Urukingo rwa mRNA rwa Pfizer kuri COVID rwongeye kwifuza gukoresha aside ribonucleic (RNA) nk'intego yo kuvura.Ariko, kwibasira RNA hamwe na molekile nto biragoye cyane.

RNA ifite ibice bine byubaka gusa: adenine (A), cytosine (C), guanine (G), na uracil (U) isimbuza thymine (T) iboneka muri ADN.Ibi bituma guhitamo ibiyobyabwenge ari inzitizi hafi ya zose.Ibinyuranye na byo, hari aside amine 22 isanzwe ikora poroteyine, isobanura impamvu imiti myinshi yibasira poroteyine ifite guhitamo neza.

Imiterere n'imikorere ya RNA

Kimwe na poroteyine, molekile ya RNA ifite ibyiciro bya kabiri na kaminuza, nkuko bigaragara ku gishushanyo gikurikira.Nubwo ari urunigi rumwe rwa macromolecules, urwego rwakabiri rufata imiterere iyo guhuza shingiro bitera ibibyimba, imirongo, na helices.Noneho, ibipimo bitatu-biganisha ku miterere ya kaminuza ya RNA, ni ngombwa kugirango ituze kandi ikore.

Igicapo 1. Imiterere ya RNA

Hariho ubwoko butatu bwa RNA:

• Intumwa RNA (mRNA)yandukura amakuru akomoka kuri ADN kandi yimurwa nkurwego rwibanze kuri ribosome;l
• Ribosomal RNA (rRNA)ni igice cya poroteyine-ikomatanya ingirangingo yitwa ribosomes, zoherezwa muri cytoplazme kandi bigafasha guhindura amakuru muri mRNA muri poroteyine;
• Kwimura RNA (tRNA)ni ihuriro hagati ya mRNA numuyoboro wa aside amine ugize proteine.

Kwibanda kuri RNA nkintego yo kuvura irashimishije cyane.Byagaragaye ko 1.5% gusa ya genome yacu ihindurwamo poroteyine, mugihe 70% -90% byanditswe muri RNA.Molekile ya RNA ningirakamaro cyane kubinyabuzima byose.Dukurikije “dogma nkuru” ya Francis Crick, uruhare runini rwa RNA ni uguhindura amakuru akomoka kuri ADN muri poroteyine.Uretse ibyo, molekile ya RNA nayo ifite indi mirimo, harimo:

• Gukora nka molekile ya adapt muri synthesis ya protein;l
• Gukora nk'intumwa hagati ya ADN na ribosome;l
• Ni abatwara amakuru ya genetike muri selile zose nzima;l
• Gutezimbere guhitamo ribosomal ya acide ikwiye ya aminide, ikenewe muguhuza poroteyine nshyamuri vivo.

Antibiyotike

Nubwo byavumbuwe nko mu 1940, uburyo bwo gukora antibiyotike nyinshi ntabwo bwigeze busobanurwa kugeza mu mpera za 1980.Byagaragaye ko umubare munini wa antibiyotike ukora uhuza na ribosomes ya bagiteri kugirango wirinde gukora poroteyine ziboneye, bityo bikica bagiteri.

Kurugero, antibiyotike ya aminoglycoside ihuza A-site ya 16S rRNA, igizwe na 30S ribosome subunit, hanyuma ikabangamira synthesis ya protein kugirango ibangamire imikurire ya bagiteri, amaherezo iganisha ku rupfu.A-urubuga bivuga urubuga rwa aminoacyl, ruzwi kandi nkurubuga rwakira tRNA.Imikoranire irambuye hagati yibiyobyabwenge bya aminoglycoside, nkaparomomycin, na A-Urubuga rwaE. coliRNA irerekanwa hepfo.

Igishushanyo 2. Imikoranire hagati ya paromomycine na A-urubuga rwaE. coliRNA

Kubwamahirwe, inzitizi nyinshi za A-site, harimo imiti ya aminoglycoside, ifite ibibazo byumutekano nka nephrotoxicity, biterwa na dose, hamwe na ototoxicity idasubirwaho.Ubu burozi ni ibisubizo byo kubura guhitamo imiti ya aminoglycoside kugirango tumenye molekile nto ya RNA.

Nkuko bigaragara ku gishushanyo gikurikira: (a) imiterere ya bagiteri, (b) ururenda rwumuntu, na (c) A-site ya mitochondrial A-site irasa cyane, bigatuma inzitizi za A-zihuza zose.

Igishushanyo 3. Guhitamo A-urubuga inhibitor guhuza

Antibiyotike ya Tetracycline nayo ibuza A-site ya rRNA.Bahitamo guhagarika intungamubiri za poroteyine za bagiteri mu guhuza bidasubirwaho akarere kegeranye (H34) kuri 30S subunit igizwe na Mg²⁺.

Ku rundi ruhande, antibiyotike ya macrolide ihuza hafi yo gusohoka (E-site) ya bagiteri ya ribosome ya bagiteri ya peptide ivuka (NPET) ikayihagarika igice, bityo ikabuza intungamubiri za poroteyine.Hanyuma, antibiyotike ya oxazolidinone nkaumurongo(Zyvox) ihuza ibice byimbitse muri bagiteri 50S ribosomal subunit, ikikijwe na 23S rRNA nucleotide.

Antisense oligonucleotide (ASO)

Imiti igabanya ubukana ni imiti ihindura nucleic aside polymers yibasira RNA.Bishingikiriza kuri Watson-Crick base base kugirango bahuze intego ya mRNA, bikaviramo gucecekesha gene, guhagarika steric, cyangwa guhindura ibintu.ASOs irashobora gukorana na pre-RNAs muri selile selile na mRNAs zikuze muri cytoplazme.Barashobora kwibasira exons, intron, hamwe n'uturere tudasobanuwe (UTR).Kugeza ubu, ibiyobyabwenge birenga icumi ASO byemejwe na FDA.

Igicapo 4. Ikoranabuhanga rya Antisense

Imiti mito ya molekile yibasira RNA

Muri 2015, Novartis yatangaje ko bavumbuye SMN2 igenzura imiti yitwa Branaplam, itezimbere ishyirahamwe U1-pre-mRNA ikanakiza imbeba za SMA.

Ku rundi ruhande, Risdiplam ya PTC / Roche (Evrysdi) yemejwe na FDA mu 2020 yo kuvura SMA.Kimwe na Branaplam, Risdiplam nayo ikora muguhuza ikwirakwizwa rya genes ya SMN2 kugirango ikore proteine ​​zikora SMN.

RNA itesha agaciro

RBM bisobanura poroteyine ya RNA ihuza.Byibanze, indole sulfonamide ni molekile ifata.Ihitamo kwinjiza RBM39 muri CRL4-DCAF15 E3 ubiquitin ligase, iteza imbere RBM39 polyubiquitination no kwangirika kwa poroteyine.Kugabanuka kw'irondakoko cyangwa sulfonamide-yunganirwa no kwangirika kwa RBM39 itera ingirabuzima fatizo zigaragara cyane, amaherezo bikaviramo urupfu.

RNA-PROTACs yatunganijwe kugirango itesha agaciro poroteyine RNA ihuza (RBPs).PROTAC ikoresha umuhuza kugirango uhuze E3 ligase ligand na RNA ligand, ihuza RNA na RBPs.Kubera ko RBP ikubiyemo imiterere yimiterere ishobora guhuza na oligonucleotide yihariye, RNA-PROTAC ikoresha urutonde rwa oligonucleotide nka ligand ya proteine ​​yinyungu (POI).Igisubizo cyanyuma ni ugutesha agaciro RBPs.

Vuba aha, Porofeseri Matthew Disney wo mu kigo cya Scripps Institute of Oceanography yahimbye RNAribonuclease-yibasira chimeras (RiboTACs).RiboTAC ni molekile idafite imbaraga ihuza ligande ya RNase L na ligand ya RNA hamwe nu muhuza.Irashobora kwinjiza mu buryo bwihariye endogenous RNase L ku ntego yihariye ya RNA, hanyuma igakuraho neza RNA ikoresheje uburyo bwa selile nucleic aside yamenetse (RNase L).

Mugihe abashakashatsi bamenye byinshi kubyerekeye imikoranire hagati ya molekile nto nintego za RNA, imiti myinshi ikoresha ubu buryo izagaragara mugihe kizaza.