CJC-1295 hmoovyog ib qho khoom siv hluavtaws peptide cov tshuaj hormones, teej tug mus rau kev loj hlob hormone tso tawm hormone (GHRH) analogs. Tsim los ntawm 30 amino acids, nrog rau cov qauv molecular ntawm C152H252N44O42 thiab molecular hnyav ntawm kwv yees li 3367.89. Nws cov qauv yog raws li cov khoom nquag ntawm ntuj GHRH (amino acids 1-29), uas txuas nws ib nrab-lub neej los ntawm kev hloov kho tshuaj. Cov hmoov yog dawb nyob rau hauv daim ntawv thiab feem ntau muaj ib tug purity ntawm Greater los yog sib npaug rau 98%. Nws yuav tsum tau muab kaw thiab khaws cia ntawm -20℃rau -80℃kom tsis txhob degradation. Nws tau tsim los ntawm Canadian biotechnology tuam txhab ConjuChem, uas ua rau kev loj hlob hormone tso tawm receptors los txhawb kev tso tawm ntawm cov tshuaj endogenous loj hlob, yog li cuam tshuam rau kev tswj cov metabolism thiab cov leeg nqaij loj hlob hauv lub cev.
Peb Cov Khoom Muag Khoom
CJC-1295 COA
CJC-1295 hmoovactivates GHRH receptor nyob rau hauv lub anterior pituitary caj pas, txhawb lub secretion ntawm endogenous loj hlob hormone (GH), thiab yog li upregulates insulin{0}}zoo li kev loj hlob factor-1 (IGF-1) qib. Nws mechanism ntawm kev txiav txim muaj cov yam ntxwv hauv qab no:
1. Tswj GH secretion kom raug
Pulse raws li kev tso tawm optimization: Ntuj GHRH yog tso tawm nyob rau hauv ib tug mem tes daim ntawv, uas tsis tu ncua nkoos pituitary caj pas thaum lub sij hawm GH mem tes ncua sij hawm los ntawm kev ncua nws ib nrab - lub neej, nce tus nqi ntawm GH tso tawm nyob rau hauv ib tug mem tes. Kev tshawb fawb tau pom tias nws tuaj yeem nce GH mem tes amplitude los ntawm 300% thaum tsis txhob receptor desensitization tshwm sim los ntawm ntev - lub sij hawm tas li stimulation.
Inhibition effect: Nrog lub hnub nyoog, qib ntawm somatostatin (ib yam tshuaj uas inhibits GH secretion) nce. Lub sij hawm tsis sib xws ntawm somatostatin secretion tuaj yeem siv los xaiv txhim kho GHRH teeb liab thiab ua kom GH secretion efficiency.
2. Multidimensional metabolic kev cai
Cov leeg nqaij synthesis thiab kho: GH txhawb nqa cov protein synthesis los ntawm kev ua kom IGF-1 txoj hauv kev, ua kom cov leeg nqaij ntuag thiab lub zog. Hauv kev sim tshuaj, cov neeg mob uas tau siv CJC-1295 rau 6 lub hlis tau pom tias nce 10% ntawm cov leeg nqaij ntshiv thiab kev txhim kho tseem ceeb hauv cov leeg nqaij.
Cov rog rog: GH ncaj qha ua kom lipase, txhawb cov roj oxidation rau lub zog. Cov neeg siv feem ntau muaj 5-10% txo qis hauv lub cev rog hauv 3 lub hlis, tshwj xeeb tshaj yog txo cov rog hauv plab.
Txhim kho pob txha pob txha: GH txhawb nqa kev ua haujlwm ntawm osteoblast thiab ua kom cov pob txha pob txha pob txha. Kev siv lub sijhawm ntev tuaj yeem txo qhov kev pheej hmoo ntawm pob txha pob txha thiab txhim kho kev sib koom tes.
Kev ua haujlwm ntawm lub cev tiv thaiv kab mob: GH txhim kho lub cev tiv thaiv kab mob los ntawm kev tswj T thiab B cell muaj nuj nqi, txo qhov tshwm sim ntawm tus kab mob hauv cov neeg siv los ntawm 27%.
3. Neuroprotection thiab kev txawj ntse txhim kho
Kev pw tsaug zog qeeb qeeb: GH secretion ncov synchronizes nrog rau theem pw tsaug zog, ua rau 40% kev txhim kho pw tsaug zog zoo thiab kev txhim kho tseem ceeb hauv kev nco thiab kev mloog rau cov neeg siv.
Neural regeneration: GH mediates hippocampal neurogenesis los ntawm IGF-1, uas yuav ncua kev loj hlob ntawm cov kab mob neurodegenerative xws li Alzheimer's kab mob.
Txoj kev siv tshuaj lom neeg ntawm CJC-1295 feem ntau yog cov khoom sib txuas-theem synthesis, thiab nws lub hauv paus ntsiab lus tseem ceeb yog maj mam muab ob peb amino acids nrog amino resin cov cab kuj los tsim cov chains polypeptide, ua ke nrog DAC kev hloov kho thev naus laus zis los txhim kho cov tshuaj ib nrab-lub neej. Cov hauv qab no yog cov txheej txheem tshwj xeeb thiab cov kauj ruam tseem ceeb:
Txoj Kev 1: Fragment Condensation Method
Txoj kev txo fragment ntawmCJC-1295 hmoovtsis yog nws txoj kev sib xyaw ua ke tseem ceeb, tab sis nws muaj qhov ua tau zoo hauv cov xwm txheej tshwj xeeb, xws li kev sib xyaw ua ke ultra ntev peptides uas muaj cov kev hloov kho tshwj xeeb lossis tsis yog ntuj amino acids. Hauv qab no yog cov lus qhia ntxaws ntxaws rau fragment condensation method:
Cov hauv paus ntsiab lus
Fragment condensation method yog cov txheej txheem uas faib cov saw hlau polypeptide rau hauv ntau qhov tawg, ua ke sib cais, thiab sib txuas cov tshuaj sib txuas los ua kom tiav polypeptide. Nws lub ntsiab lus yog nyob rau hauv kev ua tau zoo thiab kev xaiv peptide los ua ke los ntawm kev tswj cov kev sib txuas ntawm cov khoom tawg. Muab piv nrog cov khoom sib txuas-theem synthesis, fragment condensation method yog qhov tsim nyog rau kev sib txuas ntawm ultra-ntev peptides lossis complex hloov peptides, tab sis kev ua haujlwm nyuaj thiab cov txiaj ntsig qis dua.
Cov kauj ruam tshwj xeeb
Fragment division: Raws li cov amino acid sequence ntawm CJC-1295 (30 amino acids), muab faib ua 2-3 fragments. Cov hauv paus ntsiab lus faib muaj xws li: zam kev tawg ntawm cov amino acids uas nquag mus rau racemization los yog muaj steric hindrance; Ua kom muaj qhov nruab nrab ntawm qhov ntev (feem ntau yog 10-15 amino acids) kom sib npaug ntawm kev sib txuas thiab kev sib txuas ua haujlwm.
Fragment synthesis: Cov txheej txheem txheej txheej txheej txheej yog siv los ua ke txhua qhov sib cais. Piv txwv li, cov amino resins nrog Fmoc tiv thaiv pab pawg yog siv los ua cov khoom siv los tsim cov hlua khi los ntawm maj mam sib txuas cov amino acids. Tom qab kev sib xyaw ua ke, cov khoom tawg tau raug txiav los ntawm cov resin siv lub lysis buffer (xws li trifluoroacetic acid) thiab purified los ntawm HPLC.
Txoj kev sib txuas: Cov txheej txheem kev sib txuas feem ntau suav nrog thioester bonds, azides, thiab lwm yam. Siv cov thioester daim ntawv cog lus ua piv txwv, nws cov kev mob tshwm sim yog mos thiab xaiv, ua rau nws tsim nyog rau kev sib txuas cov khoom uas muaj Cys (cysteine). Cov kauj ruam tshwj xeeb yog: qhia ib pab pawg thioester ntawm C- qhov kawg ntawm ntu 1, khaws cov amino pawg dawb ntawm N-terminus ntawm fragment 2, thiab txhawb kev tsim cov thioester daim ntawv cog lus ntawm ob los ntawm tus neeg sawv cev condensing (xws li HBTU).
Kev ua kom zoo ntawm cov tshuaj tiv thaiv: Nws yog ib qho tsim nyog los tswj cov tshuaj tiv thaiv qhov kub thiab txias (feem ntau yog chav tsev kub), pH tus nqi (7-8), thiab lub sij hawm tshuaj tiv thaiv (ntau teev rau ib hmos) txhawm rau txhim kho kev sib txuas ua haujlwm thiab txo cov kev mob tshwm sim.
Purification:
Kev sib txuas ua tiav peptide yuav tsum tau ua kom huv ntxiv los ntawm HPLC kom tshem tawm cov khoom tsis zoo lossis los ntawm - khoom.
Kev txheeb xyuas:
Molecular hnyav tau lees paub tias siv huab hwm coj spectrometry (MS), thiab cov txheej txheem raug raug txheeb xyuas los ntawm kev txheeb xyuas cov amino acid ib ntus.
Kev siv nyob rau hauv synthesis
Qhov hnyav molecular ntawm CJC-1295 yog qhov me me (3534.03 g / mol), thiab tsis muaj kev hloov kho tshwj xeeb lossis tsis muaj cov amino acids hauv nws cov qauv, yog li cov txheej txheem sib xyaw ua ke ntawm cov khoom siv tau zoo txaus. Daim ntawv thov ntawm fragment condensation txoj kev nyob rau hauv lub synthesis ntawm CJC-1295 yog ib tug kuj txwv, feem ntau vim hais tias nws zoo (xws li saj zawg zog) tsis pom meej nyob rau hauv CJC-1295, thaum nws tsis zoo (xws li tsis tshua muaj yield thiab tus nqi siab) yog qhov tseem ceeb.
Method 2: Liquid phase synthesis method
Txoj Cai:
Maj mam ntxiv cov amino acids rau cov kev daws teeb meem thiab tswj cov tshuaj tiv thaiv xaiv los ntawm cov pab pawg tiv thaiv.
Qhov tsis zoo:
Yuav tsum tau ua kom huv si ntau zaus ntawm cov khoom nruab nrab, kev ua haujlwm nyuaj thiab tsis tshua muaj txiaj ntsig, tsuas yog tsim rau me me - nplai synthesis hauv chav kuaj.
Cov ntsiab lus tseem ceeb tswj
Resin xaiv:
Nws cuam tshuam rau kev sib txuas ua haujlwm thiab cov khoom purity, thiab cov cab kuj tsim nyog yuav tsum raug xaiv raws li cov khoom ntawm peptide.
Coupling tej yam kev mob:
Kub, pH tus nqi, thiab lub sij hawm tshuaj tiv thaiv yuav tsum tau tswj xyuas kom meej kom tsis txhob muaj kev sib tw los yog kev cuam tshuam sab.
Tshem tawm cov pab pawg tiv thaiv:
Xaiv cov reagents me me (xws li ammonia / DMF sib tov) kom tsis txhob ua rau cov saw hlau polypeptide puas.
Purification txheej txheem:
HPLC tej yam kev mob (xws li mobile theem muaj pes tsawg leeg thiab kem kub) yuav tsum tau optimized los txhim kho kev sib cais efficiency.
CJC-1295 hmoovtsis yog ib yam khoom tshwm sim nyob rau hauv cov xwm txheej, tab sis ib qho kev loj hlob hormone tso tawm cov tshuaj hormone (GHRH) analog tsim los ntawm cov khoom siv hluavtaws hluavtaws. Nws qhov kev tshoov siab tsim los ntawm - kev tsom xam qhov tob thiab kev ua haujlwm simulation ntawm lub ntuj GHRH molecular qauv.
Lub hauv paus ntsiab lus tshawb fawb: Ua raws li cov txheej txheem physiological ntawm ntuj GHRH
1. Lub luag haujlwm ntawm natural GHRH
Ntuj GHRH yog secreted los ntawm lub hypothalamus thiab txhawb lub pulsatile tso tawm ntawm kev loj hlob hormone (GH) los ntawm kev khi rau GHRH receptors nyob rau hauv lub anterior pituitary caj pas. GH txhawb ntxiv kev sib txuas ntawm insulin-zoo li kev loj hlob zoo-1 (IGF-1) hauv daim siab, sib koom ua ke tswj cov txheej txheem physiological xws li cov leeg loj hlob, rog metabolism, thiab pob txha ceev. Txawm li cas los xij, ib nrab-lub neej ntawm natural GHRH yog luv heev (tsuas yog ob peb feeb) thiab yuav tsum tau tso tseg tsis tu ncua los tswj lub cev muaj zog.
2. Lub hom phiaj tsim
Cov kws tshawb fawb tau tsim cov analogues nrog kev ncua ntev ib nrab - lub neej los ntawm kev hloov kho cov qauv molecular ntawm ntuj GHRH, aiming kom ua tiav cov hom phiaj hauv qab no:
Txo qhov txhaj tshuaj ntau zaus:
Los ntawm kev ncua ib nrab -lub neej thiab txo qhov zaus ntawm kev tswj hwm.
Stable ntshav tshuaj concentration:
Zam kev hloov pauv hauv cov ntshav tshuaj concentration tshwm sim los ntawm ib nrab luv luv -lub neej ntawm natural GHRH.
Txhim kho cov teebmeem physiological:
Los ntawm kev txhawb nqa GH tsis tu ncua, nce IGF-1 qib, thiab txhim kho cov teeb meem kev laus xws li cov leeg nqaij atrophy thiab rog.
Kev txhim kho keeb kwm yav dhau: Kev kho mob xav tau los daws qhov poob ntawm kev loj hlob hormone secretion
1. Hnub nyoog cuam tshuam txog kev poob qis hauv GH secretion
Raws li lub hnub nyoog nce, GH secretion maj mam txo qis, ua rau muaj kev laus phenomena xws li cov nqaij ntshiv, rog tsub zuj zuj, thiab txo cov tawv nqaij elasticity. Ib txwm siv cov tshuaj exogenous GH supplementation yuav ua rau muaj kev phiv xws li insulin tsis kam thiab acromegaly, thaum stimulating endogenous GH secretion yog xam tias muaj kev nyab xeeb dua.
2. Kev txwv ntawm Short acting GHRH Analogs
Thaum ntxov tsim luv luv ua yeeb yam GHRH analogs (xws li Mod GRF 1-29) muaj ib nrab-lub neej ntawm tsuas yog 30 feeb thiab xav tau ntau yam kev txhaj tshuaj txhua hnub, ua rau cov neeg mob ua tsis zoo. Txoj kev loj hlob aims los daws qhov teeb meem no.
Txoj Kev: Kev hloov kho tshuaj ua kom ntev ib nrab -lub neej
1. Molecular qauv optimization
Tsim los ntawm 30 amino acids, nws cov qauv tseem ceeb yog raws li thawj 29 active amino acids ntawm natural GHRH, thiab nws ib nrab - lub neej yog txuas ntxiv los ntawm kev hloov kho hauv qab no:
DAC Technology:
Ntxiv "drug affinity complexes" (DAC) ntawm qhov kawg molecular tuaj yeem khi nrog albumin hauv cov ntshav, tsim cov complexes ruaj khov thiab txuas ntxiv ib nrab - lub neej mus rau 6-8 hnub.
Amino acid hloov pauv:
Los ntawm kev hloov cov amino acids tshwj xeeb (xws li hloov Lys nrog D-Ala), molecular stability yog txhim kho thiab enzymatic degradation txo.
2. Muaj nuj nqi pov thawj
Cov kev tshawb fawb preclinical tau pom tias nws tuaj yeem nce qib plasma GH thiab IGF-1:
GH theem:
Tom qab ib qho kev txhaj tshuaj, plasma GH concentration tuaj yeem nce 2-10 zaug rau ntau tshaj 6 hnub.
IGF-1 theem:
Plasma IGF-1 concentration tuaj yeem nce 1.5-3 zaug, kav ntev li 9-11 hnub, thiab txawm tias khaws cia ntawm cov koob tshuaj siab ntev txog 28 hnub.
Cim npe nrov: cjc 1295 hmoov, Tuam Tshoj cjc 1295 hmoov manufacturers, lwm tus neeg
