Umuthi wokugomela i-mRNA we-Pfizer we-COVID usuvuselele uthando lokusebenzisa i-ribonucleic acid (RNA) njengendlela yokwelapha.Kodwa-ke, ukukhomba i-RNA ngama-molecule amancane kuyinselele enkulu.

I-RNA inamabhulokhi wokwakha amane kuphela: i-adenine (A), i-cytosine (C), i-guanine (G), ne-uracil (U) ethatha indawo ye-thymine (T) etholakala ku-DNA.Lokhu kwenza ukukhetha kwezidakamizwa kube yisithiyo cishe esingenakunqotshwa.Ngokuphambene, kunama-amino acid emvelo angama-22 enza amaprotheni, okuchaza ukuthi kungani izidakamizwa eziningi eziqondiswe ngamaprotheni zinokukhetha okuhle.

Isakhiwo kanye nomsebenzi we-RNA

Njengamaprotheni, ama-molecule e-RNA anezakhiwo zesibili neziphakeme, njengoba kukhonjisiwe emfanekisweni ongezansi.Nakuba zingama-macromolecule e-single-chain, ukwakheka kwawo kwesibili kwakheka lapho ukubhanqa kwesisekelo kubangela amaqhuqhuva, izihibe, nama-helices.Khona-ke, ukugoqa okunezinhlangothi ezintathu kuholela esakhiweni esiphakeme se-RNA, esibalulekile ekuzinzeni nasekusebenzeni kwayo.

Umfanekiso 1. Isakhiwo se-RNA

Kunezinhlobo ezintathu ze-RNA:

• Isilayezi se-RNA (mRNA)ibhala ulwazi lofuzo olusuka ku-DNA futhi ludluliselwe njengokulandelana kwesisekelo ku-ribosome;l
• I-Ribosomal RNA (rRNA)iyingxenye yama-organelle ahlanganisa amaprotheni abizwa ngokuthi ama-ribosomes, athunyelwa ku-cytoplasm futhi asize ukuhumusha ulwazi oluku-mRNA lube amaprotheni;
• Dlulisa i-RNA (tRNA)isixhumanisi phakathi kwe-mRNA neketango le-amino acid elakha amaprotheni.

Ukukhomba i-RNA njengenhloso yokwelapha kuyathandeka kakhulu.Kutholwe ukuthi yi-1.5% kuphela ye-genome yethu egcina ihunyushwe ibe amaprotheni, kanti ama-70% -90% alotshwe ku-RNA.Ama-molecule e-RNA abaluleke kakhulu kuzo zonke izinto eziphilayo.Ngokusho "kwemfundiso eyinhloko" kaFrancis Crick, indima ebaluleke kakhulu ye-RNA ukuhumusha ulwazi lofuzo olusuka ku-DNA lube amaprotheni.Ngaphandle kwalokho, ama-molecule e-RNA aneminye imisebenzi, kuhlanganise:

• Ukusebenza njengama-adaptha ama-molecule ku-protein synthesis;l
• Ukukhonza njengesithunywa phakathi kwe-DNA kanye ne-ribosome;l
• Bangabathwali bolwazi lofuzo kuwo wonke amangqamuzana aphilayo;l
• Ukukhuthaza ukukhethwa kwe-ribosomal kwama-amino acid alungile, okudingekayo ekuhlanganiseni amaprotheni amashange vivo.

Ama-antibiotics

Naphezu kokutholakala ekuqaleni kwawo-1940, indlela yokusebenza yama-antibiotic amaningi ayizange ichazwe kuze kube sekupheleni kwawo-1980.Kutholwe ukuthi ingxenye enkulu yemithi elwa namagciwane isebenza ngokubopha ama-ribosomes ebhaktheriya ukuwavimbela ekwenzeni amaprotheni afanele, ngaleyo ndlela abulale amagciwane.

Isibonelo, ama-antibiotic e-aminoglycoside abophezela ku-A-site ye-16S rRNA, eyingxenye ye-30S ribosome subunit, bese iphazamisa ukuhlanganiswa kwamaprotheni ukuze iphazamise ukukhula kwebhaktheriya, okuholela ekufeni kweseli.I-A-site ibhekisela kusayithi ye-aminoacyl, eyaziwa nangokuthi isayithi yokwamukela i-tRNA.Ukuxhumana okuningiliziwe phakathi kwezidakamizwa ze-aminoglycoside, njengei-paromomycin, kanye ne-A-site yeE. coliI-RNA ikhonjiswe ngezansi.

Umfanekiso 2. Ukusebenzisana phakathi kwe-paromomycin kanye ne-A-site yeE. coliI-RNA

Ngeshwa, ama-A-site inhibitor amaningi, okuhlanganisa nezidakamizwa ze-aminoglycoside, anezinkinga zokuphepha ezifana ne-nephrotoxicity, ukuncika kumthamo, kanye ne-ototoxicity ethile engalungiseki.Lobu buthi buwumphumela wokuntuleka kokukhetha emithini ye-aminoglycoside yokubona ama-molecule amancane e-RNA.

Njengoba kuboniswe emfanekisweni ongezansi: (a) ukwakheka kwebhaktheriya, (b) ulwelwesi lweseli lomuntu, kanye (c) nesizinda se-mitochondrial A kufana kakhulu, okwenza ama-A-site inhibitors abophe kuzo zonke.

Umfanekiso 3. Ukubopha okungakhethi kwe-A-site inhibitor

I-Tetracycline antibiotics iphinde ivimbele indawo ye-A ye-rRNA.Ngokukhetha zivimbela ukwakheka kwamaprotheni ebhaktheriya ngokubopha ngokuhlehlayo endaweni ye-helical (H34) ku-30S subunit ehlanganiswe ne-Mg.²⁺.

Ngakolunye uhlangothi, ama-macrolide antibiotics abopha eduze kwendawo yokuphuma (E-site) yomhubhe webhaktheriya we-ribosome we-nascent peptides (NPET) futhi awuvimbe kancane, ngaleyo ndlela avimbele ukuhlanganiswa kwamaprotheni ebhaktheriya.Ekugcineni, oxazolidinone antibiotic ezifanai-linezolid(I-Zyvox) ibophezela endaweni ejulile ku-bacterial 50S ribosomal subunit, ezungezwe ama-nucleotide angu-23S rRNA.

I-Antisense oligonucleotides (ASO)

Izidakamizwa ze-antisense ziyi-chemical-modified nucleic acid polymers eziqondise i-RNA.Bathembela ekumatanisweni kwesisekelo se-Watson-Crick ukuze babophezele ekuqondisweni kwe-mRNA, okuholela ekuthulisweni kofuzo, ukuvinjwa kwe-steric, noma ukuguqulwa kwe-splicing.Ama-ASO angasebenzisana nama-pre-RNA ku-nucleus yeseli kanye nama-mRNA avuthiwe ku-cytoplasm.Bangaqondisa ama-exons, ama-intron, nezifunda ezingahumushiwe (ama-UTR).Kuze kube manje, izidakamizwa ze-ASO ezingaphezu kweshumi nambili zivunyelwe yi-FDA.

Umfanekiso 4. Ubuchwepheshe be-Antisense

Izidakamizwa ze-molecule ezincane eziqondise i-RNA

Ngo-2015, uNovartis wabika ukuthi bathole isilawuli sokuhlanganisa i-SMN2 esibizwa nge-Branaplam, esithuthukisa ukuhlangana kwe-U1-pre-mRNA futhi sihlenge amagundane e-SMA.

Ngakolunye uhlangothi, i-PTC/Roche's Risdiplam (Evrysdi) yagunyazwa yi-FDA ngo-2020 ukuze zelashwe i-SMA.Njenge-Branaplam, i-Risdiplam iphinde isebenze ngokulawula ukuhlukaniswa kwezakhi zofuzo ezifanele ze-SMN2 ukuze kukhiqizwe amaprotheni e-SMN asebenzayo.

I-RNA yokwehlisa amandla

I-RBM imele i-RNA-binding motif protein.Eqinisweni, i-indole sulfonamide iyingcina yamangqamuzana.Ikhetha ngokukhetha i-RBM39 ku-CRL4-DCAF15 E3 ubiquitin ligase, ithuthukisa i-RBM39 polyubiquitination kanye nokuwohloka kwamaprotheni.Ukuncipha kwezakhi zofuzo noma ukuwohloka kwe-sulfonamide-mediated ye-RBM39 kudala ukuphazamiseka okuphawulekayo kokuhlukanisa i-genome-wide, okuholela ekufeni kweseli.

Ama-RNA-PROTAC athuthukiswa ukuze alulaze amaprotheni abopha i-RNA (RBPs).I-PROTAC isebenzisa isixhumanisi ukuze ixhume i-E3 ligase ligand ku-RNA ligand, ebophezela ku-RNA nama-RBP.Njengoba i-RBP iqukethe izizinda zesakhiwo ezingabopha ukulandelana kwe-oligonucleotide ethile, i-RNA-PROTAC isebenzisa ukulandelana kwe-oligonucleotide njenge-ligand ye-protein of interest (POI).Umphumela wokugcina uwukucekelwa phansi kwama-RBP.

Muva nje, uProfesa Matthew Disney we-Scripps Institution of Oceanography usungule i-RNAi-ribonuclease-targeting chimeras (RiboTACs).I-RiboTAC iyi-molecule ye-heterofunctional ehlanganisa i-RNase L ligand kanye ne-RNA ligand enesixhumanisi.Ingakwazi ukuqasha ngokukhethekile i-RNase L engapheli ekuqondisweni kwe-RNA ethile, bese iqeda ngempumelelo i-RNA isebenzisa indlela yokuwohloka kwe-nucleic acid yeselula (RNNase L).

Njengoba abacwaningi befunda kabanzi mayelana nokusebenzisana phakathi kwama-molecule amancane nokuhlosiwe kwe-RNA, izidakamizwa eziningi ezisebenzisa le ndlela zizovela esikhathini esizayo.