Kunobva: Medical Micro
Mushure mekubuda kweCCIDID-19, majekiseni maviri eMRNA akakurumidza kubvumidzwa kushambadzira, izvo zvakwezva kutarisisa zvakanyanya mukuvandudzwa kweiyo nucleic acid mishonga.Mumakore achangopfuura, akati wandei nucleic acid zvinodhaka zvine mukana wekuva blockbuster zvinodhaka zvakaburitsa data yekiriniki, inovhara moyo uye metabolic zvirwere, zvirwere zvechiropa, uye zvakasiyana-siyana zvisingawanzo zvirwere.Nucleic acid mishonga inotarisirwa kuve inotevera diki molecule mishonga uye antibody mishonga.Mhando yechitatu yakakura yemishonga.
Nucleic acid drug category
Nucleic acid is biological macromolecular compound yakaumbwa nekupolymerization kweakawanda nucleotides, uye ndechimwe chezvinhu zvakakosha zvehupenyu.Nucleic acid mishonga yakasiyana-siyana ye oligoribonucleotides (RNA) kana oligodeoxyribonucleotides (DNA) ine mabasa akasiyana-siyana, ayo anogona kuita zvakananga pane zvirwere zvinokonzera zvirwere zvemajini kana kutarisa mRNAs kurapa zvirwere pazera rejini Basa re.
▲ Iyo synthesis maitiro kubva kuDNA kuenda kuRNA kuenda kumapuroteni (Mufananidzo sosi: bing)
Parizvino, iyo huru nucleic acid mishonga inosanganisira antisense nucleic acid (ASO), diki inopindira RNA (siRNA), microRNA (miRNA), diki activating RNA (saRNA), mutumwa RNA (mRNA), aptamer, uye ribozyme., Antibody nucleic acid conjugated drugs (ARC), nezvimwewo.
Pamusoro pemRNA, kutsvagisa uye kuvandudzwa kwemamwe nucleic acid zvinodhaka zvakagamuchirawo kutariswa kwakanyanya mumakore achangopfuura.Muna 2018, yekutanga pasirese siRNA mushonga (Patisiran) yakatenderwa, uye yaive yekutanga nucleic acid mushonga kushandisa iyo LNP yekuburitsa system.Mumakore achangopfuura, kumhanyisa kwemusika kweiyo nucleic acid mishonga yakawedzerawo.Muna 2018-2020 chete, kune 4 siRNA mishonga, matatu ASO mishonga yakabvumidzwa (FDA neEMA).Pamusoro pezvo, Aptamer, miRNA nedzimwe minda zvakare ine mishonga yakawanda muchikamu chekiriniki.
Zvakanakira uye zvinonetsa zve nucleic acid zvinodhaka
Kubva kuma1980, kutsvagisa nekuvandudzwa kwemishonga mitsva yavanovavarira yakawedzera zvishoma nezvishoma, uye nhamba huru yemishonga mitsva yakawanikwa;echinyakare madiki-morekuru kemikari mishonga nemishonga inorwisa utachiona zvese zvinounza mhedzisiro yemishonga nekusunga kune kunanga mapuroteni.Mapuroteni anonangwa anogona kunge ari Enzymes, receptors, ion nzira, nezvimwe.
Kunyangwe mishonga midiki-morekuru ine zvakanakira kugadzirwa nyore, kutonga nemuromo, zvirinani pharmacokinetic zvimiro, uye nyore kupfuura nemukati memembrane yesero, kukura kwayo kunokanganisa nekugoneka kwezvinodhaka kwechinangwa (uye kana protein yainonangwa ine yakafanira homwe chimiro uye saizi)., Kudzika, polarity, nezvimwewo);maererano nechinyorwa chiri muNature2018, chete zviuru zvitatu zve ~ 20,000 mapuroteni akavharidzirwa nejenome remunhu anogona kuva mishonga, uye mazana manomwe chete ane mishonga inoenderana yakagadzirwa (muMakuru mamorekuru kemikari).
Kubatsira kukuru kwemishonga ye nucleic acid ndeyekuti mishonga yakasiyana inogona kugadzirwa chete nekushandura kutevedzana kwenheyo ye nucleic acid.Kuenzaniswa nemishonga inoshanda pachiyero cheprotein yechinyakare, budiriro yayo iri nyore, inoshanda, uye yakanangana nebiologically;zvichienzaniswa nejenomic DNA-level treatment, nucleic acid zvinodhaka hazvina ngozi yekubatanidza gene uye zvinonyanya kushanduka panguva yekurapa.Mushonga unogona kumiswa kana pasina kurapwa kunodiwa.
Nucleic acid zvinodhaka zvine mabhenefiti ari pachena akadai seyakanyanya kujeka, kushanda kwepamusoro uye mhedzisiro yenguva refu.Nekudaro, nezvakawanda zvakanakira uye nekukurumidza kukura, nucleic acid mishonga iri kutarisana nematambudziko akasiyana.
Imwe ndeyeRNA shanduko yekusimudzira kugadzikana kweiyo nucleic acid zvinodhaka uye kuderedza immunogenicity.
Yechipiri ndeyekusimudzirwa kwevatakuri kuti vave nechokwadi chekugadzikana kweRNA panguva ye nucleic acid transfer process uye nucleic acid zvinodhaka kusvika kune chinangwa chemasero / nhengo dzinotarirwa;
Chechitatu kuvandudzwa kwehurongwa hwekuendesa zvinodhaka.Maitiro ekuvandudza dhizaini yekuunza dhizaini kuti iwane mhedzisiro yakafanana neiyo yakaderera doses.
Kemikari shanduko ye nucleic acid zvinodhaka
Exogenous nucleic acid mishonga inoda kukunda zvipingamupinyi zvakawanda kuti ipinde mumuviri kuita basa.Zvipingamupinyi izvi zvakakonzerawo kunetsa mukugadzirwa kwemishonga inonzi nucleic acid.Zvisinei, nekuvandudzwa kwemichina mitsva, mamwe ematambudziko akatogadziriswa nekugadzirisa kemikari.Uye budiriro yedhisheni system tekinoroji yakaita basa rakakosha mukuvandudza nucleic acid mishonga.
Kugadziriswa kwemakemikari kunogona kusimudzira kugona kwemishonga yeRNA kuramba kuderedzwa ne endo native endonucleases uye exonucleases, uye kuwedzera zvakanyanya kushanda kwemishonga.Kune mishonga yeSiRNA, kugadziridzwa kwemakemikari kunogonawo kuwedzera kusarudzwa kwetambo dzavo dzeantisense kudzikisa kure-kunangwa RNAi chiitiko, uye kushandura muviri nemakemikari zvivakwa kuti uwedzere kugona kuburitsa.
1. Kemikari kugadziriswa kweshuga
Muchikamu chekutanga chekugadzirwa kwemishonga nucleic acid, akawanda nucleic acid makomisheni airatidza yakanaka biological chiitiko mu vitro, asi basa ravo mu vivo rakadzikiswa zvakanyanya kana kurasika zvachose.Chikonzero chikuru ndechekuti unmodified nucleic acids inoputswa zviri nyore nema enzymes kana zvimwe zvinhu zvinopera mumuviri.Kugadziriswa kwekemikari yeshuga kunonyanya kusanganisira kuchinjwa kwe2-position hydroxyl (2'OH) yeshuga kune methoxy (2'OMe), fluorine (F) kana (2'MOE).Aya magadzirirwo anogona kubudirira kuwedzera basa uye kusarudza, kuderedza off-chinangwa mhedzisiro, uye kuderedza mhedzisiro.
▲ Chemical kuchinjwa kweshuga (chinyorwa chemufananidzo: referensi 4)
2. Phosphoric acid skeleton kugadziriswa
Iyo inonyanya kushandiswa kemikari inogadziriswa ye phosphate backbone ndeye phosphorothioate, kureva, isina-bridging okisijeni mumusana wephosphate we nucleotide inotsiviwa nesarufa (PS modification).Iyo PS shanduko inogona kuramba kushatiswa kwema nuclease uye kuwedzera kupindirana kweiyo nucleic acid zvinodhaka uye mapuroteni eplasma.Kusunga simba, kuderedza renal clearance rate uye kuwedzera hafu yeupenyu.
▲ Shanduko yephosphorothioate (kunobva mufananidzo: referensi 4)
Kunyange zvazvo PS inogona kuderedza kushamwaridzana kwe nucleic acids uye chinangwa chemajini, kuchinjwa kwePS kunowedzera hydrophobic uye yakagadzikana, saka ichiri shanduko yakakosha mukupindira nediki nucleic acids uye antisense nucleic acids.
3. Kugadziriswa kwemhete ine nhengo shanu dze ribose
Iko kugadziridzwa kwemhete ine nhengo shanu dzeribose inonzi yechitatu-chizvarwa chemakemikari shanduko, kusanganisira yakavharwa nucleic acid-yakakiyiwa nucleic acid BNAs, peptide nucleic acid PNA, phosphorodiamide morpholino oligonucleotide PMO, shanduko idzi dzinogona kuwedzera nucleic acid zvinodhaka Kuramba, kunatsiridza nuclease nezvimwe.
4. Mamwe magadzirirwo emakemikari
Mukupindura kune zvakasiyana-siyana zvinodiwa zve nucleic acid zvinodhaka, vatsvakurudzi vanowanzoita shanduko uye shanduko pazvigadziko uye nucleotide maketani kuti vawedzere kugadzikana kwe nucleic acid zvinodhaka.
Parizvino, ese maRNA-anonangidzira mishonga anotenderwa neFDA akagadzirwa nemakemikari maRNA analogues, achitsigira kushandiswa kwemakemikari shanduko.One-stranded oligonucleotides kune chaiwo makemikari ekuchinja mapoka anosiyana chete mukutevedzana, asi iwo ese ane akafanana emuviri nemakemikari zvimiro, uye nekudaro ane akajairika pharmacokinetics uye biological properties.
Kuendesa uye kutonga kweiyo nucleic acid zvinodhaka
Nucleic acid zvinodhaka zvinovimba chete nekugadziriswa kwemakemikari zvichiri nyore kuderedzwa nekukurumidza mukutenderera kweropa, hazvisi nyore kuunganidza mumatishu anotangwa, uye hazvisi nyore kupinda zvakanangwa sero membrane kusvika panzvimbo yekuita mucytoplasm.Nokudaro, simba rekutumira hurongwa hunodiwa.
Parizvino, nucleic acid drug vectors inonyanya kukamurwa kuva mavhairasi uye asiri mavhairasi mavhairasi.Iyo yekare inosanganisira adenovirus-associated virus (AAV), lentivirus, adenovirus uye retrovirus, etc. Izvo zvinosanganisira lipid carriers, vesicles nezvimwe zvakadaro.Kubva pakuona kwemishonga inotengeswa, viral vectors uye lipid carriers vanonyanya kukura mukuendeswa kwemishonga yeMRNA, nepo diki nucleic acid zvinodhaka zvinoshandisa zvakawanda zvinotakura kana tekinoroji mapuratifomu akadai se liposomes kana GalNAc.
Kusvika pari zvino, marapirwo mazhinji enucleotide, kusanganisira anenge ese anotenderwa nucleic acid zvinodhaka, ave achipihwa munharaunda, semeso, musana, uye chiropa.Nucleotides anowanzo hombe hydrophilic polyanions, uye pfuma iyi inoreva kuti haigone kupfuura nepakati peplasma membrane.Panguva imwecheteyo, oligonucleotide-based therapeutic drugs kazhinji haigoni kuyambuka ropa-brain barrier (BBB), saka kuendesa kune central nervous system (CNS) ndiyo inotevera dambudziko re nucleic acid zvinodhaka.
Izvo zvakakosha kuti ticherechedze kuti nucleic acid sequence dhizaini uye nucleic acid shanduko parizvino ndiyo yakatarisana nevanoongorora mumunda.Pakugadzirisa makemikari, nucleic acid yakagadziridzwa, isiri-natural nucleic acid sequence design kana kunatsiridza, nucleic acid composition, vector construction, nucleic acid synthesis ways, etc. Zvidzidzo zveunyanzvi zvinowanzova zvekushandisa zvinotenderwa.
Tora iyo coronavirus nyowani semuenzaniso.Sezvo RNA yayo chiri chinhu chiripo muchimiro chechisikigo muchisikigo, iyo "RNA yekoronavirus nyowani" pachayo haigone kupihwa patent.Nekudaro, kana muongorori wesainzi akaparadzanisa kana kubvisa RNA kana zvimedu zvisingazivikanwe muhunyanzvi kubva kukoronavirus nyowani kekutanga ndokuishandisa (semuenzaniso, kuishandura kuita yekudzivirira), ipapo zvese nucleic acid uye yekudzivirira inogona kupihwa kodzero dzepatent zvinoenderana nemutemo.Pamusoro pezvo, mamorekuru akagadzirwa nucleic acid mukutsvaga kweiyo coronavirus nyowani, senge primers, probes, sgRNA, mavheji, nezvimwe, zvese zvinhu zvinotenderwa.
Mashoko ekupedzisira
Yakasiyana nemagadzirirwo echinyakare madiki mamorekuru emakemikari zvinodhaka uye antibody mishonga, nucleic acid mishonga inogona kuwedzera kuwanikwa kwezvinodhaka kusvika kune genetic level pamberi pemapuroteni.Zvinogara zvichionekwa kuti nekuenderera mberi kwekuwedzera kwezviratidzo uye nekuenderera mberi kwekuvandudza kwekutakura nekugadzirisa matekinoroji, nucleic acid mishonga inofarirwa nevarwere vezvirwere uye igove imwe kirasi yezvigadzirwa zvinoputika mushure mediki mamorekuru kemikari mishonga nemishonga inorwisa utachiona.
Reference materials:
1.http://xueshu.baidu.com/usercenter/paper/show?paperid=e28268d4b63ddb3b22270ea1763b2892&site=xueshu_se
2
3. Liu Xi, Sun Fang, Tao Qichang;Uchenjeri Tenzi."Kuongorora kwepatentability ye nucleic acid zvinodhaka"
4. CICC: nucleic acid zvinodhaka, nguva yasvika
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Nguva yekutumira: Sep-24-2021
