2025 yog ib lub sijhawm ntawm kev ua haujlwm hnyav hauv kev tsim cov tshuaj qog peptide. Los ntawm cyclic peptides lub hom phiaj "tsis tsim nyog" rau luv peptides nrog dual lub luag haujlwm ntawm immunomodulation thiab photodynamic kev kho mob, thiab tom qab ntawd mus rau LYTAC peptide system uas degrades cell membrane proteins, ntau qhov kev nce qib tau hloov pauv lub luag haujlwm ntawm "peptide tshuaj" hauv kev kho mob qog noj ntshav-lawv tsis yog cov khoom lag luam uas pheej yig dua, tab sis ua kom muaj kev ywj pheej rau kev hloov pauv, tab sis cov kev hloov pauv tsis tu ncua. toolbox.
I. Cyclic Peptides: Txhaum los ntawm "Undruggable" Barrier
Cyclic peptides tau dhau los ua hom molecular saib tshaj plaws hauv thaj tsam ntawm cov protein-protein interaction (PPI) targeting. Piv nrog rau cov kab peptides ib txwm muaj, cov qauv kev sib tw ua rau lawv muaj zog metabolic stability, siab dua lub hom phiaj, thiab zoo dua membrane permeability.
Paluratide (LUNA18) yog tus sawv cev ntawm cov qauv no. Qhov no cyclic peptide, tsim los ntawm Chunghwa Pharmaceutical, ncaj qha lub hom phiaj ntawm RAS-SOS1 kev sib cuam tshuam, thiab RAS tau ntev tau suav tias yog qhov ntsuas rau "tsis muaj kev tiv thaiv" lub hom phiaj. LUNA18 yog tam sim no nyob rau hauv Phase I soj ntsuam sim (NCT05012618) raug soj ntsuam raws li kev kho qhov ncauj thiab ua ke nrog cetuximab.
Hauv thaj chaw glioblastoma, VT1021 (a 638.76 Da cyclic peptide) tsom rau CD36 / CD47 lub cev tiv thaiv kab mob thiab tam sim no raug tshuaj xyuas hauv Phase III sim (NCT03970447). Cov molecule no tuaj yeem hla cov ntshav- lub hlwb teeb meem thiab hloov kho qhov kev tiv thaiv kab mob microenvironment tshwj xeeb rau glioblastoma, hais txog qhov xav tau ceev rau kev kho tshiab hauv daim teb no.
Zelenectide pevedotin (BT8009) sawv cev rau lwm qhov kev taw qhia hauv kev hloov pauv ntawm cyclic peptide thev naus laus zis-bicyclic peptide- tshuaj conjugates. Cov molecule no tsom rau Nectin-4 nthuav tawm cov qog, thiab nws qhov ua tau zoo hauv urothelial carcinoma yog tam sim no raug soj ntsuam hauv Phase III sim (NCT06225596). Cov qauv bicyclic peptide khaws cov phiaj xwm zoo ntawm cyclic peptides thaum muab kev sib xyaw ua ke ntau dua, uas muaj txiaj ntsig zoo rau kev ua kom zoo ntawm cov tshuaj pharmacokinetic.
II. PDCs: Lub Platform tshiab rau Precision Drug tua
Peptide-Drug conjugates (PDCs) tab tom ua lub luag haujlwm tseem ceeb hauv kev kho mob qog noj ntshav. Piv rau ADCs, PDCs muaj qhov hnyav me me (feem ntau 2-10 kDa vs. ~ 150 kDa rau ADCs), uas ua rau cov qog nkag tau zoo dua thiab qis dua kev pheej hmoo ntawm kev tiv thaiv kab mob.
Hauv thaj tsam ntawm triple-mob qog noj ntshav tsis zoo (TNBC), cov kws tshawb fawb tau tsim cov chav kawm ntawm cyclic peptide PDCs tsom rau TROP2. TROP2 yog transmembrane glycoprotein overexpressed nyob rau hauv ntau yam epithelial malignancies thiab yog txuam nrog qog invasiveness thiab tsis zoo prognosis. TROP2-binding cyclic peptides tau los ntawm phage zaub tshuaj ntsuam xyuas, tom qab alanine scanning optimization, tau conjugated nrog pro-apoptotic peptides los yog MMAEs, ua tiav cytotoxicity nrog IC50 ntawm 25.6 nM hauv TROP2-siab qhia TNBC hlwb, thaum tsis muaj cov tshuaj lom los yog tsis tshua muaj tshwm sim.
Hauv lwm txoj kev tshawb fawb, cov kws tshawb fawb tau tsim qhov txo qis - teb PDC (RGDC-SS-DTX) los ntawm kev txuas ib qho RGD- phiaj peptide nrog docetaxel (DTX) ntawm daim ntawv cog lus disulfide. Qhov kev tsim qauv no txhawb nqa qhov siab ntawm glutathione (GSH) hauv cov qog nqaij hlav: disulfide daim ntawv cog lus tau txo qis hauv cov qog hlwb, tso cov tshuaj nquag, thaum tseem nyob ruaj khov hauv cov hlwb qub. Cov kev tshawb fawb hauv vitro tau pom tias RGDC-SS-DTX yog qhov zoo tshaj rau DTX dawb hauv G2 / M theem ntes thiab apoptosis induction hauv cov qog hlwb, thaum txo cov tshuaj lom rau lub cev ib txwm muaj. Lub tswv yim no qhia tau hais tias PDC platform tuaj yeem ua tiav qhov kev xa tshuaj meej meej los ntawm kev tsim cov ntawv txuas.
III. PD-L1 Targeting Peptide: Thaum Immune Checkpoint Inhibitors yog "Miniaturized"
Cov tshuaj tiv thaiv kab mob -raws li cov tshuaj tiv thaiv kab mob tiv thaiv kab mob (ICIs) ntsib cov teeb meem xws li tus nqi siab, kev nkag mus rau qog tsis zoo, thiab kev mob toxicity. Peptide-raws li ICIs muaj lwm txoj hauv kev, tab sis feem ntau raug kev txom nyem los ntawm kev ua tsis tau zoo ntawm vivo.
IKCRPCY (IKC)-ib heptapeptide txheeb xyuas los ntawm phage zaub- muab cov lus teb sib txawv. Cov peptide no nthuav tawm nanomolar affinity rau PD-L1 thiab tuaj yeem rov qab IL-2 tso tawm hauv co-cultured T cells. Cov kws tshawb fawb ntxiv tau tsim ib qho kev sib txuas ntawm Ce6 nrog dihydroporphyrin e6 (Ce6) (Ce6-IKC), ua tiav cov txiaj ntsig zoo ntawm kev kho mob photodynamic thiab kev tiv thaiv kab mob tiv thaiv kab mob.
Hauv CT26 tus qauv qog nqaij hlav ob sab, Ce6-IKC PDT ua ke nrog kev kho IKC cuam tshuam loj heev ntawm cov qog nqaij hlav, ua rau muaj kev cuam tshuam ntawm cov kab mob immunogenic cell tuag (Calreticulin, HMGB1), thiab nce CD8+ T cell infiltration. Qhov tseem ceeb tshaj, qhov tsis sib xws (tsis kho) lub nra hnyav tau txo los ntawm 72% - cov pov thawj tseeb ntawm cov nyhuv abscopal.
Qhov kev ua haujlwm no qhia txog qhov tshwj xeeb zoo ntawm cov tshuaj peptide: lawv tuaj yeem ua ke ntau yam kev kho mob rau hauv ib qho molecule los ntawm kev hloov kho tshuaj, uas yog qhov nyuaj dua kom ua tiav hauv cov tshuaj tiv thaiv kab mob.
IV. Peptide LYTACs: Ib Txoj Cai Tshiab rau Cov Txheej Txheem Tshaj Tawm Txog Cov Txheej Txheem Txheej Txheem Txheej Txheem Txheej Txheem Txheej Txheem Txheej Txheem Txheej Txheem Txheej Txheem (TPD) thev naus laus zis- suav nrog PROTACs thiab cov kua nplaum molecular - tau hloov pauv cov qauv tsim qauv ntawm cov tshuaj molecule me. Txawm li cas los xij, cov thev naus laus zis no tsuas tuaj yeem txo qis cov proteins hauv lub cev. Cell membrane proteins thiab secreted proteins (suav txog kwv yees li 40% ntawm tib neeg coding genes) nyob sab nraum nws ncav cuag.
Lub tswv yim LYTAC (lysosomal targeted chimera) lub tswv yim los ntawm Bertozzi pab neeg hauv 2020 tau sau qhov sib txawv no. Antibody-raws li LYTACs raug kev txom nyem los ntawm kev sib xyaw ua ke, txwv cov qog nkag mus, thiab tus nqi siab.
Cov kws tshawb fawb tau tig mus rau GLP-1-based peptide LYTAC system (APCTAC). This system couples GLP-1 analogs (such as modified sequences of smegglutinin or exenatide) to target protein binding molecules, guiding target proteins (such as PD-L1) on the cell surface into lysosomes for degradation.
Hauv cov qauv tsiaj, APCTAC tau ua tiav qhov muaj zog degradation ntawm PD-L1, hloov pauv cov kab mob qog noj ntshav microenvironment rau hauv ib puag ncig immunostimulatory microenvironment. Piv nrog rau kev kho cov tshuaj tiv thaiv kab mob, APCTAC tau ua tiav qhov sib piv lossis zoo dua los tiv thaiv - qog ua haujlwm tau zoo thaum ua rau muaj kev puas tsuaj loj heev.
Qhov no taw qhia rau ib qho kev taw qhia: cov tshuaj peptide tau hloov ntawm "lub hom phiaj" mus rau "degradation," thiab los ntawm "inhibitory signals" mus rau "tshem tawm cov molecules." V. Innovative Delivery: Overcoming the Blood-Brain Barrier and Improving Pharmacokinetics
Ib qhov ntev - teeb meem sawv cev nrog cov tshuaj peptide yog lawv cov neeg pluag nyob rau hauv vivo stability thiab luv luv ib nrab- lub neej. Kev tshawb fawb tam sim no tab tom hais txog qhov kev sib tw no los ntawm ntau lub ces kaum.
Hauv kev kho mob glioblastoma, cov kws tshawb fawb tau tsim tus kheej - sib sau peptide- tshuaj conjugates (OncoPDCs) uas hla cov ntshav- lub hlwb thaiv thiab raug txhaj ncaj qha rau hauv lub hlwb parenchyma ntawm convection- txhim kho kev xa khoom (CED). Cov conjugates no muaj peb qhov kev ua haujlwm zoo: ib qho receptor-binding ligand (targeting IL4R lossis IL13R 2), intrinsically disordered peptide domain (ua tiav kev tso tawm hauv lub hlwb), thiab tshuaj tiv thaiv- qog nqaij hlav (SN38). Tus kheej-cov qauv sib dhos ua ib qho hauv-situ reservoir tshwm sim los ntawm lub cev kub, ua kom lub sijhawm nyob hauv cov tshuaj ntawm cov qog thiab muab lub tswv yim tshiab los daws qhov kev sib tw ntawm kev tshem tawm sai ntawm gliomas tom qab phais.
Nyob rau hauv cov nqe lus ntawm kev xa khoom, pH- teb cov polymer nanoparticles yog siv rau lub hom phiaj xa tawm los tiv thaiv -PD-L1 peptides thiab kev sib koom ua ke ntawm txoj kev STING. Cov nanosystem no, tus kheej- sib dhos los ntawm PEO-PC7A amphiphilic block copolymer, nyob ruaj khov ntawm nruab nrab pH thiab tso tawm cov tshuaj tiv thaiv -PD-L1 peptide nyob rau hauv acidic qog microenvironment (pH 6.2-6.8). Ib txhij, PC7A tus thawj coj nws tus kheej tuaj yeem qhib cGAS{16}}STING txoj hauv kev, ua tiav kev tiv thaiv kab mob tiv thaiv kab mob thiab ua kom lub cev tsis muaj zog. Qhov "ib zaug-khoom siv, dual-function" lub tswv yim no sawv cev rau cov kev taw qhia tshiab hauv nanodelivery system tsim.
Xaus: Los ntawm "Carrier" mus rau "Kev Kho Mob Logic"
Yav dhau los, lub luag haujlwm ntawm peptides hauv kev tshawb fawb qog nqaij hlav feem ntau ua kom yooj yim rau "cov phiajcim ligands"- tus navigator uas xa tshuaj mus rau lawv qhov chaw. Txawm li cas los xij, qhov kev nce qib tau hais tseg saum toj no nthuav tawm cov duab sib txawv kiag li:
Peptides tau dhau los ua lub hauv paus ntawm kev kho mob.
Cov no tuaj yeem yog cyclic peptide molecules uas ncaj qha thaiv PPI lub hom phiaj tsis zoo xws li RAS-SOS1; lawv tuaj yeem yog "kev lees paub modules + cov lus teb hloov pauv" hauv PDCs, xws li RGDC-SS-DTX, uas tso tawm cov tshuaj hauv cov lus teb rau qhov txo qis hauv cov qog hlwb; lawv tuaj yeem yog "bifunctional molecules" uas sib xyaw ua ke ntawm lub cev tiv thaiv kab mob thaiv thiab kev kho photodynamic los ntawm kev hloov kho tshuaj lom neeg; lawv tuaj yeem yog LYTAC cov tshuab uas tshem tawm PD-L1 los ntawm kev degradation ntau dua li inhibition; los yog lawv tuaj yeem yog cov tshuab ntse ua ke nrog nanodelivery platforms, ib txhij ua lub luag haujlwm hauv pharmacokinetic optimization thiab kev tiv thaiv kab mob.
Qhov tshiab tshiab tsis yog nyob rau hauv "tsis tau lwm yam tshuaj peptide," tab sis qhov tseeb tias peptides tau hla lawv lub luag haujlwm ua "rov qab" tshuaj rau cov tshuaj tiv thaiv kab mob, tsim kom muaj kev cuam tshuam zoo sib xws uas txawv ntawm cov tshuaj tiv thaiv thiab cov khoom me me. Lawv qhov sib xyaw ua ke ntawm qhov loj me me, lub hom phiaj txoj hauv kev, cov txheej txheem ntawm kev ua, thiab kev ua haujlwm tau muab rau lawv tsis tuaj yeem hloov pauv tus nqi hauv qee qhov ntev ntawm kev kho mob qog noj ntshav -tshwj xeeb tshaj yog hauv kev tsom PPIs, kev degradation meej, thiab kev tsim qauv molecular multifunctional.