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Isesengura ry'Ubuvanganzo (NIBA 13.7) | Igishushanyo mbonera cy'uburyo bwa Macrocyclic Peptides gikozwe na AI: Guca intege amategeko y'intego "zidakoreshwa"
2025-12-26
IntangiriroAMAKURU
Muri laboratwari, abahanga mu bya siyansi bigeze guhura n’ikibazo gikomeye cyo gutsinda kimwe muri miliyoni imwe mu isuzuma ryihariye. Muri iki gihe, ubwenge bw’ubukorano burimo kwandika amategeko y’umukino.
Ku ya 20 Kamena 2025, itsinda ry’abashakashatsi riyobowe na Porofeseri David Baker, wegukanye igihembo cya Nobel akaba n’uwatangije poroteyine, ryasohoye ibyavumbuwe bishya kuri RFpeptides mu kinyamakuru Nature Chemical Biology. Uru rwego rushya rwa RFpeptides rutuma habaho imiterere mishya ya peptides macrocyclic ifite ubufatanye bukomeye na poroteyine zigamije, bigaragaza igihe gishya mu iterambere ry’imiti. Dushobora kuba duhagaze mu ntangiriro z’igihe gishya—kuva ku buryo gakondo bushingiye ku gusuzuma ibintu mu buryo butunguranye no kuvumbura ibicuruzwa karemano tujya mu gihe cyo gushushanya ibintu neza hifashishijwe ikoranabuhanga ryo kubara.
Imbogamizi z'iterambere ry'imiti gakondo ya PeptideAMAKURU
Gushingira ku isoko no kudahuza
Kwishingikiriza cyane ku ihinduka rya peptide zikora mu buryo busanzwe cyangwa gusuzuma mu bubiko bunini bwa peptide zidasanzwe bisa no "kubona urushinge mu gipangu cy'ibyatsi," bigatuma hatabaho udushya duhagije ku isoko.
Ibibazo byinshi byo gusuzuma umusaruro mwinshi
Kwishingikiriza ku ikoranabuhanga nka phage display bisaba gusuzuma igerageza rya triliyoni z'utunyangingo mu nshuro nyinshi kugira ngo hamenyekane umubare muto cyane w'ibintu bya mbere byakubiswe.
Ohereza ikibazo
Twandikire Kubindi Bishoboka Wifuza Kumenya Birenzeho Dushobora kuguha igisubizo, Ku bibazo bijyanye n'ibicuruzwa na serivisi byacu. Nyamuneka dusigire imeri yawe kandi tuzagusubiza mu masaha 24.
Kanda kugira ngo ubazeUbushobozi buke mu gishushanyo cya Macrocyclic Peptide
Kugenzura neza uburyo peptide igenda ihinduka no guhuza imiterere yayo mu buryo butatu biragoye. Peptide zikunze kubura imbaraga nyuma yo kugenda ihinduka, bigatuma imiterere ya peptides macrocyclic ifite imiterere igoye cyane.
Ingorane zo Kwibanda ku Nzu "Zidakoreshwa"
Uburyo gakondo bwo gusuzuma poroteyine mu buryo butunguranye butuma umuntu ahura n’ibintu bidafite aho bibohera, bufite igipimo cyo hasi cyane cyo gutsinda kandi ntibushobora kugera ku gishushanyo mbonera gifite intego.
Peptide Macrocyclic na AI Design: Igihe Gishya ku Ntego "Zidakoreshwa"AMAKURU
Nubwo ibinyabuzima bishobora kwihuza n’ibintu byinshi bivura hamwe n’uburyo bwo guhitamo ibintu, ingano yabyo nini ya molekile n’uburyo bwo kugabanya imiterere y’uturemangingo akenshi bibuza kwambuka uturemangingo tw’uturemangingo, bigatuma ibikorwa byatwo bigarukira ku bintu bituruka hanze y’uturemangingo. Ku rundi ruhande, molekile nto zishobora kugera ku bintu bituruka mu turemangingo ariko ntizikwiriye kwibasira poroteyine zidafite aho zibogamira cyane. Muri rusange, peptides macrocyclic—ingana hagati ya molekile nto na poroteyine—zishobora guterwa imbere kugira ngo zihindure ibintu bitagerwaho n’uburyo gakondo bwo kuvura. Ariko, imiterere yazo y’ubwenge yakomeje kuba ikibazo kidakemutse.
Urubuga rwa RFpeptides rwakozwe n'itsinda rya Porofeseri David Baker rugaragaza impinduka muri uru rwego. Iri koranabuhanga rihuza ubushobozi bwo guhanura neza bwa RoseTTAFold2 n'imbaraga zo guhanga za AI, bigatuma habaho ihinduka ry'ibanze kuva ku "gusuzuma" kugera ku "gushushanya." Ntabwo rigishingiye ku bubiko bw'ibitabo butunguranye ahubwo rikora mu buryo butaziguye urukurikirane rwa peptide ya macrocyclic ijyanye n'imiterere ya 3D ya poroteyine y'ingenzi, bityo bigatangiza igihe gishya cyo gushushanya imiti ya digitale—bihindura inzira kuva ku guteganya kugera ku guteganya no gukora porogaramu.
Gukoporora neza icyitegererezo cya mudasobwaAMAKURU
RFpeptides ni inzira yo kwigisha byimbitse (DL) ikoreshwa mu gushushanya neza ibintu bishya bihuza poroteyine zitandukanye. Ugereranyije n'uburyo gakondo bwo gushushanya, RFpeptides itanga inyungu nyinshi z'ingenzi:
Gukora neza
Ubu buryo bwo gushushanya butuma habaho kuvumbura byihuse kandi neza kw'ibifunga bya macrocyclic. Mu gihe hageragezwaga ibipimo biri munsi ya 20 kuri buri ntego (ugereranije na za tiriyari za peptides zageragejwe mu buryo gakondo bushingiye ku isomero), ibifunga bifite isano ikomeye ku ntego ebyiri byabonetse nta bundi buryo bwo kugerageza, bigera ku gipimo cyo gutsinda kiri hejuru cyane kurusha ubundi buryo bwose bwabanje.
Guteganyiriza ku buryo buboneye
Bitandukanye n’uburyo gakondo butari bushingiye ku masomero asanzwe, RFpeptides zishobora gukoreshwa mu gushushanya ibikoresho byihariye byo gufunga ahantu runaka n’ahantu runaka ku ntego.
Ubuziranenge bw'urwego rwa atomiki
Ubuhanga mu miterere y’icyitegererezo cy’igishushanyo butuma habaho uburyo bwo kunoza imiterere y’ikintu kugira ngo kirusheho kunoza imiterere y’ikintu, bityo kikarenga ku ntego yo kumenya imiterere y’ikintu. Mu gushyira mu bikorwa amahame y’igishushanyo kugira ngo imiterere y’ikintu igere ku ruhu, RFpeptides zishobora gukora peptides zinoza icyarimwe uburyo bwo gufatana kw’ikintu n’uburyo ingirabuzimafatizo zinjira cyangwa uburyo ingirabuzimafatizo ziboneka mu kanwa.
Igishushanyo cya 1 Urwego rwa tekiniki rwa RFpeptides
Igishushanyo cya 1 kigaragaza imiterere ya tekiniki ya RFpeptides, kigaragaza uburyo guhuza imikorere ya cyclic relative positional na modified RoseTTAFold2 (RF2) na RFdiffusion models bituma habaho neza imikorere ya macrocyclic peptide backbones.
Igishushanyo cya 2 cyerekana kandi urubuga rw’ubushakashatsi hibandwa ku ntego ebyiri zisanzwe zo kurwanya kanseri, MCL1 na MDM2, poroteyine zombi z’ingenzi zigenzura ubuzima bw’uturemangingo hamwe n’udupfunyika twinshi tugizwe na α-helices.
Kuri MCL1, peptide ya macrocyclic MCB_D2 yakozwe yagaragaje Cα RMSD ya 0.7 Å gusa (0.4 Å kuri atome z'umugongo gusa) ubwo imiterere yayo ya kristale ya X-ray yagereranywaga n'icyitegererezo cy'igishushanyo, hamwe n'imiterere y'uruhererekane rw'impande isa neza n'igishushanyo. Ibipimo bya SPR byemeje ko ifatana rya 2.0 μM. Imikoranire y'ibanze yakubiyemo gusa ifatana rya hydrophobic mu gace ka helical ahubwo yanahuje intera yihariye ya cation-π iturutse mu gace ka loop.
Kuri MDM2, peptide MDB_D8 yakozwe yahuzaga intego n'uburemere bwa 1.9 μM. Imiterere yayo y'ingenzi isa n'iyagaragaye muri MDM2-p53 complex karemano, byerekana ubushobozi bwa RFpeptides bwo gushushanya neza intego zifite imiterere myiza.
Igishushanyo cya 3 Igishushanyo mbonera cya Novo cy'ibifunga bya Macrocyclic bigamije GABARAP
Akamaro ka RFpeptides karushaho kugaragara iyo habayeho intego zifite imiterere igoye cyane yo gufatanya, nk'uko bigaragazwa neza ku Ishusho ya 3. Gutega GABARAP, poroteyine y'ingenzi mu kugenzura autophagy kandi ikaba ishobora kuba intego yo kuvura kanseri n'indwara zo mu bwonko, bituma hakenerwa cyane uburyo bwo gushushanya bitewe n'imiterere yayo igoye.
Isuzuma rya SPR ryagaragaje ko peptide zakozwe GAB_D8 na GAB_D23 zageze ku gaciro ka Kd kari hasi cyane nka 6 nM na 36 nM, uko bikurikirana. Mu bushakashatsi bwa AlphaScreen, agaciro kabo ka IC50 kari 0.7 nM na 2.5 nM. Ikigaragara ni uko GAB_D8 ari yo ifata GABARAP ikomeye cyane yavuzwe kugeza ubu.
Kwemeza kristalografiya ya X-ray byemeje ukuri kw'igishushanyo: GAB_D8 ifatanye na poroteyine GABARAPL1 ifite Cα RMSD ya 1.2 Å (0.47 Å kuri atome z'umugongo gusa), mu gihe GAB_D23 ifatanye na GABARAP ifite RMSD ijyanye nayo ya 1.7 Å (0.74 Å kuri atome z'umugongo gusa). Byongeye kandi, ibisubizo bya multiple sequence alignment (MSA) byagaragaje ko icyitegererezo cyateguwe neza cyageze ku bwumvikane buhanitse n'imiterere y'igerageza, byemeza ubushobozi bw'uburyo bwo guhangana n'intego zikomeye hamwe n'ubwoko bw'imiterere ya kabiri itari imwe.
Igishushanyo cya 4 Igishushanyo mbonera cya Novo cy'udusimba twa Macrocyclic twibasira RbtA duturutse kuri Acinetobacter baumannii
Ishusho ya 4 igaragaza iterambere rirenze imiterere gakondo yo kwishingikiriza ku nyubako zizwi zo kugerageza hifashishijwe ikoranabuhanga rya RbtA, poroteyine yo hejuru ya Acinetobacter baumannii idafite imiterere ihari yo kugerageza. Ubushakashatsi bwabanje guhanura imiterere ya RbtA hakoreshejwe AlphaFold2 (AF2) na RoseTTAFold2 (RF2), hanyuma bushushanya RBB_D10 ishingiye ku nyubako yahanuwe.
Ibisubizo by'igerageza byagaragaje ko RBB_D10 idafatana gusa n'ubuso bwa poroteyine bugororotse—ikibazo ku buryo gakondo—ariko kandi igaragaza ubushobozi bwo gufatana bufite Kd ya 9.4 nM. X-ray crystallography yemeje neza ukuri: imiterere y'igerageza ya RbtA ijyanye n'icyitegererezo cyahanuwe hamwe na Cα RMSD ya 1.1-1.2 Å, kandi imiterere igoye ya RBB_D10 ijyanye n'icyitegererezo yahuje icyitegererezo cy'igishushanyo na Cα RMSD ya 1.4 Å (0.4 Å kuri atome z'umugongo gusa). Imikoranire y'uruhererekane rw'impande ijyanye neza n'ibyahanuwe. Iki gikorwa cyatsinze neza imbogamizi za tekiniki z'imiterere idahari, gitanga inzira nshya yo guteza imbere imiti irwanya intego nshya za bagiteri cyangwa intego "zidakoreshwa".
IncamakeAMAKURU
Muri make, binyuze mu nzira yo kugenzura intambwe ku ntambwe yo "gutunganya icyitegererezo → kwemeza intego zijyanye n'imiterere izwi → iterambere hamwe n'intego zikomeye → kwagura intego zijyanye n'imiterere itazwi," RFpeptides ishyiraho uburyo bwihariye bwo gushushanya ibintu binini bikoreshwa mu bwoko butandukanye bw'imiterere. Imbaraga zayo z'ingenzi ziri mu guhuza ubushobozi bwo gukora imiterere bushingiye ku kwiga cyane hamwe no guhanura neza imikoranire ya poroteyine na ligand. Ubu buryo ntibureba gusa imikorere mike y'uburyo busanzwe bwo gusuzuma ahubwo bunatsinda uburyo bwo gushushanya bwa mudasobwa busanzwe ku makuru azwi y'igerageza, bityo byihutisha iterambere ry'ibinini bipima bishingiye kuri peptide ya macrocyclic hamwe n'imiti ivura.
Gukoresha urubuga rw'ingenzi rwashyizweho kugira ngo poroteyine ivanze na kuvumbura antibody, Alpha Lifetech ishyigikira neza ibisabwa mu gutegura poroteyine yihariye no kwemeza ibikorwa by'ingenzi mu gushushanya bishingiye ku buhanga bwa AI. Binyuze mu guhuza ikoranabuhanga gakondo nka Kubaka isomero rya phage display, twashyizeho uburyo bwuzuye bwo "Gushushanya AI - Kwemeza Igerageza - Gutunganya Imikorere". Ubu buryo buhuriweho butanga serivisi imwe yo guhangana n'intego "zidakoreshwa", bukubiyemo inzira yose kuva ku gishushanyo mbonera cya mbere kugeza ku ishyirwa mu bikorwa rifatika, kandi bukorohereza guhindura vuba ikoranabuhanga rya RFpeptides mu bisubizo bifatika by'ubushakashatsi.
Ibibazo Bikunze KubazwaAMAKURU
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1. Peptide macrocyclic ni iki, kandi ni izihe nyungu zidasanzwe zifite ugereranije n'imiti gakondo ya molecule nto na biological?
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2. Kuki abantu benshi bafatwa nk'abadashobora gukoresha imiti? Ni hehe imbogamizi zikomeye ziri?
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3. Ni gute AI igira uruhare kandi igahindura imikorere y’imiti ya macrocyclic peptide?
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4. Ni iki cyihariye ku buryo bwo gufatanya kwa peptides macrocyclic zakozwe na AI mu gihe zigamije "kurwanya imiti"?
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5. Lorem ipsum dolor yicara amet consectetur adipisising elit.
(i)) Ubushobozi bwo kwemerera uturemangingo:
Uburemere bwa polarity n'uburemere bwa molekile za peptides macrocyclic akenshi bibangamira ikwirakwira ry'uturemangingo mu buryo butunguranye. Kwibanda ku bice by'uturemangingo bisaba gushyiraho ingamba zihariye, nko guhuza peptides zinjira mu turemangingo cyangwa guhindura imiterere ya fizikiki binyuze mu ngamba zo gusimbuka.
(ii)) Guhagarara neza mu mikorere y'umubiri no kuboneka neza mu kanwa:
Molekile zishingiye kuri peptide zishobora kwangirika bitewe na poroteyine mu mubiri kandi muri rusange ntizifata neza mu kanwa. Kongera ubudahangarwa ku kwangirika kwa enzyme bisaba ingamba nko gushyiramo aside D-amino, aside amino zitari karemano, cyangwa impinduka zihariye ku mugongo.
(iii) Muri Vivo Pharmacokinetics na Potential Ubudahangarwa bw'umubiri:
Uburyo bwa AI bugomba guhuza ubushobozi bwo guhanura ADMET, bugatuma iyi miterere irushaho kuba myiza mu gihe cyo gushushanya. Byongeye kandi, kongera uburyo bwo guhuza imiti n'uburyo bwo kuyikora bitanga imbogamizi zikomeye z'ubuhanga zigomba gukemurwa kugira ngo inganda zigere ku ntego.
IndangamuntuAMAKURU
[1] Rettie SA, Juergens D, Adebomi V, n'abandi. Igishushanyo mbonera gishya cy'imizunguruko ihuza poroteyine nyinshi hakoreshejwe ubumenyi bwimbitse. Nat Chem Biol. Yasohotse kuri interineti ku ya 20 Kamena 2025.