Puna: Medical Micro
Ma hope o ka laha ʻana o COVID-19, ua ʻae koke ʻia ʻelua mau kano mRNA no ke kūʻai aku ʻana, kahi i ʻoi aku ka nui o ka nānā ʻana i ka hoʻomohala ʻana i nā lāʻau lapaʻau nucleic acid.I nā makahiki i hala iho nei, ua paʻi ka nui o nā lāʻau nucleic acid i hiki ke lilo i mau lāʻau blockbuster i ka ʻikepili lapaʻau, e uhi ana i ka naʻau a me nā maʻi metabolic, nā maʻi ate, a me nā ʻano maʻi like ʻole.Manaʻo ʻia nā lāʻau lapaʻau nucleic e lilo i mau lāʻau liʻiliʻi liʻiliʻi a me nā lāʻau antibody.ʻO ke kolu o nā ʻano lāʻau nui loa.
Māhele lāʻau nucleic acid
ʻO ka waika nucleic kahi pūhui macromolecular biological i hoʻokumu ʻia e ka polymerization o nā nucleotides he nui, a ʻo ia kekahi o nā mea maʻamau o ke ola.ʻO nā lāʻau lapaʻau nucleic acid he ʻano oligoribonucleotides (RNA) a i ʻole oligodeoxyribonucleotides (DNA) me nā hana like ʻole, hiki ke hana pololei i nā genes i hoʻokumu ʻia i ka maʻi a i ʻole nā mRNA i hoʻopaʻa ʻia e mālama i nā maʻi ma ka pae gene Ke kuleana o.
▲ ʻO ke kaʻina hana synthesis mai DNA a RNA i protein (Kumu kiʻi: bing)
I kēia manawa, ʻo nā lāʻau lapaʻau nucleic acid ka antisense nucleic acid (ASO), RNA interfering liʻiliʻi (siRNA), microRNA (miRNA), RNA hoʻoulu liʻiliʻi (saRNA), messenger RNA (mRNA), aptamer, a me ribozyme., Antibody nucleic acid conjugated drugs (ARC), etc.
Ma waho aʻe o ka mRNA, ʻo ka noiʻi ʻana a me ka hoʻomohala ʻana i nā lāʻau lapaʻau nucleic acid i loaʻa hou ka nānā ʻana i nā makahiki i hala.I ka makahiki 2018, ua ʻae ʻia ka lāʻau siRNA mua loa o ka honua (Patisiran), a ʻo ia ka lāʻau nucleic acid mua e hoʻohana i ka ʻōnaehana lawe LNP.I nā makahiki i hala iho nei, ua wikiwiki pū ka mākeke o nā lāʻau nucleic acid.Ma 2018-2020 wale nō, aia he 4 mau lāʻau siRNA, ʻekolu mau lāʻau ASO i ʻae ʻia (FDA a me EMA).Eia kekahi, ʻo Aptamer, miRNA a me nā māla ʻē aʻe he nui nā lāʻau lapaʻau i ka pae lapaʻau.
Nā pōmaikaʻi a me nā pilikia o nā lāʻau nucleic acid
Mai ka 1980s, ua hoʻonui mālie ʻia ka noiʻi a me ka hoʻomohala ʻana i nā lāʻau lapaʻau hou e pili ana i ka pahuhopu, a ua ʻike ʻia ka nui o nā lāʻau hou;ʻO nā lāʻau kemika liʻiliʻi liʻiliʻi kuʻuna a me nā lāʻau antibody e hoʻokō i nā hopena pharmacological ma o ka hoʻopaʻa ʻana i nā protein target.Hiki i nā protein target ke Enzymes, receptors, ion channels, etc.
ʻOiai ʻo nā lāʻau liʻiliʻi liʻiliʻi ka maikaʻi o ka hana maʻalahi, hoʻokele waha, ʻoi aku ka maikaʻi o ka pharmacokinetic waiwai, a me ka maʻalahi o ka hele ʻana ma waena o nā membrane cell, ua hoʻopilikia ʻia ko lākou ulu ʻana e ka lāʻau lapaʻau o ka pahuhopu (a inā loaʻa i ka protein target ke ʻano o ka ʻeke kūpono a me ka nui)., Hohonu, polarity, etc.);e like me ka ʻatikala ma Nature2018, ʻo 3,000 wale nō o ka ~ 20,000 protein i hoʻopaʻa ʻia e ka genome kanaka hiki ke lilo i lāʻau lapaʻau, a ʻo 700 wale nō ka mea i hoʻomohala ʻia i nā lāʻau lapaʻau (ma ka nui o nā kemika mole liʻiliʻi).
ʻO ka pōmaikaʻi nui loa o nā lāʻau nucleic acid ʻo ia ka hiki ke hoʻomohala ʻia nā lāʻau like ʻole ma ka hoʻololi ʻana i ke kaʻina kumu o ka waikawa nucleic.Ke hoʻohālikelike ʻia me nā lāʻau lapaʻau e hana ana i ka pae protein kuʻuna, ʻo kāna kaʻina hoʻomohala maʻalahi, kūpono, a me ke ʻano biologically;ke hoʻohālikelike ʻia me ka genomic DNA-level treatment, ʻaʻohe pilikia o nā lāʻau nucleic acid i ka hoʻohui pū ʻana a ʻoi aku ka maʻalahi i ka manawa o ka mālama ʻana.Hiki ke ho'ōki i ka lāʻau inā ʻaʻole pono ka lāʻau lapaʻau.
Loaʻa i nā lāʻau lapaʻau nucleic acid nā pōmaikaʻi e like me ke kikoʻī kiʻekiʻe, ka hana kiʻekiʻe a me ka hopena lōʻihi.Eia nō naʻe, me ka nui o nā pono a me ka hoʻomohala wikiwiki ʻana, ke kū nei nā lāʻau nucleic acid i nā pilikia like ʻole.
ʻO kekahi ka hoʻololi RNA e hoʻonui i ka paʻa o nā lāʻau nucleic acid a hōʻemi i ka immunogenicity.
ʻO ka lua, ʻo ka hoʻomohala ʻana i nā mea lawe e hōʻoia i ka paʻa o ka RNA i ka wā o ke kaʻina hoʻoili nucleic acid a me nā lāʻau lapaʻau nucleic acid e hiki ai i nā cell target / target organs;
ʻO ke kolu ka hoʻomaikaʻi ʻana i ka ʻōnaehana lawe lāʻau.Pehea e hoʻomaikaʻi ai i ka ʻōnaehana lawe lāʻau e hoʻokō i ka hopena like me nā haʻahaʻa haʻahaʻa.
Hoʻololi kemika o nā lāʻau nucleic acid
Pono nā lāʻau lapaʻau nucleic exogenous e lanakila i nā pilikia he nui i hiki ke komo i ke kino e hana i kahi kuleana.Ua pilikia pū kēia mau pilikia i ka hoʻomohala ʻana i nā lāʻau nucleic acid.Eia nō naʻe, me ka hoʻomohala ʻana o nā ʻenehana hou, ua hoʻopau ʻia kekahi o nā pilikia e ka hoʻololi kemika.A he mea koʻikoʻi ka holomua o ka ʻenehana ʻōnaehana lawe i ka hoʻomohala ʻana i nā lāʻau lapaʻau nucleic acid.
Hiki i ka hoʻololi kemika ke hoʻonui i ka hiki o nā lāʻau RNA e pale aku i ka hoʻohaʻahaʻa ʻana e nā endonucleases endogenous a me exonucleases, a hoʻonui nui i ka pono o nā lāʻau lapaʻau.No nā lāʻau lapaʻau siRNA, hiki i ka hoʻololi kemika ke hoʻonui i ka koho o kā lākou mau kaula antisense e hōʻemi i ka hana RNAi ma waho, a hoʻololi i nā waiwai kino a me nā kemika e hoʻomaikaʻi i ka hiki ke hoʻopuka.
1. Hoʻololi kemika o ke kō
I ka hoʻomaka ʻana o ka hoʻomohala ʻana i ka lāʻau lapaʻau nucleic acid, nui nā pūhui nucleic acid i hōʻike i ka hana olaola maikaʻi i loko o ka vitro, akā ua hōʻemi nui ʻia kā lākou hana ma vivo a nalowale loa.ʻO ke kumu nui ʻo ia ka mea hiki ke wāwahi ʻia nā nucleic acids e nā enzymes a i ʻole nā mea endogenous i loko o ke kino.ʻO ka hoʻololi kemika o ke kō ka mea nui i ka hoʻololi ʻana o ka hydroxyl (2'OH) kūlana 2 o ke kō i methoxy (2'OMe), fluorine (F) a i ʻole (2'MOE).Hiki i kēia mau hoʻololi ke hoʻonui maikaʻi i ka hana a me ke koho, hoʻemi i nā hopena i waho o ka pahuhopu, a hōʻemi i nā hopena ʻaoʻao.
▲ Hoʻololi kemika o ke kō (kumu kiʻi: kuhikuhi 4)
2. ʻO ka hoʻololi ʻana i ka iwi iwi phosphoric acid
ʻO ka hoʻololi kemika maʻamau o ka iwi kuamoʻo phosphate he phosphorothioate, ʻo ia hoʻi, kahi oxygen non-bridging i loko o ka iwi hope phosphate o ka nucleotide ua pani ʻia me ka sulfur (PS modification).Hiki i ka hoʻololi PS ke pale aku i ka hoʻohaʻahaʻa ʻana o nā nucleases a hoʻonui i ka pilina o nā lāʻau nucleic acid a me nā protein plasma.Hiki ke hoʻopaʻa ʻia, hoʻemi i ka helu hoʻomaʻemaʻe renal a hoʻonui i ka hapalua o ke ola.
▲ Ka hoʻololi ʻana o ka phosphorothioate (kumu kiʻi: kuhikuhi 4)
ʻOiai hiki ke hoʻemi ʻo PS i ka pilina o nā ʻakika nucleic a me nā genes i hoʻopaʻa ʻia, ʻoi aku ka hydrophobic a paʻa ka hoʻololi ʻana o PS, no laila he hoʻololi koʻikoʻi ia i ka hoʻopili ʻana i nā waikawa nucleic liʻiliʻi a me nā waikawa nucleic antisense.
3. Hoʻololi i ke apo lima lālā o ribose
ʻO ka hoʻololi ʻana i ke apo lima ʻelima o ka ribose i kapa ʻia ʻo ke kolu o ka hanauna chemical modification, me ka bridged nucleic acid-locked nucleic acid BNAs, peptide nucleic acid PNA, phosphorodiamide morpholino oligonucleotide PMO, hiki i kēia mau hoʻololi ke hoʻomaikaʻi hou i nā lāʻau nucleic acid Resistance to nucleases, affinity affinity.
4. Nā hoʻololi kemika ʻē aʻe
I ka pane ʻana i nā pono like ʻole o nā lāʻau lapaʻau nucleic acid, hana maʻamau nā mea noiʻi i nā hoʻololi a me nā hoʻololi ʻana i nā kumu a me nā kaulahao nucleotide e hoʻonui i ka paʻa o nā lāʻau nucleic acid.
I kēia manawa, ʻo nā lāʻau lapaʻau RNA-targeting āpau i ʻae ʻia e ka FDA he mau mea hoʻohālikelike RNA i hana ʻia, e kākoʻo ana i ka pono o ka hoʻololi kemika.ʻOkoʻa wale nō nā oligonucleotides i hoʻopaʻa ʻia no nā ʻāpana hoʻololi kemika kikoʻī ma ke kaʻina wale nō, akā loaʻa iā lākou nā ʻano kino like ʻole a me nā waiwai kemika, a no laila loaʻa nā pharmacokinetics maʻamau a me nā waiwai olaola.
Ka lawe ʻana a me ka lawelawe ʻana i nā lāʻau lapaʻau nucleic acid
ʻO nā lāʻau lapaʻau nucleic acid e hilinaʻi wale ana i ka hoʻololi kemika, hiki ke hoʻohaʻahaʻa koke ʻia i ke kahe koko, ʻaʻole maʻalahi e hōʻiliʻili i nā ʻiʻo i hoʻopaʻa ʻia, a ʻaʻole maʻalahi ke komo pono i ka membrane cell target e hiki i ke kahua o ka hana i ka cytoplasm.No laila, pono ka mana o ka ʻōnaehana hoʻouna.
I kēia manawa, hoʻokaʻawale nui ʻia nā vectors nucleic acid i nā vectors viral a me non-viral vectors.ʻO ka mua e pili ana i ka adenovirus-associated virus (AAV), lentivirus, adenovirus a me retrovirus, a pēlā aku.Mai ka hiʻohiʻona o nā lāʻau lapaʻau i kūʻai ʻia, ʻoi aku ka makua o nā vectors viral a me nā mea lawe lipid i ka lawe ʻana i nā lāʻau lapaʻau mRNA, ʻoiai nā lāʻau liʻiliʻi nucleic acid e hoʻohana i nā mea lawe a i ʻole nā mea ʻenehana e like me liposomes a i ʻole GalNAc.
I kēia lā, ua lawelawe ʻia ka hapa nui o nā lāʻau lapaʻau nucleotide, me nā lāʻau lapaʻau nucleic acid i ʻāpono ʻia, e like me nā maka, spinal cord, a me ka ate.ʻO nā nucleotides ka nui o nā polyanions hydrophilic, a ʻo kēia waiwai ʻaʻole hiki ke hele maʻalahi i ka membrane plasma.I ka manawa like, ʻaʻole hiki i nā lāʻau lapaʻau e pili ana i ka oligonucleotide ke hele i ka pale koko-lolo (BBB), no laila ʻo ka hāʻawi ʻana i ka ʻōnaehana nūnū waena (CNS) ʻo ia ka luʻi hou no nā lāʻau nucleic acid.
Pono e ʻike ʻia ʻo ka hoʻolālā ʻana o ka nucleic acid sequence a me ka hoʻololi ʻana i ka waikawa nucleic i kēia manawa ke kumu o ka nānā ʻana o nā mea noiʻi ma ke kula.No ka hoʻololi kemika, kemika nucleic acid, non-natural nucleic sequence sequence design or improvement, nucleic acid composition, vector construction, nucleic acid synthesis method, etc.
E lawe i ka coronavirus hou ma ke ʻano he laʻana.No ka mea he waiwai kona RNA i ke ʻano kūlohelohe, ʻaʻole hiki ke hāʻawi ʻia ka "RNA o ka coronavirus hou" ponoʻī i kahi patent.Eia nō naʻe, inā hoʻokaʻawale a hoʻokaʻawale paha kahi mea noiʻi ʻepekema i ka RNA a i ʻole nā ʻāpana i ʻike ʻole ʻia i ka ʻenehana mai ka coronavirus hou no ka manawa mua a hoʻohana iā ia (no ka laʻana, e hoʻololi iā ia i kano), a laila hiki ke hāʻawi ʻia ka nucleic acid a me ke kano i nā kuleana patent e like me ke kānāwai.Eia kekahi, ʻo nā molekole nucleic acid i hana ʻia i ka noiʻi ʻana i ka coronavirus hou, e like me nā primers, probes, sgRNA, vectors, etc., he mau mea patentable.
Olelo hoopau
ʻOkoʻa mai ke ʻano o nā lāʻau kemika liʻiliʻi liʻiliʻi a me nā lāʻau antibody, hiki i nā lāʻau nucleic acid ke hoʻonui i ka ʻike lāʻau i ka pae genetic ma mua o nā protein.Hiki ke ʻike ʻia me ka hoʻonui mau ʻana o nā hōʻailona a me ka hoʻomau mau ʻana o ka lawe ʻana a me ka hoʻololi ʻana i nā ʻenehana, e hoʻolaha nui nā lāʻau nucleic acid i nā maʻi maʻi a lilo maoli i kahi papa o nā huahana pahū ma hope o nā lāʻau kemika liʻiliʻi a me nā lāʻau antibody.
Mea kuhikuhi:
1.http://xueshu.baidu.com/usercenter/paper/show?paperid=e28268d4b63ddb3b22270ea1763b2892&site=xueshu_se
2.https://www.biospace.com/article/releases/wave-life-sciences-announces-initiation-of-dosing-in-phase-1b-2a-focus-c9-clinical-trial-of-wve- 004-in-amyotrophic-lateral-sclerosis-and-frontotemporal-dementia/dementia
3. Liu Xi, Sun Fang, Tao Qichang;Kumu Naauao."Ka nānā ʻana o ka patentability o nā lāʻau nucleic acid"
4. CICC: nucleic acid drugs, ua hiki mai ka manawa
Nā huahana pili:
He kit PCR kino kino holoholona
Ka manawa hoʻouna: Sep-24-2021
