ʻO ka maʻi maʻi mRNA a Pfizer no COVID ua noho aliʻi i ka makemake no ka hoʻohana ʻana i ka ribonucleic acid (RNA) ma ke ʻano he therapeutic target.Eia naʻe, paʻakikī loa ka huli ʻana i ka RNA me nā molekole liʻiliʻi.

ʻEhā wale nō mau poloka hale o RNA: adenine (A), cytosine (C), guanine (G), a me ka uracil (U) e pani ana i koumine (T) i loaʻa ma DNA.Hoʻolilo kēia i ka koho lāʻau i mea pilikia ʻole.ʻO ka ʻokoʻa, aia he 22 mau amino acids e hana ai i nā proteins, e wehewehe ana i ke kumu he koho maikaʻi loa ka hapa nui o nā lāʻau lapaʻau.

ʻO ke kūkulu a me ka hana o RNA

E like me nā polokina, loaʻa i nā molekala RNA nā hale lua a me ke kula kiʻekiʻe, e like me ka mea i hōʻike ʻia ma ke kiʻi ma lalo nei.ʻOiai he macromolecules kaulahao hoʻokahi lākou, hoʻohālikelike ʻia ko lākou ʻano lua i ka wā e hoʻoulu ai ka paʻa kumu i nā bulges, nā puka lou, a me nā helices.A laila, alakaʻi ʻia ka hoʻopili ʻekolu-dimensional i ka hoʻolālā tertiary o RNA, he mea nui ia no kona kūpaʻa a me kāna hana.

Kiʻi 1. Hoʻolālā o RNA

ʻEkolu mau ʻano RNA:

• RNA ʻelele (mRNA)unuhi i ka ʻike genetic mai DNA a hoʻoili ʻia ma ke ʻano he kaʻina kumu ma luna o ka ribosome;l
• RNA Ribosomal (rRNA)he ʻāpana ia o nā ʻāpana protein-synthesizing i kapa ʻia he ribosomes, i lawe ʻia i ka cytoplasm a kōkua i ka unuhi ʻana i ka ʻike ma ka mRNA i nā protein;
• Hoʻololi RNA (tRNA)ʻo ia ka loulou ma waena o ka mRNA a me ke kaulahao amino acid i hana i ka protein.

ʻO ka huli ʻana i ka RNA ma ke ʻano he therapeutic target he nani loa.Ua ʻike ʻia ʻo 1.5% wale nō o kā mākou genome i unuhi ʻia i loko o ka protein, aʻo 70% -90% i unuhi ʻia i RNA.ʻO nā molekala RNA ka mea nui loa no nā mea ola a pau.Wahi a Francis Crick's “central dogma”, ʻo ke kuleana koʻikoʻi o RNA ka unuhi ʻana i ka ʻike genetic mai DNA i loko o nā protein.Ma waho aʻe, he mau hana ʻē aʻe nā molekala RNA, me:

• Ke hana nei ma ke ʻano he mau molekele adapter i ka synthesis protein;l
• Ke lawelawe nei ma ke ʻano he ʻelele ma waena o DNA a me ka ribosome;l
• ʻO lākou nā mea lawe i ka ʻike genetic i loko o nā cell ola a pau;l
• Hoʻoikaika i ka koho ribosomal o nā waikawa amino kūpono, pono ia no ka synthesizing i nā protein houin vivo.

Nā lāʻau lapaʻau

ʻOiai ua ʻike ʻia i ka makahiki 1940, ʻaʻole i wehewehe ʻia ke ʻano o ka hana o nā lāʻau antibiotic a hiki i ka hopena o 1980s.Ua ʻike ʻia ka hana ʻana o ka hapa nui o nā lāʻau antibiotic ma ka hoʻopaʻa ʻana i nā ribosomes bacteria e pale aku iā lākou mai ka hana ʻana i nā protein kūpono, a laila e pepehi i ka bacteria.

No ka laʻana, hoʻopaʻa nā lāʻau antibiotic aminoglycoside i ka A-site o 16S rRNA, ʻo ia kahi ʻāpana o ka 30S ribosome subunit, a laila keʻakeʻa i ka synthesis protein e hoʻopilikia i ka ulu ʻana o ka maʻi bacterial, e alakaʻi ana i ka make cell.ʻO ka pūnaewele A e pili ana i ka pūnaewele aminoacyl, i ʻike ʻia ʻo ka pūnaewele ʻae tRNA.ʻO ka pilina kikoʻī ma waena o nā lāʻau aminoglycoside, e like meparomomycin, a me ka paena A oE. coliHōʻike ʻia ka RNA ma lalo nei.

Kiʻi 2. ʻO ka pilina ma waena o paromomycin a me ka A-site oE. coliRNA

ʻO ka mea pōʻino, nui nā mea hoʻopaneʻe A-site, me nā lāʻau aminoglycoside, loaʻa nā pilikia palekana e like me ka nephrotoxicity, ka hilinaʻi ʻana, a me ka ototoxicity hiki ʻole ke hoʻololi ʻia.ʻO kēia mau meaʻawaʻawa ka hopena o ka nele o ka koho i nā lāʻau aminoglycoside no ka ʻike ʻana i nā mole liʻiliʻi RNA.

E like me ka mea i hōʻike ʻia ma ke kiʻi ma lalo nei: (a) ke ʻano o ka maʻi bacteria, (b) ka membrane cell kanaka, a (c) ʻano like loa ka pūnaewele A- mitochondrial kanaka, no laila e hoʻopaʻa ʻia nā mea hoʻopale A-site iā lākou a pau.

Kiʻi 3. ʻO ka mea hoʻopaʻa hoʻopaneʻe A-site koho ʻole

ʻO nā lāʻau'alopelo Tetracycline kekahi e kāohi i ka A-site o rRNA.Kāohi koho lākou i ka synthesis protein bacteria ma o ka hoʻopaʻa ʻana i kahi ʻāpana helical (H34) ma ka subunit 30S paʻakikī me Mg.²⁺.

Ma ka ʻaoʻao ʻē aʻe, hoʻopaʻa ʻia nā lāʻau antibiotic macrolide kokoke i ke kahua puka (E-site) o ka tunnel ribosome bacterial no nā peptides nascent (NPET) a hoʻopaʻa ʻia i kahi hapa, a laila e kāohi ai i ka synthesis protein bacterial.ʻO ka mea hope loa, nā lāʻau lapaʻau oxazolidinone e like melinezolid(Zyvox) hoʻopaʻa i kahi māwae hohonu i loko o ka 50S ribosomal subunit, i hoʻopuni ʻia e 23S rRNA nucleotides.

Antisense oligonucleotides (ASO)

ʻO nā lāʻau lapaʻau antisense he polymers nucleic acid i hoʻololi ʻia i ka RNA.Ke hilinaʻi nei lākou i ka hui pū ʻana o Watson-Crick e hoʻopaʻa i ka mRNA i hoʻopaʻa ʻia, e hopena ai i ka hoʻoheheʻe ʻana o ka gene, steric blockade, a i ʻole ka hoʻololi ʻana.Hiki i nā ASO ke launa pū me nā pre-RNA i loko o ka nucleus cell a me nā mRNA makua i ka cytoplasm.Hiki iā lākou ke kuhikuhi i nā exons, introns, a me nā ʻāina i unuhi ʻole ʻia (UTR).I kēia lā, ʻoi aku ka nui o nā lāʻau ASO i ʻae ʻia e ka FDA.

Kiʻi 4. ʻenehana Antisense

Nā lāʻau mole liʻiliʻi e huli ana i ka RNA

Ma 2015, hōʻike ʻo Novartis ua loaʻa iā lākou kahi SMN2 splicing regulator i kapa ʻia ʻo Branaplam, e hoʻonui ai i ka hui o U1-pre-mRNA a hoʻopakele i nā ʻiole SMA.

Ma ka ʻaoʻao ʻē aʻe, ua ʻae ʻia ʻo PTC/Roche's Risdiplam (Evrysdi) e ka FDA ma 2020 no ka mālama ʻana iā SMA.E like me Branaplam, hana pū ʻo Risdiplam ma ka hoʻoponopono ʻana i ka splicing o nā genes SMN2 kūpono e hana i nā protein SMN hana.

Nā mea hoʻohaʻahaʻa RNA

Kū ʻo RBM no RNA-binding motif protein.ʻO ka mea nui, ʻo ka indole sulfonamide kahi molecular adhesive.Hoʻopili ʻo ia i ka RBM39 i ka CRL4-DCAF15 E3 ubiquitin ligase, e hāpai ana i ka polyubiquitination RBM39 a me ka hoʻohaʻahaʻa ʻana i ka protein.ʻO ka pau ʻana o ka genetic a i ʻole ka sulfonamide-mediated degradation o RBM39 e hoʻoulu ai i nā mea ʻino ʻole o ka genome-ākea ākea, a hiki i ka make cell.

Hoʻokumu ʻia nā RNA-PROTAC e hoʻohaʻahaʻa i nā protein-binding protein (RBPs).Hoʻohana ʻo PROTAC i kahi loulou e hoʻopili ai i ka ligase ligase E3 i ka ligand RNA, kahi e hoʻopaʻa ai iā RNA a me RBP.No ka loaʻa ʻana o ka RBP i nā kāʻei kua hiki ke hoʻopaʻa i nā kaʻina oligonucleotide kikoʻī, hoʻohana ʻo RNA-PROTAC i kahi oligonucleotide sequence ma ke ʻano he ligand no ka protein of interest (POI).ʻO ka hopena hope loa ka hoʻohaʻahaʻa ʻana i nā RBP.

I kēia mau lā, ua haku ʻo Professor Matthew Disney o ka Scripps Institution of Oceanography i ka RNAribonuclease-targeting chimeras (RiboTACs).ʻO RiboTAC kahi mole heterofunctional e hoʻopili ai i kahi ligand RNase L a me kahi ligand RNA me kahi mea hoʻopili.Hiki iā ia ke hōʻiliʻili i ka RNase L endogenous i nā pahuhopu RNA kikoʻī, a laila hoʻopau maikaʻi i ka RNA me ka hoʻohana ʻana i ka mīkini hoʻokaʻawale ʻana i ka waika nucleic cell (RNase L).

Ke aʻo hou aku ka poʻe noiʻi e pili ana i ka pilina ma waena o nā mole liʻiliʻi a me nā pahuhopu RNA, ʻoi aku ka nui o nā lāʻau lapaʻau e hoʻohana ana i kēia ʻano hana i ka wā e hiki mai ana.