CN103736076B - 具有降血压和降血脂双功能的二肽dl及其用途 - Google Patents
具有降血压和降血脂双功能的二肽dl及其用途 Download PDFInfo
- Publication number
- CN103736076B CN103736076B CN201310743378.6A CN201310743378A CN103736076B CN 103736076 B CN103736076 B CN 103736076B CN 201310743378 A CN201310743378 A CN 201310743378A CN 103736076 B CN103736076 B CN 103736076B
- Authority
- CN
- China
- Prior art keywords
- dipeptides
- dipeptide
- lowering blood
- hmg
- ace
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 108010016626 Dipeptides Proteins 0.000 title claims abstract description 38
- 210000004369 blood Anatomy 0.000 title claims abstract description 18
- 239000008280 blood Substances 0.000 title claims abstract description 18
- 230000036772 blood pressure Effects 0.000 title claims abstract description 11
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 claims abstract description 14
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 claims abstract description 14
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 13
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 9
- 150000001413 amino acids Chemical group 0.000 claims abstract description 4
- 230000001588 bifunctional effect Effects 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 34
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 abstract description 6
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 abstract description 5
- 102000004316 Oxidoreductases Human genes 0.000 abstract description 3
- 108090000854 Oxidoreductases Proteins 0.000 abstract description 3
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 abstract 4
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 abstract 2
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000003814 drug Substances 0.000 description 20
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 14
- 238000001514 detection method Methods 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- 101000984728 Chiropsoides quadrigatus Angiotensin-converting enzyme inhibitory peptide Proteins 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 8
- AAXWBCKQYLBQKY-IRXDYDNUSA-N (2s)-2-[[(2s)-2-[(2-benzamidoacetyl)amino]-3-(1h-imidazol-5-yl)propanoyl]amino]-4-methylpentanoic acid Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)C=1C=CC=CC=1)C1=CN=CN1 AAXWBCKQYLBQKY-IRXDYDNUSA-N 0.000 description 7
- 239000005541 ACE inhibitor Substances 0.000 description 7
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 7
- 108010016268 hippuryl-histidyl-leucine Proteins 0.000 description 7
- NPOAOTPXWNWTSH-UHFFFAOYSA-N 3-hydroxy-3-methylglutaric acid Chemical compound OC(=O)CC(O)(C)CC(O)=O NPOAOTPXWNWTSH-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- -1 acyl coenzyme A Chemical compound 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- ACFIXJIJDZMPPO-NNYOXOHSSA-N NADPH Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-N 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 description 4
- 239000005516 coenzyme A Substances 0.000 description 4
- 229940093530 coenzyme a Drugs 0.000 description 4
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 description 4
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 3
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 3
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 210000005252 bulbus oculi Anatomy 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000010829 isocratic elution Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 3
- SPOMEWBVWWDQBC-UHFFFAOYSA-K tripotassium;dihydrogen phosphate;hydrogen phosphate Chemical compound [K+].[K+].[K+].OP(O)([O-])=O.OP([O-])([O-])=O SPOMEWBVWWDQBC-UHFFFAOYSA-K 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 241000251468 Actinopterygii Species 0.000 description 2
- 102000015779 HDL Lipoproteins Human genes 0.000 description 2
- 108010010234 HDL Lipoproteins Proteins 0.000 description 2
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229940125753 fibrate Drugs 0.000 description 2
- 235000019688 fish Nutrition 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000001631 hypertensive effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000003087 receptor blocking agent Substances 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 description 2
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 1
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 description 1
- ZLLVNPWAUPIQPX-UHFFFAOYSA-N 2-(dihydroxymethyl)pentanoic acid Chemical compound CCCC(C(O)O)C(O)=O ZLLVNPWAUPIQPX-UHFFFAOYSA-N 0.000 description 1
- 101710158485 3-hydroxy-3-methylglutaryl-coenzyme A reductase Proteins 0.000 description 1
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 description 1
- DJQOOSBJCLSSEY-UHFFFAOYSA-N Acipimox Chemical compound CC1=CN=C(C(O)=O)C=[N+]1[O-] DJQOOSBJCLSSEY-UHFFFAOYSA-N 0.000 description 1
- 108010072661 Angiotensin Amide Proteins 0.000 description 1
- 102400000344 Angiotensin-1 Human genes 0.000 description 1
- 101800000734 Angiotensin-1 Proteins 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 102400000345 Angiotensin-2 Human genes 0.000 description 1
- XPCFTKFZXHTYIP-PMACEKPBSA-N Benazepril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XPCFTKFZXHTYIP-PMACEKPBSA-N 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- 102400000967 Bradykinin Human genes 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 1
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 1
- 239000005537 C09CA07 - Telmisartan Substances 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 102000005367 Carboxypeptidases Human genes 0.000 description 1
- 108010006303 Carboxypeptidases Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RGJOEKWQDUBAIZ-IBOSZNHHSA-N CoASH Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS)O[C@H]1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-IBOSZNHHSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 description 1
- 241000218628 Ginkgo Species 0.000 description 1
- 235000011201 Ginkgo Nutrition 0.000 description 1
- 235000008100 Ginkgo biloba Nutrition 0.000 description 1
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 229920001499 Heparinoid Polymers 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 108010007859 Lisinopril Proteins 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- DJWYOLJPSHDSAL-UHFFFAOYSA-N Pantethine Natural products OCC(C)(C)C(O)C(=O)NCCC(=O)NCCSSCCNC(=O)CCNC(=O)C(O)C(C)(C)CO DJWYOLJPSHDSAL-UHFFFAOYSA-N 0.000 description 1
- HDSBZMRLPLPFLQ-UHFFFAOYSA-N Propylene glycol alginate Chemical compound OC1C(O)C(OC)OC(C(O)=O)C1OC1C(O)C(O)C(C)C(C(=O)OCC(C)O)O1 HDSBZMRLPLPFLQ-UHFFFAOYSA-N 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 229920000263 Rubber seed oil Polymers 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- 241000195474 Sargassum Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 229920002494 Zein Polymers 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960003526 acipimox Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229960000528 amlodipine Drugs 0.000 description 1
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 1
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 229960002274 atenolol Drugs 0.000 description 1
- 229960004530 benazepril Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960000516 bezafibrate Drugs 0.000 description 1
- IIBYAHWJQTYFKB-UHFFFAOYSA-N bezafibrate Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1CCNC(=O)C1=CC=C(Cl)C=C1 IIBYAHWJQTYFKB-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 229960000932 candesartan Drugs 0.000 description 1
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 238000003421 catalytic decomposition reaction Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960005025 cilazapril Drugs 0.000 description 1
- HHHKFGXWKKUNCY-FHWLQOOXSA-N cilazapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N2[C@@H](CCCN2CCC1)C(O)=O)=O)CC1=CC=CC=C1 HHHKFGXWKKUNCY-FHWLQOOXSA-N 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960003580 felodipine Drugs 0.000 description 1
- 229960002297 fenofibrate Drugs 0.000 description 1
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960003627 gemfibrozil Drugs 0.000 description 1
- 239000002554 heparinoid Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229960002198 irbesartan Drugs 0.000 description 1
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- GKQPCPXONLDCMU-CCEZHUSRSA-N lacidipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1C1=CC=CC=C1\C=C\C(=O)OC(C)(C)C GKQPCPXONLDCMU-CCEZHUSRSA-N 0.000 description 1
- 229960004340 lacidipine Drugs 0.000 description 1
- 229960002394 lisinopril Drugs 0.000 description 1
- RLAWWYSOJDYHDC-BZSNNMDCSA-N lisinopril Chemical compound C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 RLAWWYSOJDYHDC-BZSNNMDCSA-N 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229960002237 metoprolol Drugs 0.000 description 1
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- VWPOSFSPZNDTMJ-UCWKZMIHSA-N nadolol Chemical compound C1[C@@H](O)[C@@H](O)CC2=C1C=CC=C2OCC(O)CNC(C)(C)C VWPOSFSPZNDTMJ-UCWKZMIHSA-N 0.000 description 1
- 229960004255 nadolol Drugs 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 229960005425 nitrendipine Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- DJWYOLJPSHDSAL-ROUUACIJSA-N pantethine Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSSCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)CO DJWYOLJPSHDSAL-ROUUACIJSA-N 0.000 description 1
- 229960000903 pantethine Drugs 0.000 description 1
- 235000008975 pantethine Nutrition 0.000 description 1
- 239000011581 pantethine Substances 0.000 description 1
- 238000002161 passivation Methods 0.000 description 1
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 1
- VWBQYTRBTXKKOG-IYNICTALSA-M pravastatin sodium Chemical compound [Na+].C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC([O-])=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 VWBQYTRBTXKKOG-IYNICTALSA-M 0.000 description 1
- 235000010409 propane-1,2-diol alginate Nutrition 0.000 description 1
- 239000000770 propane-1,2-diol alginate Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 239000003998 snake venom Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
本发明属于生物技术领域,特别涉及一个能与血管紧张素转换酶结合、抑制其活性、也能抑制3-羟基-3-甲基戊二酸单酰辅酶A(HMG-CoA)还原酶的活性的二肽。具体而言,本发明公开了一种具有降血压和降血脂双功能的二肽DL,该二肽DL的氨基酸序列为:Asp?Leu。本发明还公开了上述二肽DL在制备ACE抑制肽和/或HMG-CoA还原酶抑制肽中的应用。
Description
技术领域
本发明属于生物技术领域,特别涉及一个能与血管紧张素转换酶结合,抑制其活性,也能抑制3-羟基-3-甲基戊二酸单酰辅酶A(HMG-CoA)还原酶的活性的二肽。
背景技术
血管紧张素转换酶(Angiotensin converting enzyme,ACE,EC3.4.15.1,文献中曾用名有kininaseIl,dipeptidyl carboxypeptidase I等)是一种二羧肽酶,是导致高血压的一个关键酶,它通过水解作用把血管紧张肽Ⅰ转化成血管紧张肽Ⅱ,与此同时,ACE还可钝化血管舒缓激肽,这两种作用均可导致血管收缩,从而引起高血压。因此ACE被认为是引起高血压的一个重要因素。经研究发现血管紧张素转换酶抑制剂(ACEI),可通过抑制ACE的活性而达到降血压的作用。ACE抑制剂广泛用于治疗心血管、高血压、心力衰竭、肾衰竭等疾病。ACE抑制剂最初是从蛇毒中发现的,随后人们发现从食物原料中提取的ACE抑制肽,如明胶、酪蛋白、鱼、无花果树胶、α-玉米蛋白等都可作为制备ACE抑制肽的原料。
3-羟基-3-甲基戊二酸单酰辅酶A(HMG-CoA)还原酶是体内催化3-羟基-3-甲基戊二酸单酰辅酶A(HMG-CoA)生成二羟甲基戊酸(MVA)的关键酶,这一步是体内合成胆固醇的限速步骤,也是目前最主要的高血脂症临床药物的靶点。HMG-CoA还原酶抑制剂是降血脂功效成分和药物筛选主要手段之一。
降血压的药物常见的有:
①、利尿剂:代表药物有氢氯噬嗓、氨苯蝶吮、螺内酉旨等。
②、片受体阻滞剂:代表药物有普蔡洛尔、美托洛尔、阿替洛尔、纳多洛尔等。
③、钙通道阻滞剂:代表药物有硝苯地平、氨氯地平、非洛地平、尼群地平、拉西地平等。
④、血管紧张素转换酶抑制剂:代表药物有卡托普利、苯那普利、赖诺普利、依那普利、西拉普利等。
⑤、a一受体阻滞剂:代表药物有呱哇嗓、特拉哩嗦等。
⑥、血管紧张素11受体拮抗剂:代表药物有洛沙坦、撷沙坦、厄贝沙坦、坎地沙坦、伊贝沙坦、替米沙坦等。
降血脂的药物有:
1、苯氧芳酸类:此类药物有非诺贝特、吉非罗齐、苯扎贝特等。苯氧芳酸类药物降血脂作用强,起效快,降甘油三酯的作用比降胆固醇的作用强。
2、三羟甲基戊二酰-辅酶A还原酶抑制剂:此类药物有洛伐他丁、辛伐他丁、普伐他丁等。此类药物以降胆固醇为主,降脂作用强,起效快。
3、烟酸类:此类药物中氧甲吡嗪较常用,降低血清甘油三脂的作用比降低胆固醇强。
4、多不饱和脂肪酸类:包括各种植物种子油。如橡胶种子油,月见草子,水飞蓟种子的油和海鱼的制剂。这类药物有降血脂和降低血粘度的作用,但作用比较温和。
5、泛硫乙胺:为辅酶A的衍生物,有降低血清胆固醇、甘油三脂和升高高密度脂蛋白-胆固醇的作用。
6、藻酸双酯钠(PPS):是以海藻撮物为原料的类肝素海洋药物。具有显著降低血粘度,扩张血管和降低血脂,升高HDL水平的作用。主要用于缺血性心脑血管疾病的防治。
7、其他降血脂药物:如银杏类(天保宁)实验证明能使血清甘油三脂(TG)显著降低。
现有药物报道,除中药外,同时具有降血压和降血脂作用的药物很少见。因为这两种药所作用的靶标不同。
发明内容
本发明要解决的技术问题是提供一种具有降血压和降血脂双功能的二肽DL及其用途。
为了解决上述技术问题,本发明提供一种具有降血压和降血脂双功能的二肽DL,该二肽DL的氨基酸序列为:Asp Leu。
本发明还同时提供了上述二肽DL的用途:作为ACE抑制肽和/或HMG-CoA还原酶抑制肽。
本发明的二肽DL可通过委托吉尔生化(上海)有限公司合成获得。
本发明的二肽DL针对ACE和HMG-CoA还原酶两个靶标均具有抑制活性,从而表现出同时具有降血压和降血脂双功能的特性。
本发明中所涉及的各项检测方法具体如下:
1、ACE抑制活性的检测方法:
ACE在37℃,pH值为8.3的条件下催化分解血管紧张素I的模拟物Hippuryl-L-Histidyl-L-Leucine(HHL)产生马尿酸(HA),该物质在紫外225nm处具有特征吸收峰;当加入ACE抑制剂时ACE对HHL的催化分解作用受到抑制,马尿酸的生成量减少,通过HPLC方法,测定加入抑制剂前后所生成马尿酸的量的变化即可算出抑制活性的大小。
反应体系为:依次分别加入20μL0.1U/mL的ACE、50μL ACE抑制肽(即DL二肽)在37℃温浴5min,然后加入10μL5mM的HHL底物启动ACE的催化反应,在37℃振荡水浴30min后加入250μL1.0moL/L的HCl终止反应,体系溶液过0.45μm滤膜后进行RP-HPLC检测分析马尿酸(HA)的含量。上述同样条件,以50μL0.1moL/L的硼酸缓冲液中(含0.3moL/L的NaCl,pH=8.3)代替ACE抑制剂作为空白反应体系。
注:上述ACE抑制肽、HHL底物均是以0.1moL/L的硼酸缓冲液(含0.3moL/L的NaCl,pH=8.3)为溶剂。
ACE抑制肽(DL二肽),以不同浓度溶解在0.1moL/L的硼酸缓冲液中(含0.3moL/L的NaCl,pH=8.3)中而得。
RP-HPLC检测:溶剂Ⅰ为0.05%(V/V)三氟乙酸(TFA)和0.05%(v/v)的三乙胺(TTA)溶于去离子水中,溶剂Ⅱ为100%的色谱纯乙睛。溶剂Ⅰ与溶剂Ⅱ的比例为70%:30%(体积比),流速为0.5mL/min,检测波长为225nm,检测柱温为30℃。
ACE抑制活性根据下式计算:
I%=(A-B)/A×100%
A:不加入短肽抑制剂时的马尿酸的峰面积;
B:加入短肽抑制剂时的马尿酸的峰面积;
ACE:1U单位定义为,在标准检测条件下,在37℃,1min时间内催化底物(Hippuryl-L-Histidyl-L-Leucine,HHL),产生1μM马尿酸所消耗ACE的量。即,为ACE的活性单位。
2、降血脂肽活性的体外检测方法:
色谱条件
C18色谱柱(5μm,4.6mm×250mm)。流动相为:V(K2HPO4-KH2PO4):V(甲醇)=85:15,pH7.2,等度洗脱,流速1mL/min;检测波长337nm;进样量20μL;柱温25。℃
反应体系实验步骤:
反应中各种组分的加入量及顺序如表1,反应温度37℃水浴,反应完成后加入200μL0.5mol/L NaOH溶液终止反应,按上述的色谱条件测量样品中NADPH的浓度。反应时间根据酶对照组时间梯度来确定。
表1反应体系组成成分
备注说明:反应缓冲液为0.1mol/L的磷酸钾缓冲液,HMGR溶液的浓度为6.56μg/mL,HMG-CoA溶液浓度为5.23mmol/mL,NADPH溶液浓度为1mg/mL。
实验结果的计算
加入抑制剂后,HMG-CoA还原酶的活性受到抑制,底物反应的量减少。因此,可以利用HPLC测定反应前后NADPH量的变化来评价抑制剂对HMG-CoA还原酶的抑制率。计算公式为:
R=(S抑制剂-S对照)/(S空白-S对照)×100
式中,R为抑制率(%);S空白、S对照和S抑制剂分别为空白组、酶对照组和抑制剂组中NADPH的峰面积(mAU.min)。
本发明的优点和积极效果:
(1)该二肽可以抑制血管紧张素转换酶的活性。
依据本发明所述的氨基酸序列,可委托吉尔生化(上海)有限公司合成,从而获得本发明所述的ACE抑制肽(或简称为二肽DL)。
(2)本发明的ACE抑制肽(或简称为二肽DL)同时具有HMG-CoA还原酶抑制活性。
本发明的ACE抑制肽和HMG-CoA还原酶抑制肽(或简称为二肽DL)的用法和用量如下:
本发明的二肽为口服型,用量为口服,每次1.0g,每日2~3次。
具体实施方式
实施例1、
1)、二肽DL在1.0mg/mL的浓度下的ACE抑制活性:
色谱条件:溶剂Ⅰ为0.05%三氟乙酸(TFA)和0.05%的三乙胺(TTA)溶于去离子水中(即每升溶剂Ⅰ中含有0.5mL的三氟乙酸和0.5mL的三乙胺),溶剂Ⅱ为100%的色谱纯乙睛。溶剂Ⅰ与溶剂Ⅱ的比例为70%:30%(体积比),ultimate3000戴安液相色谱仪,色谱柱为watersSymmetry C185μm4.6×250mm,流速为0.5mL/min,进样量10μL,检测波长为225nm,检测柱温为30℃。
检测方法:将通过化学合成法获得的二肽DL,进行活性检测(检测方法同上)。此时DL浓度为1.0mg/mL。
结果:二肽DL在1.0mg/mL时的ACE抑制活性为81.28%。
2)、二肽DL在1.0mg/mL的浓度下的HMG-CoA还原酶抑制活性:
色谱条件:C18色谱柱(5μm,4.6mm×250mm)。流动相为:V(K2HPO4-KH2PO4):V(甲醇)=85:15,pH7.2,等度洗脱,流速1mL/min;检测波长337nm;进样量20μL;柱温25。℃
检测方法:将通过化学合成法获得的二肽DL,进行活性检测(检测方法同上)。此时DL浓度为1.0mg/mL。
结果:二肽DL在1.0mg/mL时的HMG-CoA还原酶抑制活性为52.44%。
实施例2、
1)、二肽DL在2.0mg/mL的浓度下的ACE抑制活性:
色谱条件:溶剂Ⅰ为0.05%三氟乙酸(TFA)和0.05%的三乙胺(TTA)溶于去离子水中;溶剂Ⅱ为100%的色谱纯乙睛。溶剂Ⅰ与溶剂Ⅱ的比例为70%:30%,ultimate3000戴安液相色谱仪,色谱柱为waters Symmetry C185μm4.6×250mm,,流速为0.5mL/min,进样量10μL,检测波长为225nm,,检测柱温为30℃。
检测方法:将通过化学合成法获得的二肽DL,进行活性检测(检测方法同上)。此时DL浓度为2.0mg/mL。
结果:二肽DL在2.0mg/mL时的ACE抑制活性为87.81%。
2)、二肽DL在2.0mg/mL的浓度下的HMG-CoA还原酶抑制活性:
色谱条件:C18色谱柱(5μm,4.6mm×250mm)。流动相为:V(K2HPO4-KH2PO4):V(甲醇)=85:15,pH7.2,等度洗脱,流速1mL/min;检测波长337nm;进样量20μL;柱温25。℃
检测方法:将通过化学合成法获得的二肽DL,进行活性检测(检测方法同上)。此时DL浓度为2.0mg/mL。
结果:二肽DL在2.0mg/mL时的HMG-CoA还原酶抑制活性为74.34%。
通过实施例1和实施例2中的抑制浓度和活性数据,说明此二肽DL的活性与浓度存在量效关系,此二肽DL同时具有ACE抑制活性和HMG-CoA还原酶抑制未见报道,属于新的兼具ACE抑制活性和HMG-CoA还原酶抑制活性的双功能肽。
最后,还需要注意的是,以上列举的仅是本发明的若干个具体实施例。显然,本发明不限于以上实施例,还可以有许多变形,比如不同蛋白质来源降解分离所得的DL结构及其衍生化结构。本领域的普通技术人员能从本发明公开的内容直接导出或联想到的所有变形,均应认为是本发明的保护范围。
<110> 浙江省农业科学院
<120> 具有降血压和降血脂双功能的二肽DL及其用途
<160> 1
<210> 1
<211> 2
<212> PRT
<213> 人工序列
<220>
<223> 二肽DL
<400> 1
Asp Leu
Claims (1)
1.具有降血压和降血脂双功能的二肽DL在制备HMG-CoA还原酶抑制肽中的应用,二肽DL的氨基酸序列为:Asp Leu。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310743378.6A CN103736076B (zh) | 2013-12-30 | 2013-12-30 | 具有降血压和降血脂双功能的二肽dl及其用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310743378.6A CN103736076B (zh) | 2013-12-30 | 2013-12-30 | 具有降血压和降血脂双功能的二肽dl及其用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103736076A CN103736076A (zh) | 2014-04-23 |
CN103736076B true CN103736076B (zh) | 2015-03-25 |
Family
ID=50493192
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201310743378.6A Expired - Fee Related CN103736076B (zh) | 2013-12-30 | 2013-12-30 | 具有降血压和降血脂双功能的二肽dl及其用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN103736076B (zh) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101426513A (zh) * | 2006-04-21 | 2009-05-06 | 明治制果株式会社 | 含有肽作为有效成分的组合物 |
EP2161029A1 (en) * | 2008-09-09 | 2010-03-10 | Unilever N.V. | Composition comprising peptides |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003024012A (ja) * | 2001-07-18 | 2003-01-28 | National Institute Of Advanced Industrial & Technology | アンジオテンシンi変換酵素阻害剤及び血圧降下性機能食品 |
-
2013
- 2013-12-30 CN CN201310743378.6A patent/CN103736076B/zh not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101426513A (zh) * | 2006-04-21 | 2009-05-06 | 明治制果株式会社 | 含有肽作为有效成分的组合物 |
EP2161029A1 (en) * | 2008-09-09 | 2010-03-10 | Unilever N.V. | Composition comprising peptides |
Non-Patent Citations (2)
Title |
---|
Angiotensin I-Converting Enzyme Inhibitory Activity and Insulin Secretion Stimulative Activity of Fermented Fish Sauce;TOSHIAKI ICHIMURA et al;《JOURNAL OF BIOSCIENCE AND BIOENGINEERING》;20031231;第96卷(第5期);第497页表1 * |
Structural Requirements of Angiotensin I-Converting Enzyme Inhibitory Peptides: Quantitative Structure-Activity Relationship Study of Di- and Tripeptid;Jiangping Wu et al.;《J. Agric. Food Chem.》;20060401;第54卷(第3期);第733页表1 * |
Also Published As
Publication number | Publication date |
---|---|
CN103736076A (zh) | 2014-04-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Seca et al. | Overview on the antihypertensive and anti-obesity effects of secondary metabolites from seaweeds | |
Liu et al. | Effects of taurochenodeoxycholic acid on adjuvant arthritis in rats | |
CN103242430A (zh) | 血管紧张素转化酶抑制肽及其制备方法和应用 | |
Xiang et al. | Protective effect of tuna bioactive peptide on dextran sulfate sodium-induced colitis in mice | |
CN102573885B (zh) | 具有脂肪分解促进作用的组合物 | |
CN102399262B (zh) | 具有血管紧张素转化酶抑制活性的三肽及其应用和组合物 | |
CN108892710A (zh) | 龙须菜降压肽提取物和龙须菜降压肽及其应用 | |
Zhao et al. | Exploration, sequence optimization and mechanism analysis of novel xanthine oxidase inhibitory peptide from Ostrea rivularis Gould | |
CN103755782A (zh) | 具有降血压和降血脂双功能的二肽st及其用途 | |
Zhao et al. | Separation, identification and docking analysis of xanthine oxidase inhibitory peptides from pacific cod bone-flesh mixture | |
CN103736077B (zh) | 具有降血压和降血脂双功能的二肽es及其用途 | |
CN103992374B (zh) | 具有降血糖和降血脂双功能的二肽di及其用途 | |
Szubert et al. | Bioactive metabolites produced by Spirulina subsalsa from the Baltic Sea | |
CN103755781B (zh) | 具有降血压和降血脂双功能的二肽gd及其用途 | |
CN103739666B (zh) | 具有降血压和降血脂双功能的二肽qe及其用途 | |
CN103736076B (zh) | 具有降血压和降血脂双功能的二肽dl及其用途 | |
Fernandes et al. | Absolute Stereochemistry Determination of bioactive marine-derived cyclopeptides by liquid chromatography methods: An update review (2018–2022) | |
CN103739665B (zh) | 具有降血压和降血脂双功能的二肽te及其用途 | |
CN103772484B (zh) | 具有降血压和降血脂双功能的二肽sd及其用途 | |
CN103755783A (zh) | 具有降血压和降血脂双功能的二肽qd及其用途 | |
CN105330721A (zh) | Ace抑制肽及其应用 | |
CN114907445B (zh) | 一种高抗氧化活性富硒肽及其应用 | |
CN113480597B (zh) | 一种来源于紫苏籽粕的ace抑制肽及其制备方法与应用 | |
CN110467653A (zh) | 一种抑制血管紧张素转换酶活性的多肽及其应用 | |
CN108948143B (zh) | 具有ace抑制活性的三肽及其应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150325 |
|
CF01 | Termination of patent right due to non-payment of annual fee |