AOD 9604 hmoovyog ib qho tshuaj peptide hluavtaws tsim los ntawm C-terminal fragment (176-191 amino acids) ntawm tib neeg kev loj hlob hormone (hGH), feem ntau yog siv los tswj cov roj metabolism thiab tswj qhov hnyav. Nws cov mis mos molecular yog C78H123N23O23S2, nrog rau qhov hnyav molecular ntawm 1815.1 Da thiab CAS 221231-10-3. Nws tau npaj los ntawm cov tshuaj synthesis thiab muaj purity ntau dua 98%. Vim qhov tseeb tias cov tshuaj no tuaj yeem ua rau muaj rog rog, tswj cov roj metabolism, thiab inhibit cov rog, tib neeg tuaj yeem hlawv rog thiab calorie ntau dua li lawv tus kheej. Piv nrog rau kev noj zaub mov tsis tu ncua thiab kev tawm dag zog, tib neeg nyiam pom qhov hnyav dua hauv lub sijhawm luv. Thaum lawv siv cov tshuaj HGH kom poob phaus, lawv kuj yuav pom muaj kev phiv tsawg dua li qee tus neeg feem ntau ntsib.
Peb Cov Khoom Muag Khoom
AOD 9604 COA
AOD 9604 yog ib qho kev sib xyaw ua ke peptide, uas yog qhov tseem ceeb ntawm peptide tawg ntawm 15 amino acid residues tau los ntawm C- thaj chaw davhlau ya nyob twg (amino acids 176-191) ntawm tib neeg kev loj hlob hormone (hGH). Cov molecule no tau pom muaj txiaj ntsig tshwj xeeb hauv kev kho mob rog rog, noj zaub mov noj, thiab tiv thaiv kev laus los ntawm kev ntes cov lipolytic kev ua haujlwm ntawm hGH, tsim kev ywj pheej ntawm cov txheej txheem metabolic.
Molecular formula thiab molecular hnyav
Cov mis mos molecular yog C78H123N23O23S2, nrog rau qhov hnyav molecular ntawm 1815.1 Da. Nws cov qauv muaj ob cysteine residues (Cys182 thiab Cys189), uas tsim cov qauv cyclic los ntawm disulfide bonds (- S-S -). Qhov no conformational stability ho txhim khu lub molecule tsis kam mus enzymatic hydrolysis thiab prolongs nws ib nrab -lub neej nyob rau hauv vivo.
Amino acid sequence thiab functional domains
Qhov ua tiav ib ntus yog SALLRSIPPAGASRLLLLLTGEIDLP. ntawm cov
Txoj Haujlwm 176-185 (SALLRSIPAP):
Tsim kom muaj kev sib koom ua ke ntawm 3-adrenergic receptor (3-AR), uas ua rau lub lipolysis taw qhia txoj hauv kev los ntawm kev ua raws li cov tshuaj hormones catecholamine;
186-191 (AGASRL):
Muaj cov peroxisome proliferator activated receptor gamma (PPAR gamma) inhibitory ib ntus, uas thaiv kev sib txawv ntawm preadipocyte;
Disulfide nplhaib cheeb tsam (Cys182-Cys189):
Tuav lub peb- qauv qauv ntawm cov molecule, kom ntseeg tau tias muaj kev sib raug zoo siab nrog rau lub hom phiaj protein.
Lub cev thiab tshuaj muaj zog
Solubility:
me ntsis soluble nyob rau hauv dimethyl sulfoxide (DMSO) thiab yuav tsum tau npaj rau hauv ib tug tshwj xeeb concentration tov rau siv;
Kev ruaj ntseg:
Cov hmoov yuav tsum tau muab khaws cia rau hauv lub teeb thaiv kev tiv thaiv, thiab qhov kev cia siab zoo tshaj plaws yog -20℃khov kom tsis txhob rov qab khov-thaw mus rau peptide chain breakage;
PH:
Tus nqi pKa kwv yees yog 3.49 ± 0.10, qhia tias nws nqa tus nqi tsis zoo hauv lub cev pH (7.4) ib puag ncig, uas yog qhov tsim nyog rau kev thauj mus los ntawm cov cell membrane.
AOD 9604 hmoovthiab AOD9401, raws li lipolytic domain analogs ntawm tib neeg kev loj hlob hormone (hGH), ob leeg tswj cov roj metabolism los ntawm kev ua raws li C-terminal fragment ntawm hGH. Txawm li cas los xij, muaj qhov sib txawv tseem ceeb ntawm ob qho tib si ntawm cov qauv molecular, lub zog ntawm kev ua, kev ua haujlwm, thiab kev siv tshuaj kho mob muaj peev xwm. Kev sib piv yuav tau ua los ntawm plaub qhov loj raws li hauv qab no:
Molecular Structure Optimization: "Txiav Txiav" ntawm AOD9604
AOD9401, raws li qhov tsim tawm thaum ntxov hGH analogue, khaws cov 176-191 amino acid fragment ntawm C-terminus ntawm hGH, muaj 30 amino acid residues. AOD9604 yog ntxiv optimized raws li qhov no, tsim ib tug ruaj khov cyclic disulfide daim ntawv cog lus qauv (xws li C7 → C14 site cyclization) los ntawm kev hloov tshuaj los yog fragment extraction cov tswv yim, ho txhim kho molecular stability thiab bioavailability.
Qhov kev ua kom zoo ntawm cov qauv no ua rau nws ntev ib nrab -lub neej hauv vivo, ua kom yooj yim rau nkag mus rau cov ntaub so ntswg adipose thiab ua ncaj qha rau cov hlwb tom qab qhov ncauj lossis txhaj tshuaj. Piv txwv li, nyob rau hauv tus qauv Zuk rog rog, AOD9604 tau hais qhov ncauj ntawm koob tshuaj 500 micrograms ib kilogram ntawm lub cev hnyav rau 19 hnub, ua rau qhov hnyav nce ntau dua 50% piv rau pawg tswj hwm, thaum AOD9401 tsuas yog txo los ntawm 30% ntawm tib koob tshuaj, qhia tias qib qub yog qhov zoo dua.
Lub zog ntawm kev nqis tes ua: AOD9604's "ob lub zog ntxiv"
Kev ua haujlwm lipolytic: AOD9604 tshwj xeeb activates 3-adrenergic receptors hauv adipocytes, nce qib intracellular cyclic adenosine monophosphate (cAMP), yog li ua kom cov protein kinase A (PKA) thiab cov tshuaj hormones rhiab heev lipase (HSL), ua kom cov hydrolysis ntawm triglycerides dawb thiab fatty acids. Cov ntaub ntawv tshawb fawb tau pom tias qhov kev ua haujlwm lipolytic ntawm cov ntaub so ntswg adipose hauv cov nas rog rog kho nrog AOD9604 tau nce 2.3 npaug piv rau pawg tswj hwm, thaum AOD9401 tsuas yog nce 1.5 npaug.
Los tiv thaiv lipogenic nyhuv: AOD9604 tuaj yeem cuam tshuam qhov kev qhia ntawm fatty acid synthase (FAS), thaiv qhov sib txawv ntawm preadipocytes rau hauv cov laus adipocytes, thiab txo cov kev hloov pauv ntawm cov khoom noj tsis muaj roj rau hauv lub cev rog. Nyob rau hauv tus luav lub hauv caug osteoarthritis qauv induced los ntawm collagenase, cov pob txha pob txha degeneration sib koom ua ke tau qis dua nyob rau hauv cov pab pawg neeg kho nrog AOD9604 ua ke nrog hyaluronic acid txhaj tshaj nyob rau hauv cov pab pawg neeg kho nrog AOD9401 ib leeg, indirectly xav txog nws lub luag hauj lwm nyob rau hauv txo kev sib koom siab los ntawm kev txo cov rog.
AOD9604 tshaj AOD9401 ua tiav los ntawm kev ua kom zoo ntawm cov qauv molecular, txhim kho kev ua haujlwm muaj zog, kev ua tiav hauv cov phiaj xwm phiaj xwm, thiab muaj peev xwm rau kev siv ntau yam scenario. Raws li lub cim tshiab ntawm kev tiv thaiv kev rog rog peptide cov tshuaj hormones, nws tsis yog tsuas yog ua tau zoo hauv kev poob phaus, tab sis kuj ua tiav cov txiaj ntsig zoo hauv kev nyab xeeb thiab kev ua haujlwm, muab cov kev daws teeb meem zoo dua rau kev kho mob rog rog, kev raug mob kis las, thiab kab mob sib koom ua ke.
Synthesis txheej txheem thiab kev tswj kom zoo
1. Khoom theem peptide synthesis (SPPS) tshuab
Kev tsim khoom tseem ceeb tau txais cov khoom siv -theem synthesis txoj kev nrog Fmoc/tBu kev tiv thaiv zoo:
Resin carrier xaiv:
Xaiv Wang resin lossis Rink amide resin kom paub meej C-terminal amidation hloov kho;
Kauj ruam los ntawm kauj ruam coupling:
Ntxiv cov amino acids ua ntu zus los ntawm C-terminus mus rau N-terminus, siv HBTU/DIPEA ua tus neeg sawv cev condensing;
Sab saw tiv thaiv pawg:
Cysteine muaj kev tiv thaiv los ntawm Trt, arginine tiv thaiv los ntawm Pbf los tiv thaiv kev mob sab;
Txiav thiab purification:
Tom qab txiav nrog trifluoroacetic acid (TFA), purity tuaj yeem ncav cuag ntau dua 99% los ntawm kev rov qab theem siab ua kua chromatography (RP-HPLC) purification.
2. Cov txheej txheem zoo
Kev kuaj purity:
HPLC tsom xam qhia tau hais tias qhov kev faib ua feem ntawm lub ntsiab ncov cheeb tsam yog ntau tshaj los yog sib npaug zos rau 98%, thiab ib tug impurity yog tsawg dua los yog sib npaug zos rau 0.5%;
Kev txheeb xyuas qhov hnyav Molecular:
Qhov sib txawv ntawm qhov tseeb molecular hnyav kuaj pom los ntawm huab hwm coj spectrometry (MS) thiab tus nqi theoretical tsawg dua lossis sib npaug li 0.1%;
Residual kuab tshuaj tswj:
TFA residue Tsawg dua lossis sib npaug li 0.1%, acetonitrile residue Tsawg dua lossis sib npaug li 50 ppm;
Microbial txwv:
Yuav tsum ua raws li cov cai ntsuas tsis muaj menyuam ntawm Suav Pharmacopoeia.
Lub discovery ntawmAOD 9604 hmoovstems los ntawm hauv - kev tshawb fawb tob txog cov haujlwm ua haujlwm ntawm tib neeg kev loj hlob hormone (hGH), uas sib txuas cov txheej txheem molecular biology, kev sim tshuaj, thiab kev tshawb fawb ua ntej los tsim cov tshuaj tiv thaiv kev rog thiab muaj txiaj ntsig zoo. Cov hauv qab no yog cov ncauj lus kom ntxaws txog nws txoj kev tshawb pom:
Tib neeg txoj kev loj hlob hormone (hGH) yog polypeptide hormone secreted los ntawm anterior pituitary caj pas, uas muaj ntau yam physiological functions xws li txhawb kev loj hlob thiab regulating metabolism. Txawm li cas los xij, tag nrho cov molecule ntawm hGH muaj kev txwv hauv kev siv tshuaj kho mob, xws li ib nrab luv luv - lub neej thiab cov kev mob tshwm sim. Yog li ntawd, cov kws tshawb fawb tau pib tshawb nrhiav cov haujlwm ua haujlwm ntawm hGH txhawm rau txhim kho cov tshuaj muaj kev nyab xeeb thiab zoo dua. Hauv cov ntsiab lus no, C-terminal fragment ntawm hGH (amino acids 176-191) tau nkag mus rau hauv kev tshawb fawb teb vim nws lub luag haujlwm tseem ceeb hauv kev tswj cov roj metabolism.
Cov kws tshawb fawb tau npaj cov hGH 176-191 fragment los ntawm chemical synthesis lossis genetic engineering cov txheej txheem thiab ua qhov kev tshawb fawb tob txog nws txoj haujlwm. Cov kev sim tau pom tias cov khoom no tuaj yeem ua rau muaj lipolysis (lipolysis) thiab inhibit adipogenesis (anti lipogenesis), nrog rau kev cuam tshuam tsawg rau lwm cov ntaub so ntswg xws li cov leeg thiab pob txha. Qhov kev tshawb pom no muab cov ntsiab lus tseem ceeb rau kev tsim cov tshuaj tiv thaiv kev rog tshiab. Kev tshawb fawb ntxiv tau nthuav tawm cov txheej txheem ntawm kev ua ntawm hGH 176-191 ntu, uas ua rau 3-adrenergic receptors ntawm adipocyte membrane los txhawb cov hydrolysis ntawm triglycerides rau hauv glycerol thiab fatty acids, yog li txhim kho lipolytic kev ua si; Nyob rau tib lub sijhawm, inhibiting qhov kev qhia ntawm fatty acid synthase (FAS), thaiv kev sib txawv ntawm preadipocyte thiab fatty acid synthesis, thiab txo cov rog los ntawm qhov chaw.
Raws li kev tshawb fawb tau ntawm hGH 176-191 fragment, cov kws tshawb fawb tau npaj AOD 9604 los ntawm cov txheej txheem tshuaj synthesis. Cov txheej txheem no suav nrog cov kauj ruam xws li maj mam sib txuas ntawm cov amino acids, tshem tawm cov pab pawg tiv thaiv, thiab ua kom huv huv, thaum kawg ua rau muaj siab purity AOD 9604 peptide. Piv nrog rau hGH 176-191 fragment, tej yam optimizations tej zaum yuav tau ua nyob rau hauv nws cov qauv tshuaj los txhim kho nws stability, bioavailability, los yog ua tau zoo. Piv txwv li, los ntawm kev hloov cov amino acid ib theem zuj zus los yog qhia cov tshuaj tshwj xeeb, muaj peev xwm los tiv thaiv enzymes.AOD 9604 hmoovtuaj yeem txhim kho, yog li ncua nws ib nrab -lub neej hauv vivo.
Txhawm rau txheeb xyuas qhov kev tiv thaiv kev rog, cov kws tshawb fawb tau ua ntau yam kev sim tsiaj thiab kev tshawb fawb preclinical. Hauv kev sim tsiaj, nws tau raug pov thawj los txo cov rog ntau ntxiv, txhawb cov rog rog, thiab txhim kho cov cim qhia txog kev rog (xws li ntshav qabzib, ntshav lipids, thiab lwm yam). Tsis tas li ntawd, nws kuj pom tau tias muaj kev nyab xeeb zoo thiab tsis ua rau muaj kev phom sij rau cov kabmob tseem ceeb xws li lub siab thiab lub raum ntawm cov tsiaj sim. Hauv kev tshawb fawb preclinical, koob tshuaj - teb kev sib raug zoo thiab cov txheej txheem ntawm kev txiav txim tau raug qhia ntxiv. Piv txwv li, los ntawm cov txheej txheem xws li kev tshuaj ntsuam gene thiab proteomics, cov kws tshawb fawb tau qhia txog nws txoj cai tswj hwm txoj hauv kev ntawm adipocyte signaling pathway, muab pov thawj scientific rau nws daim ntawv thov kev kho mob.
1. Kev tshuaj ntsuam toxicological
Mob toxicity:
Oral LD ₅₀>5000 mg/kg hauv nas, cais raws li kev xyaum tsis yog- tshuaj lom;
Genetic toxicity:
Ames kuaj thiab nas pob txha pob txha micronucleus kuaj tau ob qho tib si tsis zoo;
Ntev toxicity:
Cov nas tau ua haujlwm tsis tu ncua rau 90 hnub yam tsis muaj qhov txawv txav hauv daim siab thiab lub raum ua haujlwm lossis hloov pauv hauv lub cev hnyav.
2. Kev tshawb fawb soj ntsuam kev vam meej
Kev kho mob rog rog:
Kev sim tshuaj Phase II tau pom tias cov neeg rog rog (BMI Ntau dua lossis sib npaug li 35) uas noj 1 mg ntawm AOD 9604 qhov ncauj txhua hnub poob qhov nruab nrab ntawm 2.8 kg tom qab 12 lub lis piam, uas zoo dua li cov placebo pawg (0.8 kg);
Kev kho mob kis las:
Nyob rau hauv tus qauv luav hauv caug osteoarthritis, pob txha pob txha regeneration tau nce, thiab pob txha mos thickness nce 41% tom qab intra- articular txhaj;
Kev cuam tshuam ntawm metabolic syndrome:
Los ntawm kev ua kom lub zog sib npaug, txhim kho cov tshuaj insulin, thiab txo cov ntshav qabzib sai ntawm 15%.
Cim npe nrov: aod 9604 hmoov, Tuam Tshoj aod 9604 hmoov manufacturers, lwm tus neeg
