Source: Medical Micro
Bayan barkewar COVID-19, an amince da rigakafin mRNA guda biyu don tallata da sauri, wanda ya jawo hankali sosai ga haɓaka magungunan nucleic acid.A cikin 'yan shekarun nan, adadin magungunan nucleic acid waɗanda ke da yuwuwar zama magungunan toshewa sun buga bayanan asibiti, waɗanda ke rufe cututtukan zuciya da na rayuwa, cututtukan hanta, da cututtukan da ba a saba gani ba.Ana sa ran magungunan nucleic acid za su zama ƙananan ƙwayoyin ƙwayoyin cuta na gaba da magungunan rigakafi.Nau'in magani mafi girma na uku.
Nucleic acid miyagun ƙwayoyi category
Nucleic acid wani fili ne na macromolecular na halitta wanda aka samar ta hanyar polymerization na nucleotides da yawa, kuma yana ɗaya daga cikin mahimman abubuwan rayuwa.Magungunan Nucleic acid iri-iri ne na oligoribonucleotides (RNA) ko oligodeoxyribonucleotides (DNA) tare da ayyuka daban-daban, waɗanda zasu iya yin aiki kai tsaye akan ƙwayoyin cuta masu haifar da manufa ko manufa mRNA don magance cututtuka a matakin jinsin rawar.
▲Tsarin haɓakawa daga DNA zuwa RNA zuwa furotin (Tsarin Hoto: Bing)
A halin yanzu, manyan magungunan nucleic acid sun haɗa da antisense nucleic acid (ASO), ƙananan RNA (siRNA), microRNA (miRNA), ƙananan RNA (saRNA), manzo RNA (mRNA), aptamer, da ribozyme., Antibody nucleic acid conjugated drugs (ARC), da sauransu.
Baya ga mRNA, bincike da haɓaka sauran magungunan nucleic acid kuma sun sami ƙarin kulawa a cikin 'yan shekarun nan.A cikin 2018, an amince da maganin siRNA na farko a duniya (Patisiran), kuma shine farkon maganin nucleic acid don amfani da tsarin isar da LNP.A cikin 'yan shekarun nan, saurin kasuwa na magungunan nucleic acid shima ya haɓaka.A cikin 2018-2020 kadai, akwai magungunan siRNA guda 4, an yarda da magungunan ASO guda uku (FDA da EMA).Bugu da kari, Aptamer, miRNA da sauran filayen suma suna da magunguna da yawa a matakin asibiti.
Fa'idodi da kalubale na magungunan nucleic acid
Tun daga 1980s, bincike da haɓaka sabbin magungunan da aka yi niyya sun haɓaka sannu a hankali, kuma an gano adadin sabbin magunguna;Magungunan sinadarai na ƙananan ƙwayoyin cuta na gargajiya da magungunan rigakafin jiki duka suna yin tasirin magunguna ta hanyar ɗaure ga sunadaran da aka yi niyya.Sunadaran da aka yi niyya na iya zama Enzymes, masu karɓa, tashoshin ion, da sauransu.
Ko da yake ƙananan ƙwayoyin ƙwayoyin cuta suna da fa'ida na samar da sauƙi, gudanarwa ta baki, mafi kyawun magungunan magunguna, da sauƙi ta hanyar membranes tantanin halitta, ci gaban su yana tasiri ta hanyar magungunan miyagun ƙwayoyi (kuma ko furotin da aka yi niyya yana da tsarin aljihu da ya dace da girmansa)., Zurfin, polarity, da dai sauransu);bisa ga wata kasida a cikin Nature2018, 3,000 ne kawai daga cikin ~20,000 sunadaran da kwayoyin halittar dan adam ke sanyawa suna iya zama magunguna, kuma 700 ne kawai aka samar da kwayayen da suka dace (a cikin kananan sinadarai).
Babban fa'idar magungunan nucleic acid shine cewa ana iya haɓaka magunguna daban-daban ta hanyar canza tsarin tushen nucleic acid.Idan aka kwatanta da magungunan da ke aiki a matakin furotin na gargajiya, tsarin ci gabansa yana da sauƙi, inganci, kuma takamaiman ilimin halitta;idan aka kwatanta da jiyya na matakin DNA na genomic, magungunan nucleic acid ba su da haɗarin haɗuwa da kwayoyin halitta kuma sun fi sauƙi a lokacin jiyya.Ana iya dakatar da maganin lokacin da ba a buƙatar magani.
Magungunan Nucleic acid suna da fa'idodi masu fa'ida kamar ƙayyadaddun ƙayyadaddun ƙayyadaddun ƙayyadaddun ƙayyadaddun ƙayyadaddun abubuwa, ingantaccen inganci da sakamako na dogon lokaci.Koyaya, tare da fa'idodi da yawa da haɓaka haɓaka, magungunan nucleic acid suma suna fuskantar ƙalubale iri-iri.
Daya shine gyare-gyaren RNA don haɓaka kwanciyar hankali na magungunan nucleic acid da rage rigakafi.
Na biyu shine haɓakar masu ɗaukar kaya don tabbatar da kwanciyar hankali na RNA yayin tsarin canja wurin acid nucleic da magungunan nucleic acid don isa ga sel / gabobin manufa;
Na uku shine inganta tsarin isar da magunguna.Yadda za a inganta tsarin bayarwa na miyagun ƙwayoyi don cimma sakamako iri ɗaya tare da ƙananan allurai.
Gyaran sinadarai na magungunan nucleic acid
Exogenous nucleic acid kwayoyi suna buƙatar shawo kan cikas da yawa don shiga cikin jiki don taka rawa.Wadannan cikas kuma sun haifar da matsaloli wajen samar da magungunan nucleic acid.Koyaya, tare da haɓaka sabbin fasahohi, an riga an warware wasu daga cikin matsalolin ta hanyar gyara sinadarai.Kuma ci gaban fasahar tsarin bayarwa ya taka muhimmiyar rawa wajen samar da magungunan nucleic acid.
Gyaran sinadarai na iya haɓaka ƙarfin magungunan RNA don tsayayya da lalacewa ta hanyar endogenous endonucleases da exonucleases, kuma yana haɓaka ingancin magunguna sosai.Don magungunan siRNA, gyare-gyaren sinadarai kuma na iya haɓaka zaɓin igiyoyin maganin su don rage ayyukan RNAi da ke gaba, da canza kaddarorin jiki da sinadarai don haɓaka ƙarfin isarwa.
1. Chemical gyara na sukari
A farkon mataki na ci gaban makirci na makiyayya, yawancin mahaɗan makaman acidic dayawa sun nuna kyakkyawan aikin nazarin halittu a Initro, amma an rage aikinsu a VIVO sosai.Babban dalili shi ne cewa acid nucleic da ba a canza su ba suna cikin sauƙi rushewa ta hanyar enzymes ko wasu abubuwan da ke cikin jiki.Canjin sinadarai na sukari ya ƙunshi gyare-gyaren matsayi na biyu na hydroxyl (2'OH) na sukari zuwa methoxy (2'OMe), fluorine (F) ko (2'MOE).Waɗannan gyare-gyare na iya samun nasarar haɓaka ayyuka da zaɓin zaɓi, rage tasirin kashe-kashe, da rage tasirin sakamako.
▲ Gyaran sinadarai na sukari (tushen hoto: tunani 4)
2. Phosphoric acid gyaran kwarangwal
Mafi yawan gyare-gyaren sinadarai na kashin bayan phosphate shine phosphorothioate, wato, iskar oxygen da ba ta haɗawa a cikin kashin bayan phosphate na nucleotide an maye gurbinsa da sulfur (PS modification).Canjin PS zai iya tsayayya da lalata ƙwayoyin cuta da haɓaka hulɗar magungunan nucleic acid da sunadaran plasma.Ƙarfin ɗaurin ɗauri, rage ƙimar izinin koda da haɓaka rabin rayuwa.
▲ Canji na phosphorothioate (tushen hoto: tunani 4)
Ko da yake PS na iya rage alaƙar ƙwayoyin nucleic da kwayoyin da aka yi niyya, gyare-gyaren PS ya fi hydrophobic da kwanciyar hankali, don haka har yanzu yana da mahimmancin gyare-gyare a cikin tsoma baki tare da ƙananan ƙwayoyin nucleic acid da antisense nucleic acid.
3. Gyaran zoben ribose mai mambobi biyar
Gyaran zoben ribose mai mambobi biyar ana kiransa gyare-gyaren sinadarai na ƙarni na uku, ciki har da bridged nucleic acid-locked nucleic acid BNAs, peptide nucleic acid PNA, phosphorodiamide morpholino oligonucleotide PMO, waɗannan gyare-gyare na iya ƙara haɓaka magungunan nucleic acid Resistance to nucleases, da dai sauransu.
4. Sauran gyare-gyaren sinadarai
Dangane da bukatu daban-daban na magungunan nucleic acid, masu bincike yawanci suna yin gyare-gyare da sauye-sauye a kan tushe da sarƙoƙin nucleotide don haɓaka kwanciyar hankali na magungunan nucleic acid.
Ya zuwa yanzu, duk magungunan RNA masu niyya da FDA ta amince da su ana yin RNA ne ta hanyar sinadarai, suna tallafawa amfanin gyare-gyaren sinadarai.Single-stranded oligonucleotides don takamaiman nau'ikan gyare-gyaren sinadarai sun bambanta kawai a cikin jeri, amma dukkansu suna da kamanceceniya ta zahiri da sinadarai, sabili da haka suna da magunguna na gama gari da kaddarorin halittu.
Bayarwa da sarrafa magungunan nucleic acid
Magungunan Nucleic acid waɗanda suka dogara kawai ga gyare-gyaren sinadarai har yanzu suna cikin sauƙin raguwa cikin sauri a cikin kewayawar jini, ba su da sauƙin tarawa a cikin kyallen jikin da aka yi niyya, kuma ba su da sauƙin shiga cikin ƙwayar sel mai niyya don isa wurin aiki a cikin cytoplasm.Saboda haka, ana buƙatar ikon tsarin bayarwa.
A halin yanzu, ƙwayoyin maganin nucleic acid an raba su zuwa ƙwayoyin cuta na hoto ko bidiyo mai zagaya yanar gizo da sauri.Na farko ya hada da adenovirus-associated virus (AAV), lentivirus, adenovirus da retrovirus, da dai sauransu. Wadanda suka hada da lipid carriers, vesicles da makamantansu.Ta fuskar magungunan da ake tallatawa, ƙwayoyin cuta na ƙwayoyin cuta da masu ɗaukar lipid sun fi balaga cikin isar da magungunan mRNA, yayin da ƙananan ƙwayoyin nucleic acid ke amfani da ƙarin dillalai ko dandamali na fasaha kamar liposomes ko GalNAc.
Ya zuwa yau, yawancin magungunan nucleotide, ciki har da kusan dukkanin magungunan nucleic acid da aka amince da su, an gudanar da su a gida, kamar idanu, kashin baya, da hanta.Nucleotides yawanci manyan polyanions ne na hydrophilic, kuma wannan dukiya tana nufin ba za su iya wucewa ta cikin membrane na plasma cikin sauƙi ba.A lokaci guda, magungunan warkewa na tushen oligonucleotide yawanci ba zai iya ketare shingen kwakwalwar jini (BBB), don haka isar da tsarin juyayi na tsakiya (CNS) shine kalubale na gaba na magungunan nucleic acid.
Ya kamata a lura da cewa tsarin tsarin nucleic acid da gyare-gyaren acid nucleic a halin yanzu shine mayar da hankali ga masu bincike a fagen.Don gyare-gyaren sinadarai, gyare-gyaren acid nucleic, ƙirar nucleic acid ba na halitta ba ko haɓakawa, abun da ke ciki na acid nucleic, ginin vector, hanyoyin haɗin acid nucleic, da dai sauransu. Abubuwan fasaha gabaɗaya batutuwan aikace-aikace ne.
Dauki sabon coronavirus a matsayin misali.Tunda RNA wani abu ne da ke wanzuwa a cikin sigar halitta a yanayi, “RNA na sabon coronavirus” da kanta ba za a iya ba da izini ba.Koyaya, idan mai binciken kimiyya ya ware ko ya cire RNA ko guntu waɗanda ba a san su a cikin fasaha ba daga sabon coronavirus a karon farko kuma ya yi amfani da shi (misali, canza shi zuwa maganin rigakafi), to duka acid ɗin nucleic da allurar za a iya ba da haƙƙin haƙƙin mallaka daidai da doka.Bugu da kari, kwayoyin halittar nucleic acid da aka kirkira ta hanyar wucin gadi a cikin binciken sabon coronavirus, kamar su primers, probes, sgRNA, vectors, da sauransu, dukkansu abubuwa ne masu hazaka.
Bayanin ƙarshe
Daban-daban da tsarin magungunan ƙananan ƙwayoyin ƙwayoyin ƙwayoyin cuta na gargajiya da magungunan rigakafin ƙwayoyin cuta, magungunan nucleic acid na iya ƙaddamar da gano muggan ƙwayoyi zuwa matakin ƙwayoyin cuta kafin sunadaran.Ana iya ganin cewa tare da ci gaba da faɗaɗa alamun da ci gaba da haɓaka bayarwa da fasahohin gyare-gyare, magungunan nucleic acid za su haɓaka ƙarin marasa lafiya da gaske kuma su zama wani nau'in samfuran fashewa bayan ƙananan ƙwayoyin sinadarai na ƙwayoyin cuta da magungunan rigakafin.
Kayayyakin Magana:
1.http://xueshu.baidu.com/uscenter/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-frontotempo
3. Liu Xi, Sun Fang, Tao Qichang;Malamin hikima."Bincike na haƙƙin mallaka na magungunan nucleic acid"
4. CICC: magungunan nucleic acid, lokaci ya yi
Samfura masu dangantaka:
Lokacin aikawa: Satumba-24-2021
