Katemera wa Pfizer wa mRNA wa COVID wayambitsanso chidwi chogwiritsa ntchito ribonucleic acid (RNA) ngati chandamale chachipatala.Komabe, kuloza RNA yokhala ndi mamolekyu ang'onoang'ono ndizovuta kwambiri.

RNA ili ndi zomangira zinayi zokha: adenine (A), cytosine (C), guanine (G), ndi uracil (U) yomwe imalowa m'malo mwa thymine (T) yopezeka mu DNA.Izi zimapangitsa kusankha mankhwala kukhala chopinga chosagonjetseka.Mosiyana ndi izi, pali ma amino acid 22 achilengedwe omwe amapanga mapuloteni, zomwe zimafotokoza chifukwa chake mankhwala ambiri omwe amatsata mapuloteni amakhala ndi mwayi wosankha bwino.

Kapangidwe ndi ntchito ya RNA

Monga mapuloteni, mamolekyu a RNA ali ndi mapangidwe achiwiri ndi apamwamba, monga momwe tawonetsera pachithunzichi.Ngakhale ndi ma macromolecules a single-chain, mawonekedwe awo achiwiri amachitika pamene kuphatikizika koyambira kumayambitsa zotupa, malupu, ndi ma helice.Kenako, kupindana kwa mbali zitatu kumatsogolera ku dongosolo lapamwamba la RNA, lomwe ndi lofunika kuti likhale lokhazikika ndikugwira ntchito.

Chithunzi 1. Mapangidwe a RNA

Pali mitundu itatu ya RNA:

• Mtumiki RNA (mRNA)amalemba zambiri za majini kuchokera ku DNA ndipo amasamutsidwa ngati njira yoyambira pa ribosome;l
• Ribosomal RNA (rRNA)ndi gawo la mapuloteni-synthesizing organelles otchedwa ribosomes, omwe amatumizidwa ku cytoplasm ndikuthandizira kumasulira zambiri mu mRNA kukhala mapuloteni;
• Kusamutsa RNA (tRNA)ndi mgwirizano pakati pa mRNA ndi tcheni cha amino acid chomwe chimapanga mapuloteni.

Kutsata RNA ngati chandamale chamankhwala ndikokongola kwambiri.Zapezeka kuti 1.5% yokha ya genome yathu imasinthidwa kukhala mapuloteni, pomwe 70% -90% imalembedwa mu RNA.Mamolekyu a RNA ndi ofunika kwambiri pa zamoyo zonse.Malinga ndi "chiphunzitso chapakati" cha Francis Crick, gawo lofunika kwambiri la RNA ndikumasulira zambiri zamtundu wa DNA kukhala mapuloteni.Kupatula apo, mamolekyu a RNA amakhalanso ndi ntchito zina, kuphatikiza:

• Kuchita ngati mamolekyu a adapter mu protein synthesis;l
• Kutumikira monga mthenga pakati pa DNA ndi ribosome;l
• Iwo ndi onyamula chidziwitso cha majini m'maselo onse amoyo;l
• Kulimbikitsa ribosomal kusankha olondola amino zidulo, zimene ndi zofunika synthesizing mapuloteni atsopanomu vivo.

Mankhwala opha tizilombo

Ngakhale kuti adapezeka kale m'ma 1940, njira yogwiritsira ntchito maantibayotiki ambiri sinadziwike mpaka kumapeto kwa zaka za m'ma 1980.Zapezeka kuti maantibayotiki ambiri amagwira ntchito pomanga ma ribosomes a bakiteriya kuti asapange mapuloteni oyenera, motero amapha mabakiteriyawo.

Mwachitsanzo, maantibayotiki a aminoglycoside amamanga ku A-site ya 16S rRNA, yomwe ili gawo la 30S ribosome subunit, ndiyeno imasokoneza kaphatikizidwe ka mapuloteni kuti asokoneze kukula kwa bakiteriya, zomwe zimatsogolera ku imfa ya cell.Malo A amatanthauza malo aminoacyl, omwe amadziwikanso kuti malo ovomerezeka a tRNA.Kuyanjana kwatsatanetsatane pakati pa mankhwala aminoglycoside, mongaparomomycin, ndi A-site yaE. koliRNA ikuwonetsedwa pansipa.

Chithunzi 2. Kuyanjana pakati pa paromomycin ndi A-malo aE. koliRNA

Tsoka ilo, ma A-site inhibitors ambiri, kuphatikiza mankhwala aminoglycoside, ali ndi zovuta zachitetezo monga nephrotoxicity, kudalira mlingo, ndi ototoxicity osasinthika.Poizoni izi ndi chifukwa cha kusowa selectivity mu mankhwala aminoglycoside kuzindikira RNA mamolekyu ang'onoang'ono.

Monga momwe tawonetsera mu chithunzi pansipa: (a) kapangidwe ka mabakiteriya, (b) kansalu ka selo laumunthu, ndi (c) malo a mitochondrial A-anthu ofanana kwambiri, kupanga A-site inhibitors kumangiriza kwa onsewo.

Chithunzi 3. Zosasankha A-site inhibitor kumanga

Maantibayotiki a Tetracycline amalepheretsanso A-site ya rRNA.Iwo amaletsa mosankha kaphatikizidwe ka puloteni wa bakiteriya pomanganso kudera la helical (H34) pagawo la 30S lopangidwa ndi Mg.²⁺.

Komano, maantibayotiki a macrolide amamanga pafupi ndi malo otuluka (E-site) a bakiteriya ribosome ngalande ya nascent peptides (NPET) ndikuletsa pang'ono, potero amalepheretsa kaphatikizidwe ka mapuloteni a bakiteriya.Pomaliza, oxazolidinone mankhwala mongalinezolid(Zyvox) imamangirira ku phazi lakuya mu bakiteriya 50S ribosomal subunit, yomwe yazunguliridwa ndi 23S rRNA nucleotides.

Antisense oligonucleotides (ASO)

Mankhwala a antisense ndi ma polima a nucleic acid omwe amayang'ana RNA.Amadalira Watson-Crick base pairing kuti amange ku chandamale cha mRNA, zomwe zimapangitsa kuti jini ikhale chete, steric blockade, kapena splicing kusintha.Ma ASO amatha kuyanjana ndi pre-RNAs mu cell nucleus ndi ma mRNA okhwima mu cytoplasm.Atha kuloza ma exons, introns, ndi zigawo zosamasuliridwa (UTRs).Mpaka pano, mankhwala opitilira khumi ndi awiri a ASO avomerezedwa ndi FDA.

Chithunzi 4. Antisense Technology

Mankhwala ang'onoang'ono a molekyulu omwe akulunjika ku RNA

Mu 2015, Novartis adanenanso kuti adapeza chowongolera cha SMN2 chotchedwa Branaplam, chomwe chimathandizira mgwirizano wa U1-pre-mRNA ndikupulumutsa mbewa za SMA.

Kumbali ina, PTC/Roche's Risdiplam (Evrysdi) idavomerezedwa ndi FDA mu 2020 pochiza SMA.Monga Branaplam, Risdiplam imagwiranso ntchito poyang'anira kuphatikizika kwa majini ofunikira a SMN2 kuti apange mapuloteni ogwira ntchito a SMN.

Zithunzi za RNA

RBM imayimira RNA-binding motif protein.Kwenikweni, indole sulfonamide ndi zomatira mamolekyulu.Imasankha RBM39 ku CRL4-DCAF15 E3 ubiquitin ligase, kulimbikitsa RBM39 polyubiquitination ndi kuwonongeka kwa mapuloteni.Kuwonongeka kwa ma genetic kapena kuwonongeka kwa sulfonamide-mediated kwa RBM39 kumapangitsa kuti pakhale vuto lalikulu la kuphatikizika kwa ma genome, zomwe zimapangitsa kufa kwa maselo.

Ma RNA-PROTAC amapangidwa kuti awononge mapuloteni a RNA-binding (RBPs).PROTAC imagwiritsa ntchito cholumikizira kulumikiza E3 ligase ligand ku RNA ligand, yomwe imamangiriza ku RNA ndi RBPs.Popeza RBP ili ndi madera apangidwe omwe amatha kumangirira kuzinthu zina za oligonucleotide, RNA-PROTAC imagwiritsa ntchito ndondomeko ya oligonucleotide monga ligand ya protein of interest (POI).Chotsatira chomaliza ndi kuwonongeka kwa ma RBP.

Posachedwapa, Pulofesa Matthew Disney wa m’bungwe la Scripps Institution of Oceanography anapanga RNAribonuclease-targeting chimeras (RiboTACs).RiboTAC ndi molekyulu ya heterofunctional yomwe imalumikiza RNase L ligand ndi RNA ligand yokhala ndi cholumikizira.Itha kulembera RNase L yokhazikika kuti ikwaniritse zolinga za RNA, kenako ndikuchotsa bwino RNA pogwiritsa ntchito ma cell nucleic acid breakdown mechanism (RNase L).

Pamene ochita kafukufuku akuphunzira zambiri za kugwirizana pakati pa mamolekyu ang'onoang'ono ndi zolinga za RNA, mankhwala ambiri ogwiritsira ntchito njirayi adzatuluka m'tsogolomu.