Larazotide, qhov ncauj me me, hluavtaws peptide thiab xaiv antagonist ntawm zonulin yog txawv los ntawm lwm yam tshuaj raws li cov compound no tsis khi tej receptor per se.
Nws ua haujlwm hauv ib qho adjuvant luag hauj lwm (muab los ntawm cov ntaub ntawv thiab kev sib txuas lus ntawm tus kheej) los ntawm normalizing ib tug dysfunctional plab hnyuv barrier pom tsawg kawg nyob rau hauv kab mob celiac.
Larazotide tiv thaiv gluten-mediated nruj hlws ris qhib thiab yog ib qho kev ntxim nyiam uas tsis yog kev noj haus rau cov neeg mob CD nyob rau hauv GFD.
Larazotide tau pom tias muaj txiaj ntsig zoo hauv kev txhim kho kho mob hauv Phase IIb kev tshawb fawb, tshwj xeeb tshaj yog rau cov tsos mob.
Ntxiv rau nws thawj daim ntawv thov nyob rau hauv cov kab mob gastrointestinal, Kev tshawb fawb ua ntej hauv vitro tau pom tias muaj kev tiv thaiv kab mob ntawm Larazotide tawm tsam varicella-zoster tus kab mob (VZV), ua rau muaj peev xwm siv tau tshiab hauv kev kis kab mob.
Hauv kev lag luam tshuaj, Larazotide yog qhov tseem ceeb ntawm qhov ncauj peptide kho kev ua tiav.
Kev nqus ntawm qhov ncauj ntawm cov tshuaj peptide tau pom tias tsis zoo vim tias lawv tau degraded los ntawm GI enzymes..
Qhov kev tsim tshiab no tso cai rau nws ua haujlwm ntawm cov kab mob hauv plab hauv zos nrog kev nqus tsawg kawg nkaus, thiaj li txo tau tej yam kev mob tshwm sim.
Ib ntus
H-Gly-Gly-Val-Leu-Val-Gln-Pro-Gly-OH
CAS Nr
258818-34-7
Molecular Formula
C32H55N9O10
Molecular Luj
725.83
Kev tshawb fawb ntawm Larazotide
1.Target Identification thiab Drug Design
Zonulin, cov protein uas tswj plab hnyuv (THIAB) paracellular permeability nyob rau hauv ib tug reversible thiab ua tsis taus pa zam tau pom.
Txawm tias cov hom kev ua ntawm Larazotide yog analogous rau AT-1001–uas yog hais, ib qho thaiv ntawm zonulin khi rau nws cov receptor thiab los ntawm qhov kev tiv thaiv ntawm cov hnyuv permeability los ntawm attenuation ntawm zonulin los ntawm nruj junctions-, nws tau sim ua thawj TJ modulator hauv tib neeg.
Txawm li cas los, Vim nws cov amino acid sib lawv liag thiab acetate ntsev formulation (Larazotide acetate hmoov, CAS Nr 881851-50-9), Larazotide [Ac-KPFSLSQ(Cys)] qhia superior stability thiab lub zos bioavailability nyob rau hauv lub plab.
2.Modulation ntawm plab hnyuv Barrier Function
Larazotide tuav qhov muaj txiaj ntsig ntawm kev tshawb fawb raws li txoj hauv kev tshiab thiab muaj zog rau cov kev hloov kho tshwj xeeb ntawm txoj hnyuv ua haujlwm.
Nws qhov kev txiav txim yog tsuas yog exerted los ntawm kev ua ib tug qauv analogue ntawm zonulin, sib tw nrog zonulin rau khi rau cov receptors ntawm lub luminal nto ntawm enterocytes.
Qhov no ua rau inhibition ntawm intracellular activation ntawm myosin light-chain kinase (MLCK), cytoskeletal reorganization thiab disassembly ntawm nruj junction proteins suav nrog SE-1.
Los ntawm cov txheej txheem molecular Larazotide ruaj ntseg thaiv kev ncaj ncees ntawm kev sib tshuam nruj thiab inhibits qhov tsis xav tau kev hloov pauv ntawm cov macromolecules e.g., gliadin.
3.Kev Tswj Xyuas Kab Mob Celiac
Kab mob celiac (CD) Nws yog ib qho autoimmune enteropathy, pib los ntawm kev raug gluten nyob rau hauv cov neeg muaj caj ces predisposed, thiab nws cuam tshuam txog 1% ntawm cov pejxeem thoob ntiaj teb.
Tam sim no, Kev ua raws li kev noj zaub mov tsis muaj gluten yog qhov kev kho mob nkaus xwb.
Txawm li cas los, ntev kev ua raws li kev noj haus yog qhov nyuaj; nruj kev zam ntawm kev sib cuag yuav nyuaj rau ua tiav thiab cov tsos mob tseem nyob hauv ntau tus neeg mob.
Ntawm nws qhov tseem ceeb, MOA ntawm Larazotide hauv kab mob celiac yog xaiv inhibition ntawm zonulin-induced TJ qhib.
Hauv kab mob celiac, nyob rau hauv teb rau deamidated gliadin peptides, enterocyte CXCR3 yog koom nrog ua rau tso tawm zonulin.
Cov zonulin dawb ces cuam tshuam nrog nws cov receptor ntawm txheej txheej epithelial, ua rau intracellular signaling txoj kev uas ua rau myosin teeb-chain phosphorylation.
Qhov no ua rau muaj kev hloov pauv ntawm cov protein sib txuas nruj (as ZO-1, occludin ua thiab claudins) thiab cytoskeleton tus kab mob rearrangement nrog rau qhov kev txhim kho ntawm plab hnyuv permeability.
Larazotide yog kev sib tw octapeptide antagonist, kev sib tw thiab thim rov qab khi rau zonulin receptors ntawm luminal nto ntawm cov hlwb epithelial, yog li thaiv qhov cascade signaling txheej txheem, thiab tswj qhov barrier homeostasis.
A landmark Phase IIb clinical trial included 342 patients with continued symptoms in the setting of a GFD.
A dose of 0.5 mg three times daily was shown to be effective and superior to placebo in terms of reduction of gastrointestinal symptoms with an acceptable safety and tolerability profile prior to further study.
4.Antiviral Properties
Apart from its application in intestinal inflammation, Larazotide has marked in vitro antiviral efficacy against VZV.
This discovery extends its therapeutic potential and indicates diverse mechanisms of action may be operative.
The in vitro evidence suggests that Larazotide inhibits the replication of VZV OKA and 07-1 strains with EC₅₀ ntawm 44.14 μM and 59.06 μM, respectively.
This level of activity is moderate for an antiviral agent.
Txawm li cas los, raws li cov kev ua ntawm Larazotide nyob rau hauv lub zos nrog ib tug kuj loj kho qhov rais, qhov no ntxiv rau qhov tseem ceeb hauv kev txhim kho kho mob.
Qhov tseem ceeb, tus cytotoxicity ntawm no tus neeg sawv cev nyob rau hauv lub host cell (Vero hlwb) ua qauv qhia a CC₅₀ tus nqi ntawm 82.5 μM, muab TI ratio ntawm ~ 1.4–1.9.
Qhov no qhia txog qhov me me tab sis xav tias muaj kev nyab xeeb zoo ntawm cov tshuaj tiv thaiv kab mob uas muaj txiaj ntsig zoo.
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