Pfizer's mRNA tshuaj tiv thaiv rau COVID tau ua rau muaj kev mob siab rau kev siv ribonucleic acid (RNA) ua lub hom phiaj kho.Txawm li cas los xij, tsom RNA nrog cov molecules me yog qhov nyuaj heev.

RNA tsuas muaj plaub lub tsev thaiv: adenine (A), cytosine (C), guanine (G), thiab uracil (U) uas hloov thymine (T) pom hauv DNA.Qhov no ua rau kev xaiv tshuaj yuav luag tsis muaj kev cuam tshuam.Nyob rau hauv sib piv, muaj 22 tej yam ntuj tso amino acids uas pleev proteins, uas piav qhia vim li cas feem ntau cov protein-targeting tshuaj muaj kuj zoo xaiv.

Cov qauv thiab kev ua haujlwm ntawm RNA

Zoo li cov proteins, RNA molecules muaj cov qauv theem nrab thiab qib theem, raws li pom hauv daim duab hauv qab no.Txawm hais tias lawv yog ib leeg-chain macromolecules, lawv cov qauv theem nrab yuav zoo li thaum lub hauv paus ua ke ua rau bulges, loops, thiab helices.Tom qab ntawd, peb-dimensional folding ua rau lub tertiary qauv ntawm RNA, uas yog ib qho tseem ceeb rau nws stability thiab muaj nuj nqi.

Daim duab 1. Cov qauv ntawm RNA

Muaj peb hom RNA:

• Neeg xa xov liaison RNA (mRNA)rhais cov ntaub ntawv caj ces los ntawm DNA thiab raug xa mus raws li ib theem zuj zus mus rau ribosome;l
• Ribosomal RNA (rRNA)yog ib feem ntawm cov protein-synthesizing organelles hu ua ribosomes, uas yog exported rau lub cytoplasm thiab pab txhais cov ntaub ntawv nyob rau hauv mRNA rau cov proteins;
• Hloov RNA (tRNA)yog qhov txuas ntawm mRNA thiab cov amino acid saw uas ua rau cov protein.

Targeting RNA raws li lub hom phiaj kho yog qhov txaus nyiam heev.Nws tau pom tias tsuas yog 1.5% ntawm peb cov genome thaum kawg tau muab txhais ua cov protein, thaum 70% -90% tau muab tso rau hauv RNA.RNA molecules yog qhov tseem ceeb tshaj plaws rau txhua yam muaj sia nyob.Raws li Francis Crick's "central dogma", lub luag haujlwm tseem ceeb tshaj plaws ntawm RNA yog txhais cov ntaub ntawv caj ces los ntawm DNA rau hauv cov protein.Tsis tas li ntawd, RNA molecules tseem muaj lwm yam haujlwm, suav nrog:

• Ua raws li adapter molecules hauv protein synthesis;l
• Ua haujlwm ua tus xa xov ntawm DNA thiab ribosome;l
• Lawv yog cov nqa ntawm cov ntaub ntawv caj ces hauv txhua lub hlwb nyob;l
• Txhawb nqa ribosomal xaiv ntawm qhov tseeb amino acids, uas yog tsim nyog rau synthesizing tshiab proteinshauv vivo.

Tshuaj tua kab mob

Txawm hais tias tau tshawb pom thaum ntxov li xyoo 1940, cov txheej txheem ntawm kev ua ntawm ntau cov tshuaj tua kab mob tsis tau piav qhia txog thaum xyoo 1980s.Nws tau pom tias feem ntau ntawm cov tshuaj tua kab mob ua los ntawm kev khi rau cov kab mob ribosomes los tiv thaiv lawv los ntawm kev tsim cov proteins uas tsim nyog, yog li tua cov kab mob.

Piv txwv li, cov tshuaj tua kab mob aminoglycoside khi rau A-site ntawm 16S rRNA, uas yog ib feem ntawm 30S ribosome subunit, thiab tom qab ntawd cuam tshuam cov protein synthesis los cuam tshuam cov kab mob loj hlob, thaum kawg ua rau kev tuag ntawm tes.A-site yog hais txog qhov chaw aminoacyl, tseem hu ua tRNA txais qhov chaw.Cov ncauj lus kom ntxaws ntawm cov tshuaj aminoglycoside, xws liparomomycin, thiab A-site ntawmE. coliRNA qhia hauv qab no.

Daim duab 2. Kev sib cuam tshuam ntawm paromomycin thiab A-site ntawmE. coliRNA

Hmoov tsis zoo, ntau A-site inhibitors, suav nrog cov tshuaj aminoglycoside, muaj teeb meem kev nyab xeeb xws li nephrotoxicity, koob tshuaj-dependent, thiab tshwj xeeb irreversible ototoxicity.Cov tshuaj toxicity no yog tshwm sim los ntawm qhov tsis muaj kev xaiv hauv cov tshuaj aminoglycoside kom paub txog RNA me me molecules.

Raws li pom hauv daim duab hauv qab no: (a) cov qauv ntawm cov kab mob, (b) tib neeg cell membrane, thiab (c) tib neeg mitochondrial A-site zoo sib xws, ua rau A-site inhibitors khi rau tag nrho lawv.

Daim duab 3. Qhov tsis xaiv A-site inhibitor khi

Tetracycline tshuaj tua kab mob kuj inhibit A-site ntawm rRNA.Lawv xaiv inhibit cov kab mob protein synthesis los ntawm reversibly khi rau thaj tsam helical (H34) ntawm 30S subunit complexed nrog Mg.²⁺.

Ntawm qhov tod tes, cov tshuaj tua kab mob macrolide khi ze ntawm qhov chaw tawm (E-site) ntawm cov kab mob ribosome qhov rau nascent peptides (NPET) thiab ib feem thaiv nws, yog li inhibiting kab mob protein synthesis.Thaum kawg, oxazolidinone tshuaj tua kab mob xws lilinezolid(Zyvox) khi rau qhov tob tob hauv cov kab mob 50S ribosomal subunit, uas nyob ib puag ncig los ntawm 23S rRNA nucleotides.

Antisense oligonucleotides (ASO)

Cov tshuaj antisense yog tshuaj hloov kho nucleic acid polymers uas tsom RNA.Lawv cia siab rau Watson-Crick puag ua khub los khi rau lub hom phiaj mRNA, uas ua rau cov noob nyob ntsiag to, steric blockade, lossis hloov pauv hloov pauv.ASOs tuaj yeem cuam tshuam nrog pre-RNAs hauv cell nucleus thiab mRNAs paub tab hauv cytoplasm.Lawv tuaj yeem tsom mus rau exons, introns, thiab thaj chaw tsis tau txhais lus (UTRs).Txog niaj hnub no, ntau tshaj li kaum ob cov tshuaj ASO tau pom zoo los ntawm FDA.

Daim duab 4. Antisense Technology

Cov tshuaj molecule me tsom rau RNA

Xyoo 2015, Novartis tau tshaj tawm tias lawv tau pom SMN2 splicing regulator hu ua Branaplam, uas txhim kho kev koom tes ntawm U1-pre-mRNA thiab cawm SMA nas.

Ntawm qhov tod tes, PTC / Roche's Risdiplam (Evrysdi) tau pom zoo los ntawm FDA hauv 2020 rau kev kho SMA.Zoo li Branaplam, Risdiplam kuj ua haujlwm los ntawm kev tswj cov kev sib txuas ntawm cov noob SMN2 uas tsim nyog los tsim cov SMN proteins ua haujlwm.

RNA degraders

RBM stands rau RNA-binding motif protein.Qhov tseem ceeb, indole sulfonamide yog cov nplaum molecular.Nws xaiv xaiv RBM39 rau CRL4-DCAF15 E3 ubiquitin ligase, txhawb nqa RBM39 polyubiquitination thiab protein degradation.Genetic depletion los yog sulfonamide-mediated degradation ntawm RBM39 induces genome-wide splicing abnormalities, thaum kawg ua rau cell tuag.

RNA-PROTACs yog tsim los degrade RNA-binding proteins (RBPs).PROTAC siv lub linker los txuas E3 ligase ligand rau RNA ligand, uas khi rau RNA thiab RBPs.Txij li RBP muaj cov qauv tsim uas tuaj yeem khi rau cov kab ke oligonucleotide tshwj xeeb, RNA-PROTAC siv cov txheej txheem oligonucleotide raws li ligand rau cov protein ntawm kev txaus siab (POI).Qhov kawg tshwm sim yog degradation ntawm RBPs.

Tsis ntev los no, xibfwb Matthew Disney ntawm Scripps Institution of Oceanography tau tsim RNAribonuclease-targeting chimeras (RiboTACs).RiboTAC yog ib tug heterofunctional molecule uas txuas RNase L ligand thiab RNA ligand nrog ib tug linker.Nws tuaj yeem tshwj xeeb nrhiav cov endogenous RNase L rau cov hom phiaj RNA tshwj xeeb, thiab tom qab ntawd ua tiav tshem tawm RNA siv lub cellular nucleic acid tawg mechanism (RNase L).

Raws li cov kws tshawb fawb kawm paub ntau ntxiv txog kev sib cuam tshuam ntawm cov molecules me thiab RNA lub hom phiaj, ntau cov tshuaj siv cov qauv no yuav tshwm sim yav tom ntej.