanisa kwe-nucleic acids kunye ne-target genes, ukuguqulwa kwe-PS kuninzi kwe-hydrophobic kwaye kuzinzile, ngoko ke kusengukuguqulwa okubalulekileyo ekuphazamiseni i-nucleic acids encinci kunye ne-antisense nucleic acids.
3. Ukuguqulwa komsesane onamalungu amahlanu e-ribose
Ukuguqulwa komsesane onamalungu amahlanu e-ribose kuthiwa yisizukulwana sesithathu sokuguqulwa kweekhemikhali, kubandakanywa i-nucleic acid-itshixiwe i-nucleic acid BNAs, i-peptide nucleic acid PNA, i-phosphorodiamide morpholino oligonucleotide PMO, ezi zilungiso zinokuphucula ngakumbi i-nucleic acid iziyobisi Ukuchasana, ukuphuculwa kwe-nucleases, njl njl.
4. Okunye ukuguqulwa kweekhemikhali
Ukuphendula kwiimfuno ezahlukeneyo zeziyobisi ze-nucleic acid, abaphandi bavame ukwenza ukuguqulwa kunye nokuguqulwa kwiziseko kunye neentambo ze-nucleotide ukwandisa ukuzinza kweziyobisi ze-nucleic acid.
Ukuza kuthi ga ngoku, onke amachiza ajoliswe kwi-RNA avunywe yi-FDA awenziwe ngamachiza e-RNA analogs, exhasa ukusetyenziswa kokuguqulwa kweekhemikhali.I-oligonucleotides enemisonto enye kwiindidi ezithile zokuguqulwa kweekhemikhali zihluke kuphela ngokulandelelana, kodwa zonke zineempawu ezifanayo zomzimba kunye neekhemikhali, kwaye ngoko ke zineempawu eziqhelekileyo ze-pharmacokinetics kunye ne-biological properties.
Ukuhanjiswa kunye nokulawulwa kweziyobisi ze-nucleic acid
Izidakamizwa ze-Nucleic acid ezithembele kuphela ekuguqulweni kweekhemikhali ziselula ngokukhawuleza ngokukhawuleza kwi-blood circulation, akulula ukuqokelela kwizicubu ezijoliswe kuyo, kwaye akulula ukungena ngokufanelekileyo kwi-membrane yeseli ekujoliswe kuyo ukufikelela kwindawo yesenzo kwi-cytoplasm.Ngoko ke, amandla enkqubo yokuhanjiswa ayafuneka.
Okwangoku, iivectors zamachiza e-nucleic acid zahlulwe ikakhulu kwi-viral and non-viral vectors.Owokuqala uquka i-adenovirus-associated virus (AAV), i-lentivirus, i-adenovirus kunye ne-retrovirus, njl. Ezi ziquka abathwali be-lipid, i-vesicles kunye nokunye.Ngokombono wamachiza athengiswayo, ii-viral vectors kunye nabathwali be-lipid bakhulile ngakumbi ekuhanjisweni kwamachiza e-mRNA, ngelixa iziyobisi ezincinci ze-nucleic acid zisebenzisa abathwali abaninzi okanye iiplatifomu zobuchwepheshe ezifana ne-liposomes okanye i-GalNAc.
Ukuza kuthi ga ngoku, uninzi lwezonyango ze-nucleotide, ezibandakanya phantse zonke iziyobisi ezivunyiweyo ze-nucleic acid, ziye zalawulwa ekuhlaleni, njengamehlo, intambo yomgogodla kunye nesibindi.I-Nucleotides idla ngokuba yi-hydrophilic polyanions enkulu, kwaye le propati ithetha ukuba ayinakudlula ngokulula kwi-membrane ye-plasma.Ngelo xesha, iziyobisi zonyango ezisekelwe kwi-oligonucleotide ngokuqhelekileyo azikwazi ukuwela umqobo we-blood-brain barrier (BBB), ngoko ke ukuhanjiswa kwinkqubo ye-nervous central (CNS) ngumngeni olandelayo kwi-nucleic acid drug.
Kuyafaneleka ukuba uqaphele ukuba uyilo lokulandelelana kwe-nucleic acid kunye nokuguqulwa kwe-nucleic acid okwangoku kugxilwe ingqalelo yabaphandi kwintsimi.Ukulungiswa kweekhemikhali, i-nucleic acid eguqulwe ngamachiza, i-nucleic acid engeyiyo yendalo yoyilo okanye uphuculo lokulandelelana kwe-nucleic acid, ukwakhiwa kwe-vector, iindlela ze-nucleic acid synthesis, njl.
Thatha i-coronavirus entsha njengomzekelo.Kuba i-RNA yayo iyinto ekhoyo kwimo yendalo kwindalo, "i-RNA ye-coronavirus entsha" ngokwayo ayinakunikwa ipatent.Nangona kunjalo, ukuba umphandi wesayensi ubeka yedwa okanye akhuphe i-RNA okanye amaqhekeza angaziwa kwitekhnoloji evela kwi-coronavirus entsha okokuqala kwaye ayisebenzise (umzekelo, ukuyiguqula ibe sisitofu sokugonya), ngoko zombini i-nucleic acid kunye nesitofu sokugonya sinokunikwa amalungelo elungelo elilodwa lomenzi ngokuhambelana nomthetho.Ukongeza, iimolekyuli ze-nucleic acid ezenziwe ngobuqhetseba kuphando lwekoronavirus entsha, ezinje nge-primers, probes, sgRNA, vectors, njl., zonke zizinto ezinelungelo elilodwa lomenzi wechiza.
Amagqabaza okuqukumbela
Ngokwahlukileyo kwindlela yamachiza amancinci eekhemikhali zemolekyuli kunye neziyobisi ze-antibody, amachiza e-nucleic acid anokwandisa ukufunyanwa kwechiza ukuya kwinqanaba lemfuza ngaphambi kweeprotheni.Kuyabonakala ukuba ngolwandiso oluqhubekayo lwezalathisi kunye nokuphuculwa okuqhubekayo konikezelo kunye nohlengahlengiso lwetekhnoloji, amachiza e-nucleic acid aya kwenza ukuba izigulana ezigulayo zidume ngakumbi kwaye ngokwenene zibe lolunye udidi lweemveliso eziqhumayo emva kwechiza lemolekyuli encinci kunye namachiza e-antibody.
Izixhobo ezibhekiselele:
1.http://xueshu.baidu.com/usercenter/paper/show?paperid=e28268d4b63ddb3b22270ea1763b2892&site=xueshu_se
2.https://www.biospace.com/article/releases/wave-life-sciences-announces-initiation-of-dosing-in-phase-1b-2a-focus-c9-clinical-trial-of-wve- 004-in-amyotrophic-lateral-sclerosis-and-frontotemporal/
3. ULiu Xi, uSun Fang, uTao Qichang;Bulumko Master."Uhlalutyo lwelungelo lomenzi lweziyobisi ze-nucleic acid"
4. I-CICC: iziyobisi ze-nucleic acid, ixesha lifikile
Iimveliso ezinxulumeneyo:
Ixesha lokuposa: Sep-24-2021
