Pfizer's mRNA yekudzivirira yeCOVID yakadzora chishuwo chekushandisa ribonucleic acid (RNA) sechinangwa chekurapa.Nekudaro, kunanga RNA nemamorekuru madiki kunonetsa zvakanyanya.

RNA inongova nematombo mana ekuvaka: adenine (A), cytosine (C), guanine (G), uye uracil (U) inotsiva thymine (T) inowanikwa muDNA.Izvi zvinoita kuti kusarudza zvinodhaka kuve chipingamupinyi chisingakundiki.Kusiyana neizvi, kune makumi maviri nemaviri echisikigo amino acids ayo ekugadzira mapuroteni, izvo zvinotsanangura kuti nei akawanda mapuroteni-anonangidzira mishonga ane sarudzo yakanaka.

Chimiro uye basa reRNA

Semapuroteni, mamorekuru eRNA ane zvimiro zvechipiri uye zvepamusoro, sezvakaratidzwa mumufananidzo uri pazasi.Kunyangwe iwo ari ma-single-chain macromolecules, chimiro chavo chechipiri chinotora chimiro kana base pairing ichikonzera bulges, zvishwe, uye helices.Zvadaro, kupeta kwemativi matatu kunotungamira kuchimiro chepamusoro cheRNA, icho chakakosha pakugadzikana uye kushanda kwayo.

Mufananidzo 1. Chimiro cheRNA

Kune marudzi matatu eRNA:

• Nhume RNA (mRNA)inonyora ruzivo rwemajini kubva kuDNA uye inotamiswa senheyo yekutevedzana pane ribosome;l
• Ribosomal RNA (rRNA)chikamu cheprotein-synthesizing organelles inonzi ribosomes, iyo inotengeswa kune cytoplasm uye inobatsira kushandura ruzivo mumRNA kuita mapuroteni;
• Kutamisa RNA (tRNA)ndicho chinongedzo pakati pemRNA neamino acid cheni inoumba puroteni.

Kutarisa RNA sechinangwa chekurapa kunoyevedza.Zvakaonekwa kuti chete 1.5% yegenome yedu inozoshandurwa kuita mapuroteni, nepo 70% -90% inonyorwa muRNA.Mamorekuru eRNA ndiwo anonyanya kukosha kune zvese zvipenyu.Sekureva kwaFrancis Crick's "central dogma", basa rakakosha reRNA kushandura ruzivo rwemajini kubva kuDNA kuita mapuroteni.Kunze kwezvo, mamorekuru eRNA anewo mamwe mabasa, anosanganisira:

• Kuita seadapter mamorekuru muprotein synthesis;l
• Kushanda semutumwa pakati peDNA uye ribosome;l
• Ndivo vatakuri veruzivo rwemajini mumasero mapenyu ose;l
• Kusimudzira ribosomal kusarudzwa kweiyo chaiyo amino acids, inodiwa pakugadzira mapuroteni matsvain vivo.

Mishonga inorwisa mabhakitiriya

Kunyangwe zvakawanikwa kare kuma1940, maitiro ekuita kwemishonga yakawanda inorwisa mabhakitiriya haina kujekeswa kusvika pakupera kwema1980.Zvinoonekwa kuti chikamu chikuru chemishonga inorwisa mabhakitiriya inoshanda nekusunga kune bhakitiriya ribosomes kudzivirira kubva pakugadzira mapuroteni akakodzera, nekudaro vachiuraya bhakitiriya.

Semuenzaniso, maantibioti aminoglycoside anosunga kuA-saiti ye16S rRNA, inova chikamu che30S ribosome subunit, yobva yakanganisa maprotein synthesis kuvhiringa kukura kwebhakitiriya, zvichizoguma nekufa kwesero.Iyo A-saiti inoreva iyo aminoacyl saiti, inozivikanwawo seiyo tRNA yekugamuchira saiti.Iyo yakadzama yekudyidzana pakati peaminoglycoside zvinodhaka, sengeparomomycin, uye A-saiti yeE. coliRNA inoratidzwa pazasi.

Mufananidzo 2. Kudyidzana pakati peparomomycin neA-saiti yeE. coliRNA

Nehurombo, mazhinji A-saiti inhibitors, anosanganisira aminoglycoside zvinodhaka, ane chengetedzo nyaya dzakadai nephrotoxicity, dose-dependent, uye chaiyo isingachinjiki ototoxicity.Izvi huturu mhedzisiro yekushaikwa kwekusarudza mune aminoglycoside mishonga yekuziva RNA mamorekuru madiki.

Sezvinoratidzwa mumufananidzo uri pasi apa: (a) chimiro chebhakitiriya, (b) membrane yemasero evanhu, uye (c) mitochondrial A-saiti yevanhu yakafanana zvikuru, zvichiita kuti A-site inhibitors isungirire kune vose.

Mufananidzo 3. Iyo isina-selective A-site inhibitor inosunga

Tetracycline mishonga inorwisa mabhakitiriya inodzivisawo A-saiti yeRRNA.Ivo vanosarudza kuvharira mabhakitiriya mapuroteni synthesis nekudzokera kumashure achisunga kune helical dunhu (H34) pane iyo 30S subunit yakasanganiswa neMg.²⁺.

Kune rimwe divi, macrolide mishonga inorwisa mabhakitiriya inosunga pedyo nenzvimbo yekubuda (E-saiti) yebhakitiriya ribosome tunnel ye nascent peptides (NPET) uye ichivharira zvishoma, nekudaro ichitadzisa bhakitiriya mapuroteni synthesis.Pakupedzisira, oxazolidinone antibiotics akadailinezolid(Zyvox) inosunga kune yakadzika cleft mubhakitiriya 50S ribosomal subunit, iyo yakakomberedzwa ne23S rRNA nucleotides.

Antisense oligonucleotides (ASO)

Iyo antisense mishonga ikemikari-modified nucleic acid polymers inonangana neRNA.Ivo vanovimba neWatson-Crick base pairing kuti vasunge kunanga mRNA, zvichikonzera kunyarara kwemajini, steric blockade, kana splicing shanduko.MaASO anogona kudyidzana nepre-RNAs musero nucleus uye mature mRNAs mucytoplasm.Ivo vanogona kunanga exons, introns, uye nzvimbo dzisina kushandurwa (UTRs).Parizvino, anopfuura gumi nemaviri emishonga yeASO yakabvumidzwa neFDA.

Mufananidzo 4. Antisense Technology

Mishonga midiki yemamorekuru inonangana neRNA

Muna 2015, Novartis vakashuma kuti vakawana SMN2 splicing regulator inonzi Branaplam, iyo inosimudzira kushamwaridzana kweU1-pre-mRNA uye kununura SMA mbeva.

Kune rimwe divi, PTC/Roche's Risdiplam (Evrysdi) yakabvumidzwa neFDA muna 2020 kurapwa kweSMA.Kufanana neBranaplam, Risdiplam inoshandawo nekudzora kupatsanurwa kweakakodzera SMN2 majini kuburitsa anoshanda eSMN mapuroteni.

RNA degraders

RBM inomirira RNA-binding motif protein.Chaizvoizvo, indole sulfonamide inonamira yemamorekuru.Iyo inosarudza kutora RBM39 kune CRL4-DCAF15 E3 ubiquitin ligase, inosimudzira RBM39 polyubiquitination uye kuderera kweprotein.Genetic depletion kana sulfonamide-mediated degradation yeRBM39 induces akakosha genome-wide splicing abnormalities, zvinozopedzisira zvakonzera kufa kwesero.

RNA-PROTACs inogadzirwa kuderedza RNA-binding proteins (RBPs).PROTAC inoshandisa chinongedzo kubatanidza iyo E3 ligase ligand kuRNA ligand, iyo inosunga kuRNA neRBPs.Sezvo RBP ine zvimiro zvemaitiro zvinogona kusunga kune chaiyo oligonucleotide sequences, RNA-PROTAC inoshandisa oligonucleotide sequence se ligand yeprotein yekufarira (POI).Mhedzisiro yekupedzisira ndeyekuderedzwa kweRBPs.

Munguva pfupi yapfuura, Purofesa Matthew Disney weScripps Institution of Oceanography akagadzira RNAribonuclease-targeting chimeras (RiboTACs).RiboTAC iheterofunctional molecule inobatanidza RNase L ligand uye RNA ligand ine linker.Inogona kunyatso tora endo native RNase L kune chaiyo RNA tarisiro, uye yozobudirira kubvisa RNA uchishandisa cellular nucleic acid breakdown mechanism (RNNase L).

Sezvo vaongorori vachidzidza zvakawanda nezve kudyidzana pakati pemamorekuru madiki nezvinangwa zveRNA, mishonga yakawanda inoshandisa nzira iyi ichabuda mune ramangwana.