Ugonyo lwe-Pfizer lwe-mRNA lwe-COVID lulawule ukuthanda ukusebenzisa i-ribonucleic acid (RNA) njengento ekujoliswe kuyo kunyango.Nangona kunjalo, ukujolisa kwi-RNA ngeemolekyuli ezincinci kulucelomngeni olukhulu.

I-RNA ineebhloko ezine zokwakha kuphela: i-adenine (A), i-cytosine (C), i-guanine (G), kunye ne-uracil (U) ethatha indawo ye-thymine (T) efumaneka kwi-DNA.Oku kwenza ukuba ukukhetha amachiza kube ngumqobo ophantse ungoyiswa.Ngokwahlukileyo koko, kukho ii-amino acids zendalo ezingama-22 ezenza iiproteni, nto leyo echaza ukuba kutheni uninzi lwamachiza ajolise kwiproteni enokukhetha okulungileyo.

Ubume kunye nomsebenzi we-RNA

Njengeeprotheyini, iimolekyuli ze-RNA zinezakhiwo zesibini kunye neziphezulu, njengoko kuboniswe kumzobo ongezantsi.Nangona ziyi-macromolecules enye-chain, ulwakhiwo lwazo lwesibini luthatha imilo xa ukubhanqa isiseko kubangela i-bulges, looops, kunye ne-helices.Emva koko, ukusongwa kwamacala amathathu kukhokelela kulwakhiwo olukwinqanaba eliphezulu le-RNA, nto leyo ebalulekileyo kuzinzo nokusebenza kwayo.

Umzobo 1. Ubume be-RNA

Kukho iintlobo ezintathu zeRNA:

• Isithunywa se-RNA (mRNA)ibhala ulwazi lofuzo olusuka kwi-DNA kwaye idluliselwe njengolandelelwano olusisiseko kwi-ribosome;l
• I-Ribosomal RNA (rRNA)yinxalenye yeprotein-synthesizing organelles ebizwa ngokuba yi-ribosomes, ethunyelwa kwi-cytoplasm kwaye incede ukuguqulela ulwazi kwi-mRNA kwiiprotheni;
• Ukutshintshela i-RNA (tRNA)likhonkco phakathi kwe-mRNA kunye nekhonkco le-amino acid elenza iprotheni.

Ukujolisa i-RNA njengenjongo yonyango inomtsalane kakhulu.Kufunyenwe ukuba kuphela i-1.5% ye-genome yethu ekugqibeleni iguqulelwe kwiprotheni, ngelixa i-70% -90% ibhalwe kwi-RNA.Iimolekyuli ze-RNA zezona zibalulekileyo kuzo zonke izinto eziphilayo.Ngokwe-“central dogma” kaFrancis Crick, eyona ndima ibalulekileyo ye-RNA kukuguqulela ulwazi lwemfuzo olusuka kwi-DNA lube ziiproteni.Ngaphandle koko, iimolekyuli zeRNA zineminye imisebenzi, kuquka:

• Ukusebenza njengeemolekyuli zeadaptha kwiprotheni synthesis;l
• Ukukhonza njengomthunywa phakathi kwe-DNA kunye ne-ribosome;l
• Bangabathwali bolwazi lwemfuza kuzo zonke iiseli eziphilayo;l
• Ukukhuthaza ukukhethwa kwe-ribosomal yee-amino acids ezichanekileyo, eziyimfuneko ekwenzeni iiprotheni ezintshakwi vivo.

Amayeza okubulala iintsholongwane

Ngaphandle kokufunyanwa kwangoko ngeminyaka yoo-1940, indlela yokusebenza yamayeza amaninzi okubulala iintsholongwane ayizange icaciswe kude kube sekupheleni kweminyaka yoo-1980.Kufunyaniswe ukuba uninzi lwamayeza okubulala iintsholongwane lusebenza ngokuzibophelela kwii-ribosomes zebhaktiriya ukuzithintela ekwenzeni iiproteni ezifanelekileyo, ngaloo ndlela zibulala iibhaktheriya.

Ngokomzekelo, i-antibiotics ye-aminoglycoside ibophelela kwi-A-site ye-16S rRNA, eyinxalenye ye-30S ye-ribosome subunit, kwaye emva koko iphazamise i-protein synthesis ukuphazamisa ukukhula kwebhaktheriya, ekugqibeleni ikhokelela ekufeni kweeseli.I-A-site ibhekisa kwindawo ye-aminoacyl, ekwaziwa ngokuba yindawo yokwamkela i-tRNA.Intsebenziswano eneenkcukacha phakathi kweziyobisi aminoglycoside, ezifanaparomomycin, kunye ne-A-site yeE. coliI-RNA iboniswe ngezantsi.

Umzobo 2. Intsebenziswano phakathi kwe-paromomycin kunye ne-A-site yeE. coliI-RNA

Ngelishwa, uninzi lwe-A-site inhibitors, kubandakanywa neziyobisi ze-aminoglycoside, zinemiba yokhuseleko efana ne-nephrotoxicity, i-dose-dependent, kunye ne-ototoxicity ethile engaguqukiyo.Ezi tyhefu zisisiphumo sokunqongophala kokukhetha kumachiza e-aminoglycoside ekuqapheliseni iimolekyuli ezincinci ze-RNA.

Njengoko kubonisiwe kumzobo ongezantsi: (a) isakhiwo sebhaktheriya, (b) i-membrane yeseli yomntu, kunye (c) i-mitochondrial A-site yabantu ifana kakhulu, okwenza i-A-site inhibitors ibophe kuzo zonke.

Umzobo 3. I-non-elective A-site inhibitor binding

I-Tetracycline antibiotics iphinda inqanda indawo ye-A ye-rRNA.Ngokukhethekileyo banqanda ukuhlanganiswa kweprotheyini yebhaktheriya ngokubopha ngokuphindaphindiweyo kwingingqi ye-helical (H34) kwi-30S subunit ehlanganiswe ne-Mg.²⁺.

Kwelinye icala, i-macrolide antibiotics ibophelela kufutshane nendawo yokuphuma (E-site) yetonela ye-ribosome yebhaktiriya ye-nascent peptides (NPET) kwaye iyithintele ngokuyinxenye, ngaloo ndlela inqanda ukuhlanganiswa kweprotheyini yebhaktiriya.Ekugqibeleni, antibiotics oxazolidinone ezifanalinezolid(Zyvox) ibophelela kumngxuma onzulu kwibhaktiriya i-50S ribosomal subunit, engqongwe yi-23S rRNA nucleotides.

I-Antisense oligonucleotides (ASO)

Amachiza e-antisense yi-chemical-modified nucleic acid polymers ezijolise kwi-RNA.Baxhomekeke kwisiseko se-Watson-Crick sokubhanqa ukubophelela ekujoliswe kuko kwi-mRNA, okukhokelela ekuthulisweni kofuzo, ukuvalwa kwe-steric, okanye ukuguqulwa kwe-splicing.Ii-ASO zinokusebenzisana ne-pre-RNAs kwi-nucleus yeseli kunye ne-mRNA evuthiweyo kwi-cytoplasm.Banokujolisa kwii-exons, ii-introns, kunye nemimandla engaguqulelwanga (UTRs).Ukuza kuthi ga ngoku, ngaphezulu kweshumi elinesibini lamachiza e-ASO avunyiweyo yi-FDA.

Umzobo 4. I-Antisense Technology

Amachiza amancinci emolekyuli ajolise kwi-RNA

Ngo-2015, uNovartis waxela ukuba bafumene umlawuli we-SMN2 wokuqhawula obizwa ngokuba yi-Branaplam, ephucula umbutho we-U1-pre-mRNA kunye nokuhlangula iigundane ze-SMA.

Ngakolunye uhlangothi, i-PTC / Roche's Risdiplam (Evrysdi) yamkelwe yi-FDA kwi-2020 yonyango lwe-SMA.Njenge-Branaplam, i-Risdiplam iphinda isebenze ngokulawula ukuchithwa kweejene ze-SMN2 ezifanelekileyo ukuvelisa iiprotheni ze-SMN ezisebenzayo.

I-RNA izokwehlisa umgangatho

I-RBM imele i-RNA-binding motif protein.Ngokusisiseko, i-indole sulfonamide sisincamathelisi semolekyuli.Ikhetha ngokukhetha i-RBM39 kwi-CRL4-DCAF15 E3 ubiquitin ligase, ukukhuthaza i-RBM39 polyubiquitination kunye nokuthotywa kweprotheni.Ukuncipha kwemfuza okanye ukuthotywa kwe-sulfonamide-mediated ye-RBM39 kubangela ukungahambi kakuhle kwe-genome-wide-wide splicing, ekugqibeleni kukhokelela ekufeni kweeseli.

I-RNA-PROTACs iphuhliswe ukuthobisa i-RNA-binding proteins (RBPs).I-PROTAC isebenzisa ikhonkco ukudibanisa i-E3 ligase ligand kwi-RNA ligand, ebophelela kwi-RNA kunye ne-RBPs.Ekubeni i-RBP iqulethe imimandla yezakhiwo ezinokuthi zibophe ukulandelelana kwe-oligonucleotide ethile, i-RNA-PROTAC isebenzisa ulandelelwano lwe-oligonucleotide njenge-ligand yeprotheni yomdla (POI).Isiphumo sokugqibela kukuthotywa kweRBPs.

Kutshanje, uNjingalwazi uMatthew Disney weScripps Institution of Oceanography uye wavelisa iRNAi-ribonuclease-targeting chimeras (RiboTACs).I-RiboTAC yi-molecule ye-heterofunctional edibanisa i-RNase L ligand kunye ne-RNA ligand ene-linker.Inokuthi ifune ngokukodwa i-RNase L engapheliyo kwiithagethi ezithile ze-RNA, kwaye emva koko isuse ngempumelelo i-RNA isebenzisa i-nucleic acid breakdown mechanism (i-RNse L).

Njengoko abaphandi befunda ngakumbi malunga nokusebenzisana phakathi kweemolekyuli ezincinci kunye neethagethi ze-RNA, amachiza amaninzi asebenzisa le ndlela aya kuvela kwixesha elizayo.