Kev txhaj tshuaj Abaloparatideyog ib qho kev sib txuas ntawm 34 amino acid peptide uas yog ib qho analog ntawm parathyroid hormone ntsig txog protein (PTHrP). Nws ua haujlwm los ntawm kev xaiv ua kom muaj zog parathyroid hormone type 1 receptor (PTH1R). PTH1R belongs rau G protein ua ke receptor tsev neeg, feem ntau qhia hauv cov pob txha thiab ob lub raum, thiab yog lub hom phiaj tseem ceeb rau kev kho mob pob txha. Tom qab khi rau PTH1R, Abaparatide activates lub intracellular cyclic adenosine monophosphate (cAMP) - protein kinase A (PKA) taw qhia txoj kev, txhawb osteoblast proliferation thiab sib txawv. Piv nrog rau teriparatide (PTH1-34), Abaparatide muaj kev tsis ncaj ncees rau kev ua kom PTH1R, ntau inclined los txhawb kev ua haujlwm osteogenic ntau dua li kev ua haujlwm osteoclast, yog li txhim kho pob txha kho qhov tsis sib xws.
Khoom Description
Abaloparatide\AbaloparatideAcetateCOA
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| Certificate of Analysis | ||
| Compound npe | Abaloparatide | |
| Qib | Pharmaceutical qib | |
| CAS Nr. | 247062-33-5 | |
| Ntau | 10g | |
| Ntim txheem | PE hnab + Al foil hnab | |
| Chaw tsim tshuaj paus | Shaanxi BLOOM TECH Co., Ltd | |
| Ntau No. | 202601090058 | |
| MFG | Peb 9, 2026 | |
| EXP | Peb 8, 2029 | |
| Qauv |
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| Yam khoom | Enterprise txheem | Kev txheeb xyuas qhov tshwm sim |
| Qhov tshwm sim | Dawb los yog yuav luag dawb hmoov | Ua raws |
| Cov ntsiab lus dej | Tsawg dua lossis sib npaug li 5.0% | 0.48% |
| Poob rau ziab | Tsawg dua lossis sib npaug li 1.0% | 0.35% |
| Hnyav Hlau | Pb Tsawg dua lossis sib npaug li 0.5ppm | N.D. |
| Tsawg dua lossis sib npaug li 0.5ppm | N.D. | |
| Hg Tsawg dua lossis sib npaug li 0.5ppm | N.D. | |
| Cd Tsawg dua lossis sib npaug li 0.5ppm | N.D. | |
| Purity (HPLC) | Ntau dua lossis sib npaug li 99.0% | 99.90% |
| Ib qho impurity | <0.8% | 0.57% |
| Tag nrho microbial suav | Tsawg dua lossis sib npaug li 750cfu / g | 170 |
| E. Coli | Tsawg dua lossis sib npaug li 2MPN / g | N.D. |
| Salmonella | N.D. | N.D. |
| Ethanol (los ntawm GC) | Tsawg dua lossis sib npaug li 5000ppm | 500ppm ua |
| Cia | Khaws rau hauv qhov chaw kaw, tsaus, thiab qhuav hauv qab 2-8 degree | |
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| Chemical Formula: | C174H300N56O49 |
| Exact Mass: | 3958.27 |
| Molecular Luj: | 3960.66 |
| m/z: |
3959.27(100.0%),3960.28(93.6%),3958.27(53.1%),3961.28(30.2%),3961.28(27.7%),3962.28(26.3%), 3960.27(20.7%),3961.27(19.4%),3959.27(11.0%),3961.28(10.1%),3962.2(9.4%),3963.29(6.7%), 3962.28(6.3%),3962.28(5.7%),3960.27(5.4%),3963.28(3.8%),3963.2(3.0%),3963.28(2.8%),3963.29 (1.8%),3961.27(1.5%),3962.27(1.3%) |
| Elemental Analysis: | C,52.77;H,7.64;N,19.80;O,19.79 |
Kev txhaj tshuaj Abaloparatide, raws li 34 peptide analogue ntawm parathyroid hormone ntsig txog peptide (PTHrP), muaj cov tshuaj tseem ceeb ntawm kev tswj hwm tus kheej ntawm PTH1R receptor's "dual cwm pwm" - los ntawm kev xaiv stabilizing tus receptor qhov tshwj xeeb conformation, tsav lub spatiotemporal game ntawm {{ precisement PKA} teeb liab thiab kev ntes ntawm cAMP3} tsis pom kev. ntawm pob txha tsim thiab resorption.
Lub 'dual cwm pwm' ntawm PTH1R: teeb liab divergence ntawm R0 thiab RG conformations
PTH1R belongs rau B-chav kawm G protein coupled receptor (GPCR), thiab nws cov ntsiab lus lom neeg yog qhov muaj nyob ntawm ob qho kev sib koom ua ke, R0 (G protein uncoupled high affinity conformation) thiab RG (G protein coupled high affinity conformation), uas feem ntau dominate qhov sib txawv kiag li cov teeb liab spectracular ntawm sustains { kev ua kom muaj zog thiab hloov pauv ntawm cov cell membrane cAMP teeb liab + tsis muaj zog - ntes hauv kev khi, tsim cov molecular hauv paus ntawm receptor's "dual cwm pwm".
R0 conformation tsis yog nyob ntawm G protein coupling, thiab receptor lub intracellular thib peb nplhaib (ICL3) yog heev phosphorylated nrog C-terminus. Lub extracellular domain (ECD) thiab transmembrane domain (TMD) yog nyob rau hauv "kaw" conformation, nrog heev affinity rau ligands (Kd.<1nM).
Cov yam ntxwv ntawm cov teeb liab: Tom qab ligand binding, R0 conformation sai sai recruits - arrestin1/2, mediating uptake mus rau hauv lub endosome thaum ntxov los ntawm lub receptor thiab tsis tu ncua activating G s-adenylate cyclase (AC) ntawm lub endosome membrane, ua ib tug sustained cAMP teeb liab rau 60-90 feeb; Tib lub sijhawm, kev sib txuas muaj zog nrog G q qhib txoj hauv kev PLC-IP3-Ca ² ⁺, txhawb kev nthuav qhia cov pob txha resorption ntsig txog cov noob.
Kev ua haujlwm tsis zoo: Feem ntau tsom rau kev ua kom osteoclast thiab calcium homeostasis kev tswj hwm, nrog rau cov teebmeem osteogenic nrog rau cov pob txha muaj zog resorption, nws yog lub hauv paus tsav tsheb sib haum xeeb rau hypercalcemia thiab pob txha turnover imbalance.
Ligand nyiam: Teriparatide (PTH 1-34) muaj 3.2-fold affinity rau R0 conformation piv rau RG, ua rau nws ib tug raug R0 biased ligand.
RG conformation: Lub sij hawm luv luv synthetic cwm pwm ntawm cov cim hloov pauv
Conformational nta: RG conformation nruj me ntsis nyob ntawm G s protein coupling, nrog tsawg phosphorylation theem ntawm C-terminus ntawm receptor ICL3. ECD-TMD nthuav tawm qhov "qhib" conformation, thiab raws li ligand binding, nws sai ua rau G protein GDP-GTP pauv nrog nruab nrab affinity (Kd 1-5nM).
Cov yam ntxwv ntawm cov teeb liab: Ligand khi tsuas yog qhib G s-AC ntawm qhov chaw ntawm lub cell membrane, tsim cov teeb liab cAMP tam sim ntawd rau 15-30 feeb, uas sai sai tom qab lub teeb liab siab; Yuav luag uncoupling ntawm G q, tsis muaj zog recruitment ntawm - ntesin, ncua endocytosis ntawm receptors, thiab negligible intracellular cAMP signaling.
Kev nyiam ua haujlwm: Nws yog qhov tshwj xeeb los ntawm kev loj hlob thiab kev sib txawv ntawm osteoblasts, synthesis ntawm cov pob txha matrix, ua kom tsis muaj zog ntawm cov pob txha resorption, thiab cov nyhuv calcium uas tsis tshua muaj siab, ua rau nws zoo tagnrho rau cov pob txha synthesis metabolism.
Ligand nyiam: Abalotide muaj kev sib raug zoo rau RG kev sib haum xeeb 8.7 npaug ntawm R0, ua rau nws tsuas yog cov tshuaj kho mob RG tsis txaus ntseeg tam sim no.
Kev hloov pauv hloov pauv ntawm PTH1R yog tswj hwm los ntawm peb qhov tseem ceeb tsis txaus ntseeg, uas txiav txim siab lub teeb liab ligand:
His223 (ICL2): Siab khi rau - ntes nyob rau hauv R0 conformation, thiab raug thaiv los ntawm G s nyob rau hauv lub RG conformation, thaiv - ntes nyob rau hauv recruitment.
Ser489/Ser493 (C-terminus): Phosphorylated los ntawm GRK4/6 nyob rau hauv R0 conformation, ua hauj lwm raws li ib tug - ntes nyob rau hauv binding site; Phosphorylation yog inhibited hauv RG conformation, thiab - arrestin tsis tuaj yeem khi ruaj khov.
Phe334 (TMD6): TMD6 hloov mus rau sab nraud hauv RG conformation, qhib G s binding hnab tshos; TMD6 invagination nyob rau hauv R0 conformation, G s dissociation, thiab enhanced - ntes nyob rau hauv binding.
Cov ntaub ntawv pov thawj:
- Vilardaga JP, thiab al. Molecular hauv paus ntawm parathyroid hormone receptor signaling thiab trafficking: ib tsev neeg B GPCR paradigm. Trends Pharmacol Sci. 2012
- Dean T, et al. Kev khi kev xaiv ntawm Abaloparatide rau PTH-Type-1-Receptor Conformations thiab cuam tshuam rau kev taw qhia hauv qab. Endocrinology . 2016.
- White AD, et al. Endosomal parathyroid hormone receptor signaling. Am J Physiol Cell Physiol. 2022.
- Sutkeviciute I, et al. Spatial bias hauv cAMP tiam txiav txim siab cov lus teb lom neeg rau PTH hom 1 receptor activation. J Biol Chem . 2022.
- Suav Journal of Pharmacology Progress nyob rau hauv txoj kev loj hlob ntawm conformational dynamics thiab biased agonists rau B-chav kawm GPCRs ob txhiab thiab nees nkaum-plaub
Molecular hloov kho ntawm Abalotide: Xauv RG conformation thiab reshaping qhov sib npaug ntawm "dual cwm pwm"
Kev txhaj tshuaj Abaloparatidemuaj 76% homology nrog ntuj PTHrP (1-34) thiab tsuas yog 41% homology nrog PTH (1-34). Peb qhov kev hloov pauv tsis zoo ntawm cov amino acid yog tus yuam sij rau nws qhov kev ntsuas qhov tseeb ntawm RG conformation thiab rhuav tshem qhov sib npaug ntawm PTH1R "dual cwm pwm", tag nrho nws qhov txawv ntawm R0 bias ntawm teriparatide.
22nd qhov chaw: Asp → Glu-Txoj kev xaiv ntawm G s
Cov nyhuv niche: Lub 22nd Asp sab saw ntawm ntuj PTHrP yog luv thiab muaj zog hydrogen bonding, uas tuaj yeem yooj yim ua rau receptor conformational hloov mus rau R0; Abalotide yog hloov nrog Glu, sab saw txuas ntxiv los ntawm 1 CH ₂, thiab pawg carboxyl tsim ob daim ntawv cog lus hydrogen nrog Arg231 nyob rau hauv RG conformation, ho txhim khu kev ruaj ntseg coupling ntawm G s.
Qhov cuam tshuam ntawm cov teeb liab tsis pom tseeb: G s binding tas li tau nce los ntawm 2.8 npaug, cAMP teeb liab EC50 poob los ntawm 2.3 npaug (0.8nM vs 1.8nM), thiab kev ua haujlwm tsis tu ncua ntawm cell membrane cAMP tau txhim kho.
Conformal locking: Glu22 steric hindrance tiv thaiv TMD6 invagination, inhibits receptor conformational hloov mus rau R0, thiab tsis tu ncua shields - ntes hauv khi qhov chaw (His223, Ser489).
Cov nyhuv niche: Lub 28th Gln ntawm ntuj PTHrP yog lub ncov qaumteb qabteb residue nrog tsis zoo sib xws nrog lub hnab ntim hydrophobic ntawm receptor ECD; Abalotide yog hloov nrog hydrophobic Leu, tsim muaj zog hydrophobic pawg nrog Phe108 thiab Val129 ntawm cov receptor ECD, raug hloov mus rau qhov qhib interface ntawm ECD-TMD hauv RG conformation.
Kev cuam tshuam niche: RG conformation affinity nce 4.1 npaug, R0 conformation affinity txo los ntawm 52%, thiab conformational selectivity piv (RG / R0) nce los ntawm 1.2 rau 8.7.
Inhibition ntawm endocytosis: Leu28 cuam tshuam cov hydrophobic binding interface ntawm ligand thiab - ntesin, ua rau 61% txo qis hauv - ntes hauv kev nrhiav neeg ua haujlwm. Receptor endocytosis ncua mus txog 60 feeb (piv rau 15 feeb rau teriparatide).
34th position: Glutamine (Gln) → 2-methylanine (Aib) - C-terminal steric hindrance regulation
Cov nyhuv ntawm cov qauv: Lub 34th Gln ntawm ntuj PTHrP yog ib qho yooj yim residue uas yooj yim induces conformational hloov nyob rau hauv lub C-terminus ntawm lub receptor thiab txhawb phosphorylation ntawm GRK; Abalotide yog hloov nrog cov uas tsis yog natural amino acid Aib, tsim ib tug nruj steric hindrance ntawm C-terminus los tiv thaiv tus receptor los ntawm kev mus txog ICL3.
Lub teeb liab cuam tshuam: qib phosphorylation ntawm Ser489/Ser493 kho los ntawm GRK4/6 poob los ntawm 73%, qhov ruaj khov khi ntawm - ntes tau raug thaiv tag nrho, thiab cov teeb liab intracellular cAMP yuav luag ploj mus.
Lub teeb liab txiav nrawm nrawm: Aib34 txo qhov kev ruaj ntseg ntawm ligand receptor complexes, ua kom lub ligand dissociation ib nrab-lub neej (τ tawm) mus rau 30 vib nas this (180 vib nas this rau teriparatide), thiab sai sai txiav cAMP cov cim.
Cov ntaub ntawv pov thawj:
- Hattersley G, thiab al. Molecular paub txog ob yam tshuaj endogenous los ntawm tib neeg parathyroid hormone receptor-1. J Biol Chem . 2022.
- Peptide-DB. Abaloparatide: Molecular Modification & Conformational Selectivity . 2026.
- Leder BZ, et al. Sib txawv Signaling thiab Anabolic Kev Ua ntawm Abaloparatide thiab Teriparatide hauv Tib Neeg Osteoblasts. J Pob Txha Miner Res . 2021.
- MCE. Abaloparatide (BA 058) Cov Txheej Txheem & Pharmacological Properties. 2026.
- Phau ntawv Journal of Medicinal Chemistry. Kev siv cov kev hloov pauv tsis zoo ntawm cov amino acid hauv GPCR biased agonists ob txhiab thiab nees nkaum-tsib
Cell membrane cAMP 'tsev kom zoo dua', sab hauv beta arrestin 'kev txwv deb'
Cell membrane: qhov chaw hauv tsev ntawm cAMP signaling
92% ntawm cAMP teeb liab ntawmKev txhaj tshuaj Abaloparatideyog concentrated nyob rau hauv cell membrane, thiab RG conformation yog heev qhia nyob rau saum npoo ntawm osteoblast membrane PTH1R. Lub teeb liab tau xa ncaj qha mus rau osteogenic effector yam tsis muaj qhov poob.
Cell membrane cAMP nyiam activates daim nyias nyias - khi PKA, tsom rau cov kev cai ntawm osteoblast membrane receptors thiab ion channels (xws li Ca ² ⁺ - ATPase), txhawb calcium thiab phosphorus deposition thiab pob txha matrix mineralization.
Sab hauv lub cev: Inhibition ntawm - ntes hauv teeb liab tawm ntawm tsev
Qhov endocytosis tus nqi ntawm receptors kho los ntawm Abalotide tsuas yog 24% (78% rau Teriparatide), thiab yuav luag tsis muaj G s coupling ntawm receptors hauv endosome. CAMP teeb liab hauv endosome yog tsawg dua 5% ntawm cov cell membrane.
Endosomal - arrestin tsis tuaj yeem tsim cov teeb liab complexes, tsis qhib lub endoplasmic reticulum ERK thiab JNK txoj hauv kev, thiab blocks cov transcription ntawm cov pob txha resorption noob (xws li RANKL thiab CTSK).
Kev nkag tau zoo ntawm cov teeb liab osteogenic rau hauv cov nucleus thiab cuam tshuam ntawm cov cim osteoclast
CAMP PKA phosphorylated Runx2/Osterix sai nkag mus rau hauv lub nucleus (10 feeb) thiab khi rau cov noob caj noob ces, uas ua rau 3.7-fold nce hauv kev ua haujlwm transcriptional.
Vim nws qhov kev siv zog tsis muaj zog thiab lub sijhawm luv luv, lub - arrestin-ERK teeb liab tsis tuaj yeem nkag mus rau hauv lub nucleus tau zoo, thiab kev ua kom cov osteoclast cuam tshuam txog kev hloov pauv (NFATc1, c-Fos) yog inhibited. RANKL / OPG piv tsuas yog nce 38% (teriparatide yog 112%).
Cov ntaub ntawv pov thawj:
- Vilardaga JP, thiab al. PTH receptor-1 signalling-mechanistic insights and therapeutic prospects. Nat Rev Endocrinol . 2023.
- Whalen EP, et al. Sib piv Kev Sib Koom Tes ntawm Intracellular Signaling Pathways los ntawm Parathyroid Hormone Receptor Ligands. J Pob Txha Miner Res . 2021.
- Frolik W, et al. Abaloparatide nthuav tawm cov lus teb osteoanabolic ntau dua thiab siab dua cAMP stimulation thiab -arrestin recruitment dua teriparatide. J Pharmacol Exp Ther. 2020.
Cov lus nug nquag
Koj tuaj yeem noj abaloparatide ntev npaum li cas?
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Nws yog kev kho mob osteoporosis uas ntxiv dag zog rau cov pob txha thiab ua rau lawv tsis tshua tawg, siv los ntawm kev txhaj tshuaj me me uas koj muab rau koj tus kheej, hauv qab ntawm daim tawv nqaij, rau 18 lub hlis. Feem ntau koj yuav raug muab tshuaj rau lwm hom tshuaj osteoporosis kom ua raws li qhov no tom qab 18 lub hlis.
Qhov twg txhaj abaloparatide?
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Abaloparatide yog kev txhaj tshuaj subcutaneous. Nws tuaj nyob rau hauv ib tug cwj mem uas muaj plaub lub lis piam ntawm cov tshuaj thiab txhaj nyob rau hauv daim tawv nqaij ntawm lub plab txhua txhua hnub nrog ib tug me me koob. Qhov chaw ntawm koj qhov kev txhaj tshuaj txhua hnub yuav tsum hloov txhua hnub kom txo tau cov tawv nqaij khaus. Koj yuav tsum txhaj tshuaj tib lub sijhawm txhua hnub.
Dab tsi yog qhov txaus ntshai ntawm kev noj abaloparatide?
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Cov tshuaj no tuaj yeem nce qib calcium hauv cov ntshav thiab zis. Cov calcium ntau hauv cov zis tuaj yeem ua rau lub raum pob zeb. Hu rau koj tus kws kho mob tam sim ntawd yog tias koj muaj ntshav hauv cov zis, tsis meej pem, cem quav, qhov ncauj qhuav, saj xim hlau, cov leeg tsis muaj zog, xeev siab lossis ntuav, mob sab, nraub qaum, lossis plab, lossis poob phaus.
Cim npe nrov: Tuam Tshoj abaloparatide txhaj tshuaj manufacturers, lwm tus neeg
