Tesamorelinyog tsim los ntawm 44 amino acid sequences ntawm human growth hormone releasing factor (GRF). 3-hexenoyl yog txuas rau N-terminal residue ntawm nws tyrosine. Cov mis mos molecular yog C221H366N72O67S. XC2H4O (x ≈ 7), CAS 901758-09-6 thiab CAS 218949-48-5, nrog tus txheeb ze molecular hnyav (dawb puag) ntawm 5135.9. Analogues yog ib qho kev loj hlob hormone tso tawm tshiab uas tuaj yeem tsis tsuas yog rov ua kom lub cev tsis zoo ntawm cov tshuaj hormones loj hlob hauv lub cev, tab sis kuj txo qhov nce hauv visceral adipose cov ntaub so ntswg (VAT), txhim kho cov ntshav lipid abnormality thiab lub neej zoo, thiab tswj kom muaj qhov sib npaug ntawm cov piam thaj hauv lub cev. Cov tshuaj tau pom zoo los ntawm US Food and Drug Administration thaum lub Kaum Ib Hlis 2010 rau kev kho mob HIV ntsig txog fatty metabolism disorder syndrome. Peb muaj tesamorelin peptide muag, tab sis nws yuav tsum tau muab sau tseg tias cov khoom muab los ntawm Shaanxi BLOOM Tech Co., Ltd. yog rau kev sim siv xwb.
Peb cov khoom
Tesamorelin COA
Ib txoj hauv kev rau kev ua kom huv los ntawm kev hloov pauv theem siab ua kua chromatography suav nrog cov kauj ruam hauv qab no:
1) Timorelin ntxhib ntawm daim tawv nqaij tau los ntawm cov khoom theem synthesis yog yaj nyob rau hauv dej deionized, thiab cov theem nyob ruaj ruaj yog ib tug reversed -theem silica gel kem nrog tetraalkyl silane bonded silica gel, octaalkyl silane bonded silica gel los yog octadecyl bonded silica gel theem ob, phosphate buffer tov yog theem A, thiab chromatogram ntshiab acetonitrile yog theem B, thiab gradient elution purification yog ua los sau cov tawv nqaij daws ntawm lub hom phiaj ncov.
2) Cov tshuaj tau txais yog concentrated los ntawm lub tshuab nqus tsev evaporation, thiab cov concentrated tov yog tshwj tseg rau standby
3) Siv anion txauv resin los pauv thiab hloov mus ua kom txias
4) Qhov kawg siab tshaj -purity cortisone tov yog concentrated thiab khov- qhuav los ntawm decompressing, rotating thiab evaporating dua kom tau ib tug powdery tiav cov khoom.
Txoj kev no yog tsim rau kev ua kom huv ntawm temorelin. Nws tuaj yeem tsis tsuas yog tau txais cov tawv nqaij zoo nkauj nrog purity ntau dua 98.0%, tab sis kuj tsim cov khoom ua kom tau raws li qhov yuav tsum tau muaj ntawm purity siab, siab yield, tsawg tus nqi thiab kev ua haujlwm siab.
Synthesis method
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Cov peptide resin A tau npaj los ntawm kev sib txuas ua ke Fmoc-Leu-OH thiab lwm yam kev tiv thaiv amino acids nrog cov resin ua cov cab kuj nyob rau hauv qhov kev txiav txim ntawm temorelin
Tag nrho cov khoom tiv thaiv B1-Bn (n yog ib qho kev txaus siab 2 Tsawg dua lossis sib npaug rau n<21) was synthesized by solid phase synthesis method respectively. The sequence of the fragments is part of the sequence of temorelin, and the sequence of total amino acids after connecting A and B1-Bn is the same as that of temorelin
Cov peptide resin A tau txuas ntxiv ua ke nrog tag nrho -cov khoom tiv thaiv B1-Bn thiab trans-hexaenoic acid nyob rau theem khoom kom tau txais temorelin peptide resin
Pyrolysis ntawm temorelin peptide resin kom tau crude peptide. Txoj kev npaj temorellin yog ib qho yooj yim rau kev khiav lag luam, tsis tshua muaj nqi, yooj yim hauv purification thiab siab yield
Cov keeb kwm kev tshawb fawb tsom mus rau kev kho mob ntawm cov rog metabolism cuam tshuam nrog HIV (Human Immunodeficiency Virus). Hauv qab no yog qee cov ntsiab lus tseem ceeb ntawm kev tshawb fawb keeb kwm:
1. Kev tshawb pom ua ntej
Hauv cov kab mob HIV-cov neeg mob kis, qee cov tshuaj yuav ua rau muaj roj metabolism tsis zoo thaum kho, tshwj xeeb tshaj yog cov rog hauv plab ntau dhau. Qhov kev hloov pauv no tsis tsuas yog cuam tshuam rau lub cev ntawm cov neeg mob, tab sis kuj tseem cuam tshuam nrog kev pheej hmoo ntawm metabolic abnormality thiab kab mob plawv. Yog li ntawd, kev tshawb nrhiav cov tshuaj uas tuaj yeem kho cov rog metabolism tsis zoo no tau dhau los ua ib qho tseem ceeb ntawm kev tshawb fawb.
2. Mechanism ntawm kev kawm ua
Kev tswj hwm kev tso tawm ntawm kev loj hlob hormone (GH) hauv lub cev los ntawm kev coj ua thiab txhim kho kev ua haujlwm ntawm tib neeg kev loj hlob hormone tso tawm hormone (GHRH). Kev loj hlob hormone plays lub luag haujlwm tseem ceeb hauv kev tswj kev loj hlob, kev sib txuas thiab cov metabolism hauv lub cev, thiab nws txhawb kev tso tawm ntawm cov tshuaj hormones los ntawm kev khi rau GHRH receptor nyob rau hauv lub caj pas pituitary, yog li nce qib ntawm GH hauv lub cev. Qhov kev tshawb pom no muab lub hauv paus theoretical rau kev kho mob HIV- txuam nrog lipid metabolism cuam tshuam nrogTesamorelin.
3. Kev tshawb fawb soj ntsuam
Raws li cov txheej txheem ntawm kev nqis tes ua, cov kws tshawb fawb tau ua ntau qhov kev sim tshuaj ntsuam xyuas nws qhov ua tau zoo hauv kev kho mob HIV- txuam nrog dyslipidemia. Cov kev tshawb fawb no tau pom tias kev kho mob txo qis cov rog hauv plab thiab tseem muaj txiaj ntsig zoo hauv kev txhim kho cov neeg mob cov tsos mob ntawm cov rog. Qhov no tuaj yeem muaj kev cuam tshuam zoo rau ob qho tib si lub hlwb thiab lub cev kev noj qab haus huv ntawm cov neeg mob.
4. FDA pom zoo
Raws li cov txiaj ntsig zoo ntawm cov kev tshawb fawb soj ntsuam no, nws (Tesamorelin acetate ntsev, lub npe lag luam Egrifta) tau pom zoo los ntawm US Food and Drug Administration (FDA) rau kev kho mob HIV-kev cuam tshuam ntawm cov roj metabolism hauv xyoo 2010. Qhov no yog thawj cov tshuaj pom zoo los ntawm FDA rau kev kho mob lipid metabolism.
Hauv kev xaus, keeb kwm ntawmTesamorelinkev tshawb fawb tau yog ib qho ntawm kev tshawb pom ntawm qhov muaj peev xwm kho tau zoo, hauv - tshawb nrhiav qhov tob ntawm cov txheej txheem ntawm kev ua, kev siv tau ntawm kev ua tau zoo los ntawm kev sim tshuaj, thiab thaum kawg kev pom zoo kev tswj hwm. Txoj kev vam meej ntawm cov txheej txheem no tsis yog tsuas yog muab cov kev xaiv kho tshiab rau HIV- cov neeg mob kis, tab sis kuj muaj cov tswv yim tshiab rau kev kho mob ntawm lwm yam kab mob cuam tshuam nrog kev cuam tshuam ntawm cov rog metabolism.
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Tesamorelin inhibits GSK-3 thiab txo tau cov protein phosphorylation los ntawm IGF-1
Tesamorelin yog ib qho kev sib txuas ntawm kev loj hlob hormone tso tawm (GHRH) analog uas tuaj yeem txhawb nqa qhov tso tawm ntawm cov tshuaj hormones loj hlob (GH) los ntawm cov qog pituitary, yog li cuam tshuam rau qib ntawm insulin-zoo li kev loj hlob factor-1 (IGF-1). Nyob rau hauv xyoo tas los no, kev tshawb fawb tau pom tias Tesamorelin tuaj yeem tswj tau cov protein phosphorylation los ntawm IGF-1-txog txoj kev taw qhia, coj kev cia siab tshiab rau kev kho mob ntawm cov kab mob neurodegenerative.
Cov yam ntxwv ntawm GSK-3 thiab nws txoj kev sib raug zoo nrog tau protein phosphorylation
Qauv thiab Enzymatic yam ntxwv ntawm GSK-3
Glycogen synthase kinase-3 (GSK-3) yog ib qho serine / threonine protein kinase uas muaj dav hauv cov hlwb. GSK-3 muaj cov yam ntxwv tshwj xeeb thiab nws cov haujlwm yog tswj hwm los ntawm ntau yam. Thaum so, GSK-3 muaj qee yam kev ua haujlwm hauv nruab nrab, thiab nws cov haujlwm tseem ceeb ntxiv thaum ua haujlwm los ntawm cov teeb liab ntws. GSK-3 muaj ntau yam substrates thiab tuaj yeem phosphorylate ntau cov proteins, koom nrog ntau yam kev taw qhia thiab cov txheej txheem physiological hauv hlwb.
Phosphorylation ntawm tau protein los ntawm GSK-3
Tau protein ntau yog microtubule txuam nrog cov protein uas feem ntau koom nrog hauv kev sib dhos thiab kev ruaj ntseg ntawm microtubules hauv neurons. Muaj ntau qhov chaw phosphorylation ntawm tau protein ntau, thiab GSK-3 yog ib qho ntawm cov kinases tseem ceeb uas catalyze tau protein phosphorylation. GSK-3 tuaj yeem lees paub tshwj xeeb thiab phosphorylate tshwj xeeb serine thiab threonine residues ntawm tau cov protein, xws li Ser396, Thr231, thiab lwm yam. Cov phosphorylation ntawm tau protein ntau tuaj yeem ua rau txo qis hauv nws txoj kev khi muaj peev xwm rau microtubules, cuam tshuam ntawm microtubule qauv, uas ua rau muaj kev cuam tshuam rau cov khoom thauj thiab kev ua haujlwm ntawm neurons.
Lub luag haujlwm ntawm GSK-3 hauv cov kab mob neurodegenerative
Hauv cov kab mob neurodegenerative xws li AD, kev ua haujlwm ntawm GSK-3 yog qhov txawv txav, uas yog ze rau cov phosphorylation ntawm tau protein ntau thiab tsim cov neurofibrillary tangles. Kev tshawb fawb tau pom tias inhibiting qhov kev ua ntawm GSK-3 tuaj yeem txo cov qib phosphorylation ntawm tau protein, txhim kho neuronal pathological hloov pauv, thiab ncua kev kis kab mob. Yog li ntawd, GSK-3 tau dhau los ua ib lub hom phiaj tseem ceeb rau kev kho cov kab mob neurodegenerative.
Lub mechanism ntawm Tesamorelin stimulating IGF-1 secretion
Lorem ipsum dolor sit amet consectetur
Kev sib cuam tshuam ntawm Tesamorelin thiab GHRH receptor
Tesamorelin, raws li GHRH analog, tuaj yeem khi rau GHRH receptors nyob rau saum npoo ntawm cov qog pituitary. Qhov kev khi no muaj kev sib raug zoo thiab tshwj xeeb, zoo ib yam li kev sib cuam tshuam ntawm ntuj GHRH thiab receptors. Thaum Tesamorelin khi rau GHRH receptor, nws ua rau muaj kev hloov pauv hauv cov receptor, ua kom cov G protein ua ke nrog txoj hauv kev hauv lub cell.
Activation ntawm intracellular signaling pathways
Tom qab Tesamorelin khi rau GHRH receptors, cov activated G protein ntxiv activates adenylate cyclase (AC), ua rau kom nce qib ntawm intracellular cyclic adenosine monophosphate (cAMP). CAMP, ua tus xa xov thib ob, qhib cov protein kinase A (PKA). PKA tuaj yeem phosphorylate ntau yam hauv qab cov phiaj xwm cov proteins, suav nrog cov txheej txheem hloov pauv, yog li txhawb nqa kev hloov pauv thiab kev qhia ntawm GH noob, thaum kawg ua rau muaj kev nce hauv GH secretion.
Induction ntawm IGF-1 synthesis los ntawm GH
GH tso rau hauv cov hlab ntsha ua rau cov ntaub so ntswg xws li lub siab, ua rau JAK-STAT qhia txoj hauv kev hauv daim siab hlwb los txhawb kev hloov pauv thiab qhia txog IGF-1 noob. Tom qab khi rau GH receptors nyob rau saum npoo ntawm daim siab hlwb, GH activates receptor ntsig txog JAK kinases, uas ntxiv phosphorylate STAT proteins. Phosphorylated STAT proteins tsim dimers, nkag mus rau hauv lub nucleus, khi rau thaj tsam txhawb nqa ntawm IGF-1 noob, thiab pib ua cov synthesis thiab tso tawm ntawm IGF-1.
IGF-1 inhibits txoj kev taw qhia ntawm GSK-3 kev ua
Ua kom cov IGF-1 receptor
Tom qab IGF-1 tso rau hauv cov hlab ntsha, nws khi rau IGF-1 receptor (IGF-1R) nyob rau saum npoo ntawm lub hom phiaj hlwb. IGF-1R yog tyrosine kinase receptor. Thaum IGF-1 khi rau lub receptor, nws ua rau muaj kev hloov pauv thiab ua rau lub zog receptor's tyrosine kinase kev ua haujlwm. Ua kom IGF-1R tus kheej phosphorylates thiab phosphorylates downstream signaling molecules, xws li insulin receptor substrate (IRS) proteins.
Ua kom PI3K Akt signaling txoj kev
Phosphorylated IRS cov proteins tuaj yeem nrhiav thiab qhib phosphatidylinositol 3-kinase (PI3K). PI3K catalyzes tsim ntawm phosphatidylinositol-3,4,5-triphosphate (PIP3) los ntawm phosphatidylinositol-4,5-diphosphate (PIP2) ntawm lub cell membrane. PIP3, ua tus xa xov thib ob, tuaj yeem nrhiav cov protein kinase B (Akt) mus rau hauv cov cell membrane thiab qhib nws. Activated Akt yog ib qho tseem ceeb molecule uas inhibits GSK-3 kev ua.
Akt's inhibitory nyhuv ntawm GSK-3
Akt tuaj yeem ncaj qha phosphorylate tshwj xeeb serine residues (xws li Ser9) ntawm GSK-3, thiab cov haujlwm ntawm phosphorylated GSK-3 yog inhibited. Cov nyhuv inhibitory no tiv thaiv GSK-3 los ntawm phosphorylating substrates xws li tau protein, yog li txo qis phosphorylation txawv txav ntawm tau protein ntau.
Cov nyhuv ntawm GSK-3 kev ua haujlwm inhibition ntawm tau protein phosphorylation qib
Kev tshawb nrhiav hauv vitro
Hauv kev sim vitro cell, cov kws tshawb fawb tau nthuav tawm cov hlwb neuronal rau Tesamorelin lossis IGF-1 ib puag ncig thiab tom qab ntawd ntsuas qib phosphorylation ntawm tau protein. Cov txiaj ntsig tau pom tias tom qab kev kho mob nrog Tesamorelin thiab IGF-1, kev ua haujlwm ntawm GSK-3 hauv cov hlwb neuronal tau txo qis, thiab qib phosphorylation ntawm tau protein ntau ntawm ntau qhov chaw phosphorylation kuj tseem txo qis. Qhov no qhia tau hais tias Tesamorelin inhibits GSK-3 kev ua los ntawm IGF-1-Akt signaling pathway, zoo txo tau cov protein phosphorylation.
Kev tshawb nrhiav tsiaj txhu
Hauv cov qauv tsiaj, xws li cov qauv transgenic AD nas, tom qab kev kho mob nrog Tesamorelin, qib IGF-1 hauv nas hlwb nce, GSK-3 kev ua haujlwm raug txwv, thiab tau protein ntau phosphorylation txo qis. Nyob rau tib lub sijhawm, kev paub txog kev ua haujlwm ntawm nas tau txhim kho thiab kev puas tsuaj neuronal raug txo. Cov tsiaj sim no tau lees paub ntxiv txog qhov ua tau zoo ntawm Tesamorelin cov txheej txheem ntawm inhibiting GSK-3 thiab txo tau cov protein phosphorylation los ntawm IGF-1 hauv vivo.
FAQ
1. Nqe Lus Nug: Puas yog Tesamorelin muaj peev xwm siv tau rau cov uas tsis yog-HIV- cuam tshuam txog cov roj visceral? Cov ntaub ntawv tam sim no yog dab tsi?
Teb: Txawm hais tias Tesamorelin tam sim no tsuas yog pom zoo los ntawm FDA rau kev kho mob visceral rog txuam nrog HIV, muaj cov kev tshawb fawb me me - tshawb nrhiav nws cov teebmeem hauv lwm qhov ua rau muaj kev rog rog (xws li metabolic syndrome, tsis yog - haus dej cawv fatty siab kab mob). Cov ntaub ntawv ua ntej qhia tias nws kuj tseem tuaj yeem txo cov roj visceral thiab txhim kho insulin rhiab heev, tab sis lub sijhawm ntev - kev ua tau zoo thiab kev nyab xeeb tsis tau lees paub los ntawm cov chaw tso cai. Nws yog ib qho tsim nyog sau cia tias nws cov txheej txheem ntawm kev ua haujlwm (ib qho kev loj hlob hormone- tso tawm cov tshuaj hormones analogue) theoretically siv rau txhua qhov ua rau muaj roj ntau dhau ntawm lub cev, tab sis qhov no suav tias yog "tawm- siv daim ntawv lo" thiab tus nqi kho mob siab heev (txog li $ 30,000 toj ib xyoo), uas txwv kev nthuav dav ntawm cov kev tshawb fawb ntsig txog.
2. Q: Puas muaj cov kev cai tshwj xeeb rau qhov chaw txhaj tshuaj ntawm Tesamorelin? Vim li cas kev txhaj tshuaj plab yog pom zoo hauv kev kho mob?
A: Cov lus pom zoo rau kev kho mob yog txhaj rau hauv qab ntawm daim tawv nqaij ntawm lub plab (tsis txhob 5-centimeter cheeb tsam nyob ib ncig ntawm lub plab), thiab qhov no tsis yog ib qho kev xaiv random. Cov kev tshawb fawb pharmacokinetic thaum ntxov pom tias piv rau kev txhaj tshuaj hauv tus ncej puab lossis caj npab, qhov nqus ntawm cov tshuaj yog qhov ruaj khov dua thiab qhov tshwm sim ntawm qhov tsis zoo hauv zos (xws li liab, o, thiab tawv) qis dua me ntsis. Qhov no tej zaum yuav muaj feem xyuam rau cov ntshav thiab cov ntaub so ntswg ceev cov yam ntxwv ntawm cov roj subcutaneous nyob rau hauv lub plab mog. Tsis tas li ntawd, qhov chaw txhaj tshuaj yuav tsum tau hloov pauv kom tsis txhob muaj roj tsis txaus (atrophy lossis hyperplasia), uas yog qhov tseem ceeb tshwj xeeb rau cov neeg mob HIV uas muaj cov roj ntsha txawv txav.
3. Q: Yuav ntev npaum li cas - siv Tesamorelin cuam tshuam rau kev zais cia ntawm tus kheej txoj kev loj hlob hormone (GH) lossis ua rau kev tawm tswv yim inhibition?
A: There is a theoretical risk, but the existing clinical data (with the longest study lasting approximately 2 years) do not show that Tesamorelin causes definite GH axis feedback inhibition or permanent secretion disorder. As a growth hormone-releasing hormone (GHRH) analogue, it mimics physiological pulse stimulation and is more likely to maintain the rhythmicity of GH secretion compared to direct exogenous growth hormone supplementation. However, after discontinuation, visceral fat usually returns to the pre-treatment level within several months, suggesting that its effect is "reversible regulation" rather than a cure. The long-term impact on the hypothalamic-pituitary axis has not been sufficiently studied in the population using it for ultra-long-term use (>5 xyoo).
4. Lo lus nug: Dab tsi yog cov teeb meem tshwj xeeb hauv kev sib xyaw ntawm Tesamorelin thiab kev huv ntawm polypeptide? Vim li cas txoj kev loj hlob ntawm cov tshuaj generic nyuaj dua?
Teb: Tesamorelin yog ib qho hluavtaws peptide uas muaj 44 amino acids. Nws ntau lawm ntsib ob qhov teeb meem tsis tshua muaj:
Qhov teeb meem kev ruaj ntseg: Cov saw peptide yog nquag oxidation los yog hydrolysis, tshwj xeeb tshaj yog cov tyrosine ntawm 1st txoj hauj lwm thiab amide C-terminal ntawm 44th txoj hauj lwm. Qhov no yuav tsum muaj cov xwm txheej nruj heev rau cov txheej txheem tsim khoom (xws li cov khoom siv-theem synthesis, purification, thiab khov- ziab).
Kev pheej hmoo ntawm kev tiv thaiv kab mob: Txawm tias me me ua raws li qhov tsis raug lossis impurities (xws li peptides truncated) tuaj yeem ua rau cov tshuaj tiv thaiv kab mob, uas muaj feem cuam tshuam rau endogenous GHRH lossis txo qhov ua tau zoo. Cov tshuaj thawj tswj cov ntsiab lus impurity rau<0.1% through proprietary purification technology, while generic drugs need to prove bioequivalence not only in terms of pharmacokinetics but also in terms of immunogenicity characteristics, which increases the development barrier.
Cim npe nrov: Tesamorelin CAS 218949-48-5, lwm tus neeg, manufacturers, hoobkas, lag luam wholesale, yuav, nqe, tej, kev muag khoom