Ndi chitukuko chosalekeza chaukadaulo waukadaulo wa mamolekyulu, ubale pakati pa kusintha kwa majini ndi zolakwika ndi matenda wapeza kumvetsetsa mozama.Ma nucleic acids akopa chidwi kwambiri chifukwa cha kuthekera kwawo kwakukulu kogwiritsa ntchito pozindikira komanso kuchiza matenda.Mankhwala a Nucleic acid amatanthauza zidutswa za DNA kapena RNA zokhala ndi ntchito zochizira matenda.Mankhwalawa amatha kuchitapo kanthu mwachindunji pamajini omwe amayambitsa matenda kapena ma mRNA omwe amayambitsa matenda, ndikuchita nawo gawo pochiza matenda pamlingo wa jini.Poyerekeza ndi mankhwala ang'onoang'ono a molekyulu ndi mankhwala a antibody, mankhwala a nucleic acid amatha kuwongolera mawonekedwe a majini omwe amayambitsa matenda kuchokera muzu, ndikukhala ndi "chizindikiro chochizira ndi kuchiritsa zomwe zimayambitsa".Mankhwala a Nucleic acid alinso ndi maubwino odziwikiratu monga kuchita bwino kwambiri, kawopsedwe wochepa, komanso kutsimikizika kwakukulu.Chiyambireni mankhwala oyamba a nucleic acid fomivirsen sodium mu 1998, mankhwala ambiri a nucleic acid avomerezedwa kuti alandire chithandizo chamankhwala.
Mankhwala a nucleic acid omwe ali pamsika wapadziko lonse lapansi makamaka amaphatikiza antisense nucleic acid (ASO), yosokoneza yaying'ono ya RNA (siRNA), ndi ma nucleic acid aptamers.Kupatula ma nucleic acid aptamers (omwe amatha kupitilira ma nucleotide 30), mankhwala a nucleic acid nthawi zambiri amakhala oligonucleotides opangidwa ndi ma nucleotides 12 mpaka 30, omwe amadziwikanso kuti oligonucleotide mankhwala.Kuphatikiza apo, ma miRNAs, ribozymes ndi deoxyribozymes awonetsanso phindu lalikulu pakuchiza matenda osiyanasiyana.Mankhwala a nucleic acid akhala amodzi mwa magawo omwe amalonjeza kwambiri pakufufuza ndi chitukuko cha biomedicine masiku ano.
Zitsanzo za mankhwala ovomerezeka a nucleic acid
Antisense nucleic acid
Ukadaulo wa Antisense ndiukadaulo watsopano wopangira mankhwala kutengera mfundo ya Watson-Crick base complementation, pogwiritsa ntchito zidutswa za DNA kapena RNA zopangidwa mwaluso kapena zopangidwa ndi chamoyo kuti ziwongolere mawonekedwe amtundu womwe mukufuna.Antisense nucleic acid imakhala ndi zotsatizana zoyambira zomwe zimayenderana ndi chandamale cha RNA ndipo imatha kumangirirako.Antisense nucleic acids nthawi zambiri imaphatikizapo antisense DNA, antisense RNA ndi ribozymes.Pakati pawo, chifukwa cha kukhazikika kwakukulu komanso kutsika mtengo kwa DNA ya antisense, DNA ya antisense imakhala ndi malo apamwamba pa kafukufuku wamakono ndi kugwiritsa ntchito mankhwala a antisense nucleic acid.
Fomivirsen sodium (dzina la malonda Vitravene) idapangidwa ndi Ionis Novartis.Mu Ogasiti 1998, a FDA adavomereza kuti azichiza cytomegalovirus retinitis mwa odwala omwe alibe chitetezo chokwanira (makamaka odwala Edzi), kukhala mankhwala oyamba a nucleic acid kugulitsidwa.Fomivirsen imalepheretsa kufotokoza kwapang'onopang'ono kwa mapuloteni a CMV pomangirira ku mRNA yeniyeni (IE2), potero imayendetsa mafotokozedwe amtundu wa ma virus kuti akwaniritse chithandizo chamankhwala.Komabe, chifukwa cha kutuluka kwa mankhwala ochepetsa mphamvu ya kachilombo ka HIV, omwe achepetsa kwambiri chiwerengero cha odwala, mu 2002 ndi 2006, Novartis adaletsa chilolezo chamsika cha mankhwala a Fomivirsen ku Ulaya ndi United States motsatira, ndipo mankhwalawo adayimitsidwa pamsika.
Mipomersen sodium (dzina lamalonda Kynamro) ndi mankhwala a ASO opangidwa ndi kampani yaku France Genzyme.Mu Januwale 2013, a FDA adavomereza kuti azichiza homozygous family hypercholesterolemia.Mipomersen imalepheretsa kufotokoza kwa mapuloteni a ApoB-100 (apolipoprotein) pomanga ku ApoB-100mRNA, potero amachepetsa kwambiri cholesterol ya anthu otsika kachulukidwe lipoprotein, low-density lipoprotein ndi zizindikiro zina, koma chifukwa cha zotsatira zoyipa monga chiwopsezo cha chiwindi, Disembala 13, 2012 idakananso kugulitsa mankhwalawo.
Mu Seputembala 2016, Eteplirsen (dzina lamalonda Exon 51) lopangidwa ndi Sarepta pochiza Duchenne muscular dystrophy (DMD) idavomerezedwa ndi FDA.Odwala a DMD sangathe kufotokozera mapuloteni odana ndi atrophic chifukwa cha kusintha kwa jini ya DMD m'thupi.Eteplirsen makamaka amamangiriza ku exon 51 ya pre-messenger RNA (Pre-mRNA) ya puloteni, imachotsa exon 51, ndikubwezeretsanso majini ena akumunsi Mafotokozedwe abwinobwino a, kulemba ndi kumasulira kuti apeze gawo la dystrophin, kuti akwaniritse zotsatira zochiritsira.
Nusinersen ndi mankhwala a ASO opangidwa ndi Spinraza pofuna kuchiza matenda a spinal muscular atrophy ndipo adavomerezedwa ndi FDA pa December 23, 2016. Mu 2018, Inotesen yopangidwa ndi Tegsedi pofuna kuchiza munthu wamkulu wamtundu wa transthyretin amyloidosis adavomerezedwa ndi FDA.Mu 2019, Golodirsen, yopangidwa ndi Sarepta pochiza Duchenne muscular dystrophy, idavomerezedwa ndi FDA.Lili ndi njira yofananira ndi Eteplirsen, ndipo malo ake ogwirira ntchito amakhala exon 53. M'chaka chomwecho, Volanesorsen, yopangidwa pamodzi ndi Ionisand Akcea pofuna kuchiza hyperchylomicronemia ya banja, inavomerezedwa ndi European Medicines Agency (EMA).Volanesorsen imayang'anira kagayidwe ka triglyceride poletsa kupanga apolipoprotein C-Ⅲ, koma imakhalanso ndi zotsatira zakutsitsa mapulateleti.
Defibrotide ndi oligonucleotide osakaniza ndi plasmin katundu wopangidwa ndi Jazz.Ili ndi 90% ya DNA yamtundu umodzi wa DNA ndi 10% ya DNA yamitundu iwiri.Idavomerezedwa ndi EMA mu 2013 ndipo pambuyo pake idavomerezedwa ndi FDA pochiza mitsempha yayikulu ya chiwindi.Oclusive matenda.Defibrotide imatha kukulitsa ntchito ya plasmin, kukulitsa activator ya plasminogen, kulimbikitsa kuwongolera kwa thrombomodulin, komanso kuchepetsa mawu a von Willebrand factor ndi plasminogen activator inhibitors kuti akwaniritse chithandizo.
siRNA
siRNA ndi kachidutswa kakang'ono ka RNA kokhala ndi kutalika kwake komanso kutsatizana komwe kumapangidwa podula chandamale cha RNA.Ma siRNA awa atha kupangitsa kuwonongeka kwa chandamale cha mRNA ndikukwaniritsa zoletsa za jini.Poyerekeza ndi mankhwala ang'onoang'ono a molekyulu, mphamvu yoletsa jini ya mankhwala a siRNA imakhala yodziwika bwino komanso yothandiza kwambiri.
Pa Ogasiti 11, 2018, mankhwala oyamba a siRNA patisiran (dzina la malonda Onpattro) adavomerezedwa ndi FDA ndikukhazikitsidwa mwalamulo.Ichi ndi chimodzi mwazofunikira kwambiri m'mbiri yachitukuko chaukadaulo wosokoneza wa RNA.Patsiran adapangidwa molumikizana ndi Alnylam ndi Genzyme, othandizira a Sanofi.Ndi mankhwala a siRNA ochizira cholowa cha thyroxine-mediated amyloidosis.Mu 2019, givosiran (dzina la malonda Givlaari) idavomerezedwa ndi FDA ngati mankhwala achiwiri a siRNA ochizira pachimake porphyria mwa akulu.Mu 2020, Alnylam adapanga mankhwala amtundu woyamba wochizira ana ndi akulu.Lumasiran yokhala ndi oxaluria yayikulu idavomerezedwa ndi FDA.Mu Disembala 2020, Inclisiran, yopangidwa pamodzi ndi Novartis ndi Alnylam pochiza hypercholesterolemia wamkulu kapena dyslipidemia yosakanikirana, idavomerezedwa ndi EMA.
Aptamer
Nucleic acid aptamers ndi oligonucleotides omwe amatha kumangirira ku mamolekyu osiyanasiyana omwe amayang'ana monga mamolekyu ang'onoang'ono, DNA, RNA, polypeptides kapena mapuloteni okhala ndi kuyanjana kwakukulu komanso kutsimikizika.Poyerekeza ndi ma antibodies, ma nucleic acid aptamers ali ndi mawonekedwe osavuta kaphatikizidwe, mtengo wotsika komanso mipherezero yambiri, ndipo ali ndi kuthekera kwakukulu kogwiritsa ntchito mankhwala pozindikira matenda, kuchiza ndi kupewa.
Pegaptanib ndi mankhwala oyamba a nucleic acid aptamer opangidwa ndi Valeant pofuna kuchiza kunyowa kwa macular okhudzana ndi zaka ndipo adavomerezedwa ndi FDA mu 2004. Pambuyo pake, adavomerezedwa ndi EMA ndi PMDA mu January 2006 ndi July 2008 ndipo anapita kumsika.Pegaptanib linalake ndipo tikulephera angiogenesis kudzera osakaniza malo kapangidwe ndi mtima endothelial kukula factor kukwaniritsa achire zotsatira.Kuyambira nthawi imeneyo, yakumana ndi mpikisano wamankhwala ofanana ndi Lucentis, ndipo gawo lake la msika latsika kwambiri.
Mankhwala a Nucleic acid akhala malo otentha kwambiri pamsika wamankhwala azachipatala komanso msika watsopano wamankhwala chifukwa chakuchiritsa kwawo komanso kakulidwe kakang'ono.Monga mankhwala omwe akubwera, amakumana ndi zovuta pamene akukumana ndi mwayi.Chifukwa cha mawonekedwe ake akunja, kukhazikika, kukhazikika komanso kupereka kwabwino kwa nucleic acid kwakhala njira yayikulu yowonera ngati oligonucleotides ikhoza kukhala mankhwala othandiza kwambiri a nucleic acid.Zotsatira zomwe sizinali zolephereka nthawi zonse zakhala mfundo yofunika kwambiri ya mankhwala a nucleic acid omwe sangathe kunyalanyazidwa.Komabe, mankhwala a nucleic acid amatha kukhudza kufotokozera kwa majini omwe amachititsa matenda kuchokera ku mizu, ndipo amatha kukwaniritsa ndondomeko yeniyeni pamlingo umodzi, womwe uli ndi zizindikiro za "kuchiza zomwe zimayambitsa ndi kuchiza zizindikiro".Poona kusinthasintha kwa matenda ochulukirapo, chithandizo chokha cha majini chikhoza kupeza zotsatira zokhazikika.Ndi kusintha kosalekeza, ungwiro ndi kupita patsogolo kwa matekinoloje ofananirako, mankhwala a nucleic acid omwe amaimiridwa ndi antisense nucleic acids, siRNA, ndi ma nucleic acid aptamers adzayambitsanso njira yatsopano yochizira matenda ndi makampani opanga mankhwala.
RZotsatira:
[1] Liu Shaojin, Feng Xuejiao, Wang Junshu, Xiao Zhengqiang, Cheng Pingsheng.Kusanthula kwa msika kwa mankhwala a nucleic acid m'dziko langa ndi zoyeserera[J].Chinese Journal of Biological Engineering, 2021, 41(07): 99-109.
[2] Chen Wenfei, Wu Fuhua, Zhang Zhirong, Sun Xun.Kafukufuku akupita patsogolo mu pharmacology ya mankhwala ogulitsidwa a nucleic acid[J].Chinese Journal of Pharmaceuticals, 2020, 51 (12): 1487-1496.
[3] Wang Jun, Wang Lan, Lu Jiazhen, Huang Zhen.Kuwunika kwa mphamvu ndi kafukufuku wamankhwala omwe amagulitsidwa a nucleic acid[J].Chinese Journal of New Drugs, 2019, 28(18): 2217-2224.
Za wolemba: Sha Luo, wofufuza zamankhwala waku China komanso wogwira ntchito zachitukuko, pano akugwira ntchito kukampani yayikulu yofufuza zamankhwala ndi chitukuko chapakhomo, ndipo akudzipereka pakupanga kafukufuku ndi chitukuko chamankhwala atsopano achi China.
Zogwirizana nazo:
Nthawi yotumiza: Nov-19-2021
