Gwero: Medical Micro
Pambuyo pa mliri wa COVID-19, katemera awiri a mRNA adavomerezedwa mwachangu kuti azitha kutsatsa, zomwe zakopa chidwi kwambiri pakupanga mankhwala a nucleic acid.M'zaka zaposachedwa, mankhwala angapo a nucleic acid omwe amatha kukhala mankhwala osokoneza bongo atulutsa deta yachipatala, yophimba mtima ndi matenda a metabolic, matenda a chiwindi, ndi matenda osiyanasiyana osowa.Mankhwala a nucleic acid akuyembekezeka kukhala mankhwala ang'onoang'ono a mamolekyu ndi antibody.Mtundu wachitatu waukulu wa mankhwala.
Nucleic acid mankhwala gulu
Nucleic acid ndi biological macromolecular pawiri yopangidwa ndi polymerization ya ma nucleotides ambiri, ndipo ndi imodzi mwazinthu zofunika kwambiri pamoyo.Mankhwala a Nucleic acid ndi oligoribonucleotides (RNA) osiyanasiyana kapena oligodeoxyribonucleotides (DNA) omwe ali ndi ntchito zosiyanasiyana, zomwe zimatha kuchita mwachindunji pamagulu omwe amayambitsa matenda kapena kutsata mRNAs kuti athetse matenda pamtundu wa jini Udindo wa.
▲ Njira kaphatikizidwe kuchokera ku DNA kupita ku RNA kupita ku mapuloteni (Chithunzi gwero: bing)
Pakalipano, mankhwala akuluakulu a nucleic acid ndi antisense nucleic acid (ASO), ang'onoang'ono osokoneza RNA (siRNA), microRNA (miRNA), ang'onoang'ono activating RNA (saRNA), messenger RNA (mRNA), aptamer, ndi ribozyme., Antibody nucleic acid conjugated mankhwala (ARC), etc.
Kuphatikiza pa mRNA, kafukufuku ndi chitukuko cha mankhwala ena a nucleic acid adalandiranso chidwi kwambiri m'zaka zaposachedwa.Mu 2018, mankhwala oyamba padziko lonse a siRNA (Patisiran) adavomerezedwa, ndipo anali mankhwala oyamba a nucleic acid kugwiritsa ntchito njira yoperekera ya LNP.M'zaka zaposachedwa, kuthamanga kwa msika wa mankhwala a nucleic acid kwakweranso.Mu 2018-2020 mokha, pali mankhwala 4 a siRNA, Mankhwala atatu a ASO adavomerezedwa (FDA ndi EMA).Kuphatikiza apo, Aptamer, miRNA ndi magawo ena alinso ndi mankhwala ambiri pachipatala.
Ubwino ndi zovuta za nucleic acid mankhwala
Kuyambira zaka za m'ma 1980, kafukufuku ndi chitukuko cha mankhwala atsopano omwe akugwiritsidwa ntchito akuwonjezeka pang'onopang'ono, ndipo chiwerengero chachikulu cha mankhwala atsopano chapezeka;mankhwala achikhalidwe ang'onoang'ono ang'onoang'ono ndi mankhwala a antibody onse amakhala ndi zotsatira zachipatala pomanga kuti agwirizane ndi mapuloteni.Mapuloteni omwe amayang'aniridwa akhoza kukhala ma Enzymes, zolandilira, njira za ion, ndi zina.
Ngakhale mankhwala ang'onoang'ono a mamolekyu ali ndi ubwino wa kupanga kosavuta, kugwiritsira ntchito pakamwa, mankhwala abwino a pharmacokinetic, ndi njira yosavuta yodutsa m'maselo a maselo, kukula kwawo kumakhudzidwa ndi kutha kwa mankhwala omwe akuwafuna (komanso ngati mapuloteni omwe akuwunikirawo ali ndi dongosolo loyenera la thumba ndi kukula kwake)., Kuzama, polarity, etc.);malinga ndi nkhani ya mu Nature2018, mapuloteni 3,000 okha mwa ~ 20,000 omwe ali ndi matupi aumunthu amatha kukhala mankhwala, ndipo 700 okha ndi omwe ali ndi mankhwala ofananirako opangidwa (makamaka mamolekyu ang'onoang'ono).
Ubwino waukulu wa mankhwala a nucleic acid ndikuti mankhwala osiyanasiyana amatha kupangidwa posintha momwe ma nucleic acid amayendera.Poyerekeza ndi mankhwala omwe amagwira ntchito pamapuloteni achikhalidwe, njira yake yachitukuko ndi yosavuta, yothandiza, komanso yokhudzana ndi biologically;poyerekeza ndi mankhwala a genomic DNA-level, mankhwala a nucleic acid alibe chiopsezo chophatikizana ndi majini ndipo amatha kusinthasintha panthawi ya chithandizo.Mankhwalawa amatha kuyimitsidwa ngati palibe chithandizo chofunikira.
Mankhwala a Nucleic acid ali ndi zabwino zoonekeratu monga kutsimikizika kwakukulu, kuchita bwino kwambiri komanso nthawi yayitali.Komabe, ndi zabwino zambiri komanso chitukuko chofulumira, mankhwala a nucleic acid akukumananso ndi zovuta zosiyanasiyana.
Chimodzi ndi kusinthidwa kwa RNA kuti apititse patsogolo kukhazikika kwa mankhwala a nucleic acid ndikuchepetsa chitetezo chamthupi.
Chachiwiri ndi chitukuko cha zonyamulira kuti zitsimikizire kukhazikika kwa RNA panthawi ya nucleic acid transfer process ndi nucleic acid mankhwala kuti afikire maselo okhudzidwa / ziwalo zomwe akufuna;
Chachitatu ndikuwongolera njira yoperekera mankhwala.Momwe mungasinthire dongosolo loperekera mankhwala kuti mukwaniritse zomwezo ndi Mlingo wochepa.
Kusintha kwa mankhwala a nucleic acid mankhwala
Exogenous nucleic acid mankhwala amafunika kuthana ndi zopinga zambiri kuti alowe m'thupi kuti agwire ntchito.Zopinga izi zadzetsanso zovuta pakupanga mankhwala a nucleic acid.Komabe, ndi chitukuko cha umisiri watsopano, mavuto ena atha kale ndi kusintha kwa mankhwala.Ndipo kupita patsogolo kwaukadaulo wamakina operekera chithandizo kwathandiza kwambiri pakupanga mankhwala a nucleic acid.
Kusintha kwa mankhwala kumatha kupititsa patsogolo luso la mankhwala a RNA kukana kuwonongeka ndi ma endonucleases amkati ndi exonucleases, ndikuwonjezera mphamvu ya mankhwalawo.Kwa mankhwala a siRNA, kusinthidwa kwa mankhwala kumathanso kupititsa patsogolo kusanja kwa zingwe zawo zotsutsa kuti achepetse zochitika za RNAi zomwe sakufuna, ndikusintha mawonekedwe amthupi ndi mankhwala kuti apititse patsogolo luso loperekera.
1. Kusintha kwa mankhwala a shuga
Kumayambiriro kwa chitukuko cha mankhwala a nucleic acid, ma nucleic acid ambiri amawonetsa zochitika zabwino zamoyo mu m'galasi, koma ntchito yawo mu vivo idachepetsedwa kwambiri kapena kutayika kwathunthu.Chifukwa chachikulu ndichakuti ma nucleic acid osasinthika amaphwanyidwa mosavuta ndi ma enzymes kapena zinthu zina zotuluka m'thupi.Kusintha kwamankhwala kwa shuga kumaphatikizapo kusinthidwa kwa 2-position hydroxyl (2'OH) ya shuga kukhala methoxy (2'OMe), fluorine (F) kapena (2'MOE).Zosinthazi zitha kukulitsa bwino ntchito ndi kusankha, kuchepetsa zotsatira zomwe mukufuna, ndikuchepetsa zotsatira zoyipa.
▲ Kusintha kwa shuga kwa shuga (chithunzi gwero: 4)
2. Phosphoric acid kusintha mafupa
Kusintha kwamankhwala komwe kumagwiritsidwa ntchito kwambiri pa msana wa phosphate ndi phosphorothioate, ndiko kuti, mpweya wosatsekera mu msana wa phosphate wa nucleotide umasinthidwa ndi sulfure (PS modification).Kusintha kwa PS kumatha kukana kuwonongeka kwa ma nucleases ndikuwonjezera kuyanjana kwa mankhwala a nucleic acid ndi mapuloteni a plasma.Kumanga mphamvu, kuchepetsa aimpso chilolezo ndi kuonjezera theka la moyo.
▲ Kusintha kwa phosphorothioate (chithunzi gwero: kufotokozera 4)
Ngakhale kuti PS ikhoza kuchepetsa kuyanjana kwa ma nucleic acid ndi ma jini omwe amayang'ana, kusinthidwa kwa PS kumakhala kwa hydrophobic komanso kokhazikika, kotero ndikadali kusintha kofunikira pakusokoneza ma nucleic acid ndi antisense nucleic acid.
3. Kusintha kwa mphete zisanu za ribose
Kusinthidwa kwa mphete yamagulu asanu a ribose kumatchedwa kusinthidwa kwa mankhwala a m'badwo wachitatu, kuphatikizapo nucleic acid-locked nucleic acid BNAs, peptide nucleic acid PNA, phosphorodiamide morpholino oligonucleotide PMO, zosinthazi zimatha kupititsa patsogolo nucleic acid mankhwala Kukaniza nyukiliya, ndi zina zotero.
4. Kusintha kwina kwamankhwala
Poyankha zosowa zosiyanasiyana za mankhwala a nucleic acid, ofufuza nthawi zambiri amapanga zosintha ndi kusintha pazitsulo ndi maunyolo a nucleotide kuti awonjezere kukhazikika kwa mankhwala a nucleic acid.
Pakadali pano, mankhwala onse omwe amatsata RNA omwe amavomerezedwa ndi FDA ndi ma analogi opangidwa ndi mankhwala a RNA, omwe amathandizira kugwiritsa ntchito kusintha kwamankhwala.Oligonucleotides amtundu umodzi wamagulu apadera osintha mankhwala amasiyana motsatizana, koma onse ali ndi zinthu zofanana zakuthupi ndi zamankhwala, motero amakhala ndi ma pharmacokinetics ndi biological properties.
Kutumiza ndi kasamalidwe ka mankhwala a nucleic acid
Mankhwala a nucleic acid omwe amadalira kokha kusintha kwa mankhwala amawonongeka mosavuta mofulumira m'magazi, si ophweka kudziunjikira m'magulu omwe akukhudzidwa, ndipo sizovuta kulowa mu cell chandamale kuti afike pamalo ochitirapo kanthu mu cytoplasm.Choncho, mphamvu ya dongosolo yobweretsera ndiyofunika.
Pakali pano, ma nucleic acid mankhwala ma vectors amagawidwa kukhala ma virus komanso osakhala ma virus.Zakale zikuphatikizapo adenovirus-associated virus (AAV), lentivirus, adenovirus ndi retrovirus, etc. Izi zikuphatikizapo lipid carriers, vesicles ndi zina zotero.Kuchokera kumaganizo a mankhwala ogulitsidwa, ma vectors a ma virus ndi lipid carriers ndi okhwima kwambiri popereka mankhwala a mRNA, pamene mankhwala ang'onoang'ono a nucleic acid amagwiritsa ntchito zonyamulira zambiri kapena nsanja zamakono monga liposomes kapena GalNAc.
Mpaka pano, mankhwala ambiri a nucleotide, kuphatikizapo pafupifupi mankhwala onse ovomerezeka a nucleic acid, akhala akugwiritsidwa ntchito kumaloko, monga maso, msana, ndi chiwindi.Ma Nucleotides nthawi zambiri amakhala akuluakulu a hydrophilic polyanions, ndipo katunduyu amatanthauza kuti sangathe kudutsa mumthupi la plasma.Panthawi imodzimodziyo, mankhwala ochiritsira opangidwa ndi oligonucleotide nthawi zambiri sangathe kuwoloka chotchinga cha magazi-ubongo (BBB), kotero kuti kutumiza ku dongosolo lapakati la mitsempha (CNS) ndilo vuto lotsatira la mankhwala a nucleic acid.
Ndizofunikira kudziwa kuti mapangidwe amtundu wa nucleic acid ndi kusintha kwa nucleic acid pakadali pano ndizofunikira kwambiri ofufuza pamundawu.Pakusintha kwamankhwala, nucleic acid yosinthidwa ndi mankhwala, kapangidwe kake ka nucleic acid, kapangidwe kake ka nucleic acid, kapangidwe ka vekitala, kaphatikizidwe ka nucleic acid, ndi zina zotero. Nkhani zaukadaulo nthawi zambiri zimakhala zovomerezeka.
Tengani coronavirus yatsopano monga chitsanzo.Popeza RNA yake ndi chinthu chomwe chimapezeka mwachilengedwe, "RNA ya coronavirus yatsopano" siyingapatsidwe chilolezo.Komabe, ngati wofufuza wasayansi adzipatula kapena kuchotsa RNA kapena zidutswa zomwe sizikudziwika muukadaulo kuchokera ku coronavirus yatsopano kwanthawi yoyamba ndikuyiyika (mwachitsanzo, kuisintha kukhala katemera), ndiye kuti nucleic acid ndi katemera zitha kupatsidwa ufulu patent malinga ndi lamulo.Kuphatikiza apo, ma molekyulu a nucleic acid opangidwa mwaukadaulo pakufufuza kwa coronavirus yatsopano, monga ma primers, probes, sgRNA, vectors, ndi zina zotere, zonse ndi zinthu zovomerezeka.
Mawu omaliza
Mosiyana ndi kachitidwe ka mankhwala ang'onoang'ono a mankhwala a molekyulu ndi mankhwala a antibody, mankhwala a nucleic acid amatha kukulitsa kupezeka kwa mankhwala mpaka pamlingo wa chibadwa pamaso pa mapuloteni.Ndizodziwikiratu kuti ndikukula kosalekeza kwa zisonyezo komanso kuwongolera mosalekeza kwa njira zoperekera ndikusintha, mankhwala a nucleic acid achulukitsa odwala ambiri ndikukhala gulu lina lazinthu zophulika pambuyo pa mankhwala ang'onoang'ono amolekyu ndi antibody.
Zolozera:
1.http://xueshu.baidu.com/usercenter/paper/show?paperid=e28268d4b63ddb3b22270ea1763b2892&site=xueshu_se
2
3. Liu Xi, Sun Fang, Tao Qichang;Wisdom Master."Kusanthula patentability wa nucleic acid mankhwala"
4. CICC: mankhwala a nucleic acid, nthawi yafika
Zogwirizana nazo:
Zida za Animal Tissue Direct PCR
Nthawi yotumiza: Sep-24-2021
