Mohloli: Medical Micro
Kamora ho phatloha ha COVID-19, liente tse peli tsa mRNA li ile tsa amoheloa kapele bakeng sa ho bapatsa, e leng se hohetseng tlhokomelo e kholo ho nts'etsopele ea lithethefatsi tsa nucleic acid.Lilemong tsa morao tjena, lithethefatsi tse ngata tsa nucleic acid tse nang le monyetla oa ho fetoha lithethefatsi tse thibelang likokoana-hloko li phatlalalitse lintlha tsa kliniki, tse koahelang pelo le mafu a metabolism, mafu a sebete le mefuta e sa tšoaneng ea mafu a sa tloaelehang.Lithethefatsi tsa Nucleic acid li lebelletsoe ho ba lithethefatsi tse latelang tsa molek'hule le lithethefatsi tsa antibody.Mofuta oa boraro o moholo oa lithethefatsi.
Sehlopha sa lithethefatsi sa Nucleic acid
Nucleic acid ke biological macromolecular compound e entsoeng ke polymerization ea li-nucleotide tse ngata, 'me ke e' ngoe ea lintho tsa motheo tsa bophelo.Lithethefatsi tsa Nucleic acid ke mefuta e fapaneng ea oligoribonucleotides (RNA) kapa oligodeoxyribonucleotides (DNA) e nang le mesebetsi e fapaneng, e ka sebetsang ka ho toba ka liphatsa tsa lefutso tse bakang mafu kapa ho lebisa tlhokomelo ea mRNAs ho phekola mafu ka liphatsa tsa lefutso Karolo ea.
▲ Ts'ebetso ea ho kopanya ho tloha DNA ho ea ho RNA ho ea ho protheine(Mohloli oa setšoantšo: bing)
Hajoale, litlhare tsa mantlha tsa "nucleic acid" li kenyelletsa antisense nucleic acid (ASO), RNA e nyane (siRNA), microRNA (miRNA), e sebetsang e nyane ea RNA (saRNA), lenģosa la RNA (mRNA), aptamer le ribozyme., Antibody nucleic acid conjugated drugs (ARC), joalo-joalo.
Ntle le mRNA, lipatlisiso le nts'etsopele ea lithethefatsi tse ling tsa nucleic acid le tsona li fumane tlhokomelo e kholo lilemong tsa morao tjena.Ka 2018, sethethefatsi sa pele sa lefats'e sa siRNA (Patisiran) se ile sa amoheloa, 'me e bile moriana oa pele oa nucleic acid ho sebelisa mokhoa oa ho fana ka LNP.Lilemong tsa morao tjena, lebelo la 'maraka la lithethefatsi tsa nucleic acid le lona le potlakile.Ka 2018-2020 feela, ho na le lithethefatsi tse 4 tsa siRNA, Litlhare tse tharo tsa ASO li amohetsoe (FDA le EMA).Ntle le moo, Aptamer, miRNA le likarolo tse ling le tsona li na le lithethefatsi tse ngata sethaleng sa bongaka.
Melemo le mathata a lithethefatsi tsa nucleic acid
Ho tloha lilemong tsa bo-1980, lipatlisiso le nts'etsopele ea meriana e mecha e thehiloeng ho sepheo e ntse e eketseha butle-butle, 'me palo e kholo ea meriana e mecha e fumanoe;meriana ea setso ea molek'hule e nyane le litlhare tsa antibody ka bobeli li na le litlamorao tsa pharmacological ka ho tlama liprotheine.Liprotheine tse shebiloeng e ka ba li-Enzyme, li-receptor, liteishene tsa ion, jj.
Le hoja lithethefatsi tsa molek'hule tse nyenyane li na le melemo ea tlhahiso e bonolo, tsamaiso ea molomo, thepa e molemo ea pharmacokinetic, le ho feta habonolo ka lisele tsa lisele, tsoelo-pele ea tsona e angoa ke ho khoneha ha lithethefatsi ho sepheo (le hore na protheine e lebisitsoeng e na le sebopeho se loketseng sa pokotho le boholo)., botebo, polarity, joalo-joalo);ho latela sengoloa ho Nature2018, ke liprotheine tse 3,000 feela tsa ~ 20,000 tse kentsoeng ke genome ea motho e ka bang meriana, 'me ke tse 700 feela tse nang le lithethefatsi tse tsamaellanang tse hlahisitsoeng (Haholo-holo limolek'hule tse nyane tsa limolek'hule).
Molemo o moholo oa lithethefatsi tsa nucleic acid ke hore lithethefatsi tse fapaneng li ka hlahisoa feela ka ho fetola tatellano ea motheo ea nucleic acid.Ha ho bapisoa le lithethefatsi tse sebetsang boemong ba protheine ea setso, ts'ebetso ea eona ea nts'etsopele e bonolo, e sebetsa hantle ebile e ipapisitse le baeloji;ha li bapisoa le phekolo ea boemo ba DNA ea genomic, lithethefatsi tsa nucleic acid ha li na kotsi ea ho kopanya liphatsa tsa lefutso 'me li fetoha habonolo nakong ea phekolo.Meriana e ka emisoa ha ho sa hlokahale phekolo.
Lithethefatsi tsa Nucleic acid li na le melemo e hlakileng joalo ka ho khetheha, ho sebetsa hantle haholo le phello ea nako e telele.Leha ho le joalo, ka melemo e mengata le nts'etsopele e potlakileng, lithethefatsi tsa nucleic acid le tsona li tobane le mathata a fapaneng.
E 'ngoe ke phetoho ea RNA ho matlafatsa botsitso ba lithethefatsi tsa nucleic acid le ho fokotsa immunogenicity.
Ea bobeli ke nts'etsopele ea bajari ho netefatsa botsitso ba RNA nakong ea ts'ebetso ea ho fetisa nucleic acid le lithethefatsi tsa nucleic acid ho fihlela lisele tse lebisitsoeng / litho tse reretsoeng;
Ea boraro ke ntlafatso ea tsamaiso ea phano ea lithethefatsi.Mokhoa oa ho ntlafatsa mokhoa oa ho tsamaisa lithethefatsi ho fihlela phello e ts'oanang le litekanyetso tse tlase.
Phetoho ea lik'hemik'hale ea lithethefatsi tsa nucleic acid
Lithethefatsi tsa exogenous nucleic acid li hloka ho hlola litšitiso tse ngata ho kena 'meleng ho bapala karolo.Litšitiso tsena li boetse li bakile mathata ho nts'etsopele ea lithethefatsi tsa nucleic acid.Leha ho le joalo, ka nts'etsopele ea theknoloji e ncha, mathata a mang a se a rarollotsoe ke phetoho ea lik'hemik'hale.'Me katleho ea theknoloji ea tsamaiso ea pelehi e phethile karolo ea bohlokoa ntlafatsong ea litlhare tsa nucleic acid.
Phetoho ea lik'hemik'hale e ka ntlafatsa bokhoni ba litlhare tsa RNA ho hanela ho senyeha ka li-endonuclease tsa endogenous le exonucleases, le ho matlafatsa ts'ebetso ea lithethefatsi haholo.Bakeng sa lithethefatsi tsa siRNA, phetoho ea lik'hemik'hale e ka boela ea ntlafatsa khetho ea likhoele tsa bona tsa antisense ho fokotsa ts'ebetso ea RNAi e sa lebelloang, le ho fetola thepa ea 'mele le ea lik'hemik'hale ho ntlafatsa bokhoni ba ho fana.
1. Phetoho ea lik'hemik'hale ea tsoekere
Mokhahlelong oa pele oa nts'etsopele ea lithethefatsi tsa nucleic acid, metsoako e mengata ea nucleic acid e bonts'itse ts'ebetso e ntle ea biological in vitro, empa ts'ebetso ea bona ho vivo e ile ea fokotseha haholo kapa ea lahleha ka botlalo.Lebaka le ka sehloohong ke hore li-nucleic acid tse sa fetoloang li robeha habonolo ke li-enzyme kapa lintho tse ling tsa 'mele.Phetoho ea lik'hemik'hale ea tsoekere haholo-holo e kenyelletsa phetoho ea 2-position hydroxyl (2'OH) ea tsoekere ho methoxy (2'OMe), fluorine (F) kapa (2'MOE).Liphetoho tsena li ka eketsa ts'ebetso le khetho ka katleho, tsa fokotsa litlamorao tse sa lebelloang, 'me tsa fokotsa litlamorao.
▲ Phetoho ea lik'hemik'hale ea tsoekere (mohloli oa setšoantšo: referense 4)
2. Phosphoric acid skeleton phetolo
Phetoho ea lik'hemik'hale e sebelisoang ka ho fetisisa ea mokokotlo oa phosphate ke phosphorothioate, ke hore, oksijene e sa keneng mokokotlong oa phosphate ea nucleotide e nkeloa sebaka ke sulfur (PS modification).Phetoho ea PS e ka hanela ho senyeha ha li-nuclease le ho ntlafatsa tšebelisano ea lithethefatsi tsa nucleic acid le liprotheine tsa plasma.Matla a tlamang, a fokotsa sekhahla sa ho tlosoa ha renal le ho eketsa halofo ea bophelo.
▲ Phetoho ea phosphorothioate (mohloli oa setšoantšo: reference 4)
Le hoja PS e ka fokotsa kamano ea li-nucleic acid le liphatsa tsa lefutso, phetoho ea PS e na le hydrophobic le e tsitsitseng haholoanyane, kahoo e ntse e le phetoho ea bohlokoa ea ho kena-kenana le li-nucleic acid tse nyenyane le antisense nucleic acids.
3. Phetoho ea lesale la litho tse hlano tsa ribose
Phetoho ea selikalikoe sa litho tse hlano tsa ribose e bitsoa phetoho ea lik'hemik'hale tsa moloko oa boraro, ho kenyelletsa le nucleic acid-locked nucleic acid BNAs, peptide nucleic acid PNA, phosphorodiamide morpholino oligonucleotide PMO, liphetoho tsena li ka ntlafatsa lithethefatsi tsa nucleic acid Ho hanyetsa, ho ntlafala ha nuclease, joalo-joalo.
4. Liphetoho tse ling tsa lik'hemik'hale
E le ho arabela litlhoko tse fapaneng tsa lithethefatsi tsa nucleic acid, hangata bafuputsi ba etsa liphetoho le liphetoho holim'a metheo le liketane tsa nucleotide ho eketsa botsitso ba lithethefatsi tsa nucleic acid.
Ho fihlela joale, lithethefatsi tsohle tse lebisitsoeng ho RNA tse amohetsoeng ke FDA ke li-analogue tsa RNA tse entsoeng ka lik'hemik'hale, tse tšehetsang tšebeliso ea phetoho ea lik'hemik'hale.Li-oligonucleotide tse nang le mefuta e le 'ngoe bakeng sa likarolo tse itseng tsa phetoho ea lik'hemik'hale li fapana feela ka tatellano, empa kaofela li na le thepa e tšoanang ea' mele le ea lik'hemik'hale, ka hona li na le lisebelisoa tse tloaelehileng tsa pharmacokinetics le likokoana-hloko.
Phano le tsamaiso ea lithethefatsi tsa nucleic acid
Lithethefatsi tsa Nucleic acid tse itšetlehileng feela ka phetoho ea lik'hemik'hale li ntse li senyeha habonolo ka potlako ho potoloha ha mali, ha li bonolo ho bokella lisele tse lebisitsoeng, 'me ha li bonolo ho phunyeletsa ka katleho lera la sele e lebeletsoeng ho fihla sebakeng sa ts'ebetso ho cytoplasm.Ka hona, matla a tsamaiso ea ho fana a hlokahala.
Hona joale, li-vector tsa lithethefatsi tsa nucleic acid li arotsoe haholo-holo ka likokoana-hloko le tse seng tsa kokoana-hloko.Ea pele e kenyelletsa kokoana-hloko e amanang le adenovirus (AAV), lentivirus, adenovirus le retrovirus, joalo-joalo Tsena li kenyelletsa li-lipid carriers, vesicles le tse ling tse joalo.Ho ea ka pono ea lithethefatsi tse rekisoang, li-viral vectors le lipid carriers li hōlile haholoanyane phepelong ea lithethefatsi tsa mRNA, athe litlhare tse nyane tsa nucleic acid li sebelisa li-carriers tse ngata kapa sethala sa theknoloji joalo ka liposomes kapa GalNAc.
Ho fihlela joale, boholo ba liphekolo tsa nucleotide, ho kopanyelletsa le hoo e batlang e le lithethefatsi tsohle tse amohelehang tsa nucleic acid, li 'nile tsa sebelisoa sebakeng sa heno, tse kang mahlo, lesapo la mokokotlo le sebete.Hangata li-nucleotide ke li-hydrophilic polyanions tse kholo, 'me thepa ena e bolela hore ha e khone ho feta lera la plasma habonolo.Ka nako e ts'oanang, meriana ea phekolo e thehiloeng ho oligonucleotide hangata ha e khone ho tšela mokoallo oa mali-boko (BBB), kahoo ho isa tsamaisong ea methapo e bohareng (CNS) ke phephetso e latelang bakeng sa lithethefatsi tsa nucleic acid.
Ho bohlokoa ho hlokomela hore moralo oa tatellano ea li-nucleic acid le phetoho ea asiti ea nucleic hajoale ke sepheo sa bafuputsi tšimong.Bakeng sa phetoho ea lik'hemik'hale, nucleic acid e fetotsoeng ka lik'hemik'hale, moralo kapa ntlafatso ea tatellano ea li-nucleic acid, motsoako oa nucleic acid, kaho ea li-vector, mekhoa ea ho kopanya ea nucleic acid, joalo-joalo.
Nka mohlala oa coronavirus e ncha.Kaha RNA ea eona ke ntho e teng ka sebopeho sa tlhaho, "RNA ea coronavirus e ncha" ka boeona e ke ke ea fuoa tokelo ea molao.Leha ho le joalo, haeba mofuputsi oa mahlale a arola kapa a ntša RNA kapa likhechana tse sa tsejoeng ho thekenoloji ho tsoa ho coronavirus e ncha ka lekhetlo la pele mme a e sebelisa (mohlala, ho e fetola ente), joale nucleic acid le ente li ka fuoa litokelo tsa patent ho latela molao.Ntle le moo, limolek'hule tsa "nucleic acid" tse entsoeng ka maiketsetso lipatlisisong tsa coronavirus e ncha, joalo ka li-primers, probes, sgRNA, vectors, joalo-joalo, kaofela ke lintho tse nang le tokelo ea molao.
Lipolelo tse qetellang
Ho fapana le ts'ebetso ea litlhare tse tloaelehileng tsa lik'hemik'hale tsa molek'hule le lithethefatsi tsa antibody, lithethefatsi tsa nucleic acid li ka eketsa ho sibolloa ha lithethefatsi ho isa boemong ba liphatsa tsa lefutso pele ho liprotheine.Hoa hlokomeleha hore ka keketseho e tsoelang pele ea matšoao le ntlafatso e tsoelang pele ea ho fana le ho fetola theknoloji, lithethefatsi tsa nucleic acid li tla tsebahatsa bakuli ba bangata ba mafu 'me ka sebele e be sehlopha se seng sa lihlahisoa tse phatlohang ka mor'a lithethefatsi tse nyenyane tsa lik'hemik'hale tsa molek'hule le li-antibody.
Lisebelisoa tsa litšupiso:
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. Liu Xi, Sun Fang, Tao Qichang;Mong'a bohlale."Analysis of patentability of nucleic acid drugs"
4. CICC: lithethefatsi tsa nucleic acid, nako e fihlile
Lihlahisoa tse Amanang:
Nako ea poso: Sep-24-2021
