Alurar rigakafin mRNA na Pfizer don COVID ya sabunta sha'awar amfani da ribonucleic acid (RNA) a matsayin makasudin warkewa.Koyaya, niyya RNA tare da ƙananan ƙwayoyin cuta yana da ƙalubale sosai.

RNA kawai yana da tubalan gini guda huɗu: adenine (A), cytosine (C), guanine (G), da uracil (U) wanda ya maye gurbin thymine (T) da ake samu a DNA.Wannan ya sa zaɓin ƙwayoyi ya zama cikas kusan da ba za a iya jurewa ba.Akasin haka, akwai amino acid na halitta guda 22 waɗanda sunadaran kayan shafa, wanda ke bayyana dalilin da yasa yawancin magungunan furotin suna da zaɓi mai kyau.

Tsarin da aikin RNA

Kamar sunadaran, kwayoyin RNA suna da sifofi na biyu da na uku, kamar yadda aka nuna a hoton da ke ƙasa.Ko da yake su macromolecules ne na sarkar sarka ɗaya, tsarin su na biyu yana ɗaukar siffar lokacin da haɗin ginin tushe ya haifar da kumbura, madaukai, da helices.Sa'an nan, nadawa mai girma uku yana kaiwa ga tsarin RNA, wanda ke da mahimmanci don kwanciyar hankali da aikinsa.

Hoto 1. Tsarin RNA

Akwai nau'ikan RNA guda uku:

• Manzon RNA (mRNA)yana rubuta bayanan kwayoyin halitta daga DNA kuma ana canja shi azaman jerin tushe akan ribosome;l
• Ribosomal RNA (rRNA)wani bangare ne na kwayoyin halittar da ke hada sunadaran da ake kira ribosomes, wadanda ake fitarwa zuwa cytoplasm kuma suna taimakawa fassara bayanai a cikin mRNA zuwa sunadaran;
• Canja wurin RNA (tRNA)ita ce hanyar haɗin kai tsakanin mRNA da sarkar amino acid wanda ke yin furotin.

Nuna RNA a matsayin makasudin warkewa yana da kyau sosai.An gano cewa kawai kashi 1.5% na kwayoyin halittarmu ana fassara su zuwa furotin, yayin da 70% -90% ana rubuta su cikin RNA.Kwayoyin RNA sune mafi mahimmanci ga dukkan halittu masu rai.A cewar Francis Crick's "tsakiya akidar", mafi mahimmancin aikin RNA shine fassara bayanan kwayoyin halitta daga DNA zuwa sunadarai.Bayan haka, kwayoyin RNA suma suna da wasu ayyuka, gami da:

• Yin aiki azaman adaftar kwayoyin halitta a cikin haɗin furotin;l
• Yin hidima a matsayin manzo tsakanin DNA da ribosome;l
• Su ne masu ɗaukar bayanan kwayoyin halitta a cikin dukkanin sel masu rai;l
• Haɓaka zaɓin ribosomal na daidaitattun amino acid, wanda ya zama dole don haɗa sabbin sunadaranin vivo.

Magungunan rigakafi

Duk da cewa an gano shi tun farkon shekarun 1940, ba a bayyana tsarin aiwatar da maganin rigakafi da yawa ba har zuwa ƙarshen 1980s.An gano cewa yawancin maganin rigakafi suna aiki ta hanyar ɗaure ribosomes na ƙwayoyin cuta don hana su yin sunadaran da suka dace, ta haka ne suke kashe kwayoyin cutar.

Misali, maganin rigakafi na aminoglycoside suna ɗaure zuwa A-site na 16S rRNA, wanda shine ɓangare na 30S ribosome subunit, sa'an nan kuma tsoma baki tare da haɗin gwiwar furotin don tsoma baki tare da haɓakar ƙwayoyin cuta, a ƙarshe yana haifar da mutuwar tantanin halitta.Shafin A yana nufin rukunin aminoacyl, wanda kuma aka sani da wurin karɓar tRNA.Cikakken hulɗar tsakanin magungunan aminoglycoside, kamarparomomycin, da kuma A-site naE. coliAna nuna RNA a ƙasa.

Hoto 2. Ma'amala tsakanin paromomycin da A-site naE. coliRNA

Abin takaici, yawancin masu hanawar A-site, gami da magungunan aminoglycoside, suna da lamuran aminci kamar nephrotoxicity, dogaro da kashi, da takamaiman ototoxicity mara jurewa.Waɗannan gubar sune sakamakon rashin zaɓi a cikin magungunan aminoglycoside don gane ƙananan ƙwayoyin RNA.

Kamar yadda aka nuna a cikin hoton da ke ƙasa: (a) tsarin ƙwayoyin cuta, (b) membrane cell membranes na ɗan adam, da (c) mitochondrial A-site na ɗan adam suna da kama da juna, yana sa masu hana A-site su ɗaure su duka.

Hoto 3. Ba zaɓaɓɓen A-site inhibitor dauri

Magungunan rigakafi na Tetracycline kuma suna hana A-site na rRNA.Suna zaɓin hana haɗin furotin na kwayan cuta ta hanyar jujjuya ɗaure zuwa wani yanki mai ƙarfi (H34) akan sashin 30S wanda aka haɗa tare da Mg.²⁺.

A gefe guda kuma, maganin rigakafi na macrolide yana ɗaure kusa da wurin fita (E-site) na ramin ribosome na ƙwayoyin cuta don peptides nascent (NPET) kuma a ɗan toshe shi, ta haka yana hana haɗin furotin na kwayan cuta.A ƙarshe, oxazolidinone maganin rigakafi irin sulinezolid(Zyvox) yana ɗaure zuwa tsagi mai zurfi a cikin ɓangaren ƙwayar cuta na 50S ribosomal, wanda ke kewaye da 23S rRNA nucleotides.

Antisense oligonucleotides (ASO)

Magungunan antisense sune polymers na nucleic acid da aka gyara waɗanda ke kaiwa RNA hari.Suna dogara da haɗin tushen Watson-Crick don ɗaure zuwa manufa mRNA, wanda ke haifar da yin shiru na kwayoyin halitta, toshewa mai tsauri, ko canza canji.ASOs na iya yin hulɗa tare da pre-RNAs a cikin tsakiya tantanin halitta da mRNAs masu girma a cikin cytoplasm.Za su iya yin niyya ga exons, introns, da yankunan da ba a fassara su ba (UTRs).Har zuwa yau, fiye da dozin ASO kwayoyi sun yarda da FDA.

Hoto 4. Fasahar Antisense

Kananan magungunan ƙwayoyin cuta masu niyya ga RNA

A cikin 2015, Novartis ya ba da rahoton cewa sun gano SMN2 mai daidaitawa da ake kira Branaplam, wanda ke haɓaka ƙungiyar U1-pre-mRNA kuma yana ceton mice SMA.

A gefe guda, PTC/Roche's Risdiplam (Evrysdi) FDA ta amince da ita a cikin 2020 don maganin SMA.Kamar Branaplam, Risdiplam kuma yana aiki ta hanyar daidaita rarraba kwayoyin halittar SMN2 masu dacewa don samar da sunadaran SMN masu aiki.

RNA masu lalata

RBM yana nufin furotin motif mai ɗaure RNA.Ainihin, indole sulfonamide shine manne kwayoyin halitta.Yana zaɓar RBM39 zuwa CRL4-DCAF15 E3 ubiquitin ligase, yana haɓaka RBM39 polyubiquitination da lalata furotin.Ragewar kwayoyin halitta ko lalatawar sulfonamide-matsakaici na RBM39 yana haifar da gaɓoɓin ɓarna mai faɗin genome, a ƙarshe yana haifar da mutuwar tantanin halitta.

RNA-PROTACs an haɓaka su don ƙasƙantar da sunadarai masu ɗaure RNA (RBPs).PROTAC yana amfani da mai haɗawa don haɗa haɗin E3 ligase zuwa ligand RNA, wanda ke ɗaure zuwa RNA da RBPs.Tun da RBP ya ƙunshi sassan tsarin da za su iya ɗaure ga takamaiman jerin oligonucleotide, RNA-PROTAC yana amfani da jerin oligonucleotide a matsayin ligand don furotin na sha'awa (POI).Sakamakon ƙarshe shine lalacewar RBPs.

Kwanan nan, Farfesa Matthew Disney na Cibiyar Scripps na Oceanography ya kirkiro RNAchimeras mai nisa da ribonuclease (RiboTACs).RiboTAC kwayar halitta ce ta heterofunctional wacce ta haɗu da RNase L ligand da ligand RNA tare da mai haɗawa.Yana iya ɗaukar takamaiman RNase L na endogenous zuwa takamaiman maƙasudin RNA, sannan ya sami nasarar kawar da RNA ta amfani da tsarin rushewar acid nucleic acid (RNase L).

Yayin da masu bincike ke ƙarin koyo game da hulɗar tsakanin ƙananan ƙwayoyin cuta da maƙasudin RNA, ƙarin magunguna masu amfani da wannan hanyar za su fito nan gaba.