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Bradykinin (2-9) 是一种氨基截短的激肽肽。Bradykinin (2-9) 是由氨基肽酶 P 切割形成的一种 Bradykinin 代谢物。
Bradykinin (2-9) is an amino-truncated Bradykinin peptide. Bradykinin (2-9) is a metabolite of Bradykinin, cleaved by Aminopeptidase P.

Peptide H-PPGFSPFR-OH is a Research Peptide with significant interest within the field academic and medical research. Recent citations using H-PPGFSPFR-OH include the following: An investigation of fragmentation mechanisms of doubly protonated tryptic peptides XJ Tang, RK Boyd, MJ Bertrand - Rapid communications in , 1992 - Wiley Online Libraryhttps://analyticalsciencejournals.onlinelibrary.wiley.com/doi/abs/10.1002/rcm.1290061105 Fragmentation reactions of singly and doubly charged alkali metal ion-peptide complexes: A reaction specific to C-terminal arginine residues XJ Tang, P Thibault , RK Boyd - Organic mass spectrometry, 1993 - Wiley Online Libraryhttps://analyticalsciencejournals.onlinelibrary.wiley.com/doi/abs/10.1002/oms.1210281012 Novel HY peptide antigens presented by HLA-B27. WA Simmons, SG Summerfield - (Baltimore, Md.: 1950 , 1997 - journals.aai.orghttps://journals.aai.org/jimmunol/article-abstract/159/6/2750/30817 Mobile and localized protons: a framework for understanding peptide dissociation VH Wysocki , G Tsaprailis, LL Smith - Journal of Mass , 2000 - Wiley Online Libraryhttps://analyticalsciencejournals.onlinelibrary.wiley.com/doi/abs/10.1002/1096-9888(200012)35:12%3C1399::AID-JMS86%3E3.0.CO;2-R Structure and mechanism of a bacterial host-protein citrullinating virulence factor, Porphyromonas gingivalis peptidylarginine deiminase T Goulas , D Mizgalska, I Garcia-Ferrer, T Kantyka - Scientific reports, 2015 - nature.comhttps://www.nature.com/articles/srep11969 Dissociation mechanisms and implication for the presence of multiple conformations for peptide ions with arginine at the C-terminus: time-resolved photodissociation SH Yoon, JH Moon, MS Kim - Journal of mass spectrometry, 2010 - Wiley Online Libraryhttps://analyticalsciencejournals.onlinelibrary.wiley.com/doi/abs/10.1002/jms.1773 On-plate deposition of oxidized proteins to facilitate protein footprinting studies by radical probe mass spectrometry SD Maleknia, KM Downard - Rapid Communications in Mass , 2012 - Wiley Online Libraryhttps://analyticalsciencejournals.onlinelibrary.wiley.com/doi/abs/10.1002/rcm.6358 Unrestrictive identification of post-translational modifications through peptide mass spectrometry S Tanner, PA Pevzner , V Bafna - Nature protocols, 2006 - nature.comhttps://www.nature.com/articles/nprot.2006.10 Role of arginine in chemical cross-linking with N-hydroxysuccinimide esters S Madler , S Gschwind, R Zenobi - Analytical biochemistry, 2010 - Elsevierhttps://www.sciencedirect.com/science/article/pii/S0003269709007945 Characterization of permethylated beta-cyclodextrin-peptide noncovalently bound complexes using electron capture dissociation mass spectrometry (ECD MS) S Lee, S Ahn, S Park, HB Oh - International Journal of Mass Spectrometry, 2009 - Elsevierhttps://www.sciencedirect.com/science/article/pii/S138738060800420X backbone of the peptide and induces fragmentation2. One drawback to this method of ionization is the basicity of multiple sites throughout the peptide that could get O Ar - PROGRESS TOWARDS THE TOTAL SYNTHESIS OF , 2019 - search.proquest.comhttps://search.proquest.com/openview/9dac2491c3744c8ff33a8bcb28243402/1.pdf?pq-origsite=gscholar&cbl=2026366&diss=y#page=224 A novel triethylphosphonium charge tag on peptides: synthesis, derivatization, and fragmentation N DeGraan-Weber, SA Ward - Journal of The American , 2017 - ACS Publicationshttps://pubs.acs.org/doi/abs/10.1007/s13361-017-1694-z Correlation and convolution analysis of peptide mass spectra MJ Sniatynski, JC Rogalski , MD Hoffman - Analytical , 2006 - ACS Publicationshttps://pubs.acs.org/doi/abs/10.1021/ac051639u A comparison of the peptide fragmentation obtained from a reflector matrix-assisted laser desorption-ionization time-of-flight and a tandem four sector mass JC Rouse, W Yu , SA Martin - Journal of the American Society for Mass , 1995 - Elsevierhttps://www.sciencedirect.com/science/article/pii/1044030595003258 Soft-landing of peptides onto self-assembled monolayer surfaces J Alvarez, JH Futrell, J Laskin - The Journal of Physical Chemistry , 2006 - ACS Publicationshttps://pubs.acs.org/doi/abs/10.1021/jp0555044 A Direct Comparison of" First" and" Second" Gas Phase Basicities of the Octapeptide RPPGFSPF IA Kaltashov , CC Fenselau - Journal of the American Chemical , 1995 - ACS Publicationshttps://pubs.acs.org/doi/pdf/10.1021/ja00144a017 Proton locations in doubly charged peptides and association with specific fragmentation pathways IA Kaltashov , C Fenselau - International journal of mass spectrometry and , 1997 - Elsevierhttps://www.sciencedirect.com/science/article/pii/S0168117696044916 Peptide fragmentation during nanoelectrospray ionization H Wang , Z Ouyang , Y Xia - Analytical chemistry, 2010 - ACS Publicationshttps://pubs.acs.org/doi/abs/10.1021/ac100872x Peptide sequencing using a patchwork approach and surface-induced dissociation in sector-TOF and dual quadrupole mass spectrometers FM Fernandez , LL Smith, K Kuppannan, X Yang - Journal of the American , 2003 - Springerhttps://link.springer.com/article/10.1016/j.jasms.2003.09.003 Formation of Gaseous Peptide Ions from Electrospray Droplets: Competition between the Ion Evaporation Mechanism and Charged Residue Mechanism E Aliyari , L Konermann - Analytical chemistry, 2022 - ACS Publicationshttps://pubs.acs.org/doi/abs/10.1021/acs.analchem.2c01355 Comparison of the effects of ionization mechanism, analyte concentration, and ion"cool-times"Â\x9d on the internal energies of peptide ions produced by electrospray and DO Konn, J Murrell, D Despeyroux - Journal of the American , 2005 - ACS Publicationshttps://pubs.acs.org/doi/abs/10.1016/j.jasms.2005.01.018 Pharmacological Activities and Hydrolysis by Peptidases of Phospho-Ser6-Bradykinin (pS6-BK) DM Assis , L Juliano , T Paschoalin - Biochemical , 2015 - Elsevierhttps://www.sciencedirect.com/science/article/pii/S0006295215004220 Characterisation of Aspergillus niger prolyl aminopeptidase DEJW Basten, APHA Moers, AJJ Ooyen - Molecular Genetics and , 2005 - Springerhttps://link.springer.com/article/10.1007/s00438-004-1094-5 Selective separations of peptides with sequence deletions, single amino acid polymorphisms, and/or epimeric centers using macrocyclic glycopeptide liquid B Zhang, R Soukup, DW Armstrong - Journal of Chromatography A, 2004 - Elsevierhttps://www.sciencedirect.com/science/article/pii/S0021967304010891 Influence of peptide composition, gas-phase basicity, and chemical modification on fragmentation efficiency: evidence for the mobile proton model AR Dongre , JL Jones, acaÂ\x81 Somogyi - Journal of the American , 1996 - ACS Publicationshttps://pubs.acs.org/doi/abs/10.1021/ja9542193 Coupling 193 nm ultraviolet Photodissociation and ion mobility for sequence characterization of Conformationally-selected peptides AQ Stiving , SR Harvey , BJ Jones - Journal of the , 2020 - ACS Publicationshttps://pubs.acs.org/doi/abs/10.1021/jasms.0c00259 Derivatisation of arginine residues with malondialdehyde for the analysis of peptides and protein digests by LC-ESI-MS/MS A Foettinger, A Leitner - Journal of mass , 2006 - Wiley Online Libraryhttps://analyticalsciencejournals.onlinelibrary.wiley.com/doi/abs/10.1002/jms.1020

Definition

Bradykinin is a nonapeptide that is mainly found in animal preparations that are treated with the venom of the snake, Bothrops jararaca1,2.  It dialates blood vessels that in turn leads to decrease in blood pressure2. Bradykinin analogs are slightly modified structural derivatives of bradykinin that perform similar functions as bradykinin3.

Discovery

Bradykinin was discovered in the blood plasma of animals that were treated with the venom from the Brazilian snake, Bothrops jararaca1,2.  The discovery was part of a study that was related to toxicology of snake bites.  Bradykinin analogs were synthesized by solid-phase techniques in 1975 and their function was studied in rats and rabbits3.

Classification

Bradykinin is a 9 amino acid peptide that belongs to the kinin family of proteins4.  It has homologs in several animals including other snakes, frog, dog and humans4.

Structural Characteristics

Bradykinin has the sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg3.  Several analogs of bradykinin have been synthesized. They are also nanopeptides containing substitutions of various amino acids of bradykinin. For example two analogs of bradykinin were synthesized one with 7-beta-homo-L-proline and the other with 8-beta-homo-L-phenylalanine substitutions3.  It was found that both of them are resistant to enzymatic degradation3.

Mode of action

Bradykinin binds to two different kinin G protein coupled receptors- B1 and B25.  Upon binding to these receptors it induces conversion of GTP to GDP which in turn triggers the conversion ATP to cAM which then acts as a second messenger resulting in the activation of genes.  B1 receptor is expressed as a result of tissue injury and is found to play a role in inflammation while B2 receptor participates in the vasodilatory role of bradykinin5,6.  Bradykinin analogs function is a similar fashion although depending on their structure they might have varying affinities to the receptors compared to bradykinin7. Also analogs of bradykinin have been synthesized that are specific to one of these receptors7.

Functions

Bradykinin is a potent endothelium-dependent vasodilator, causes contraction of non-vascular smooth muscle, increases vascular permeability and also is involved in the mechanism of pain. Bradykinin also causes natriuresis, contributing to a drop in blood pressure8. Bradykinin raises internal calcium levels in neocortical astrocytes causing them to release glutamate9. Overactivation of bradykinin is thought to play a role in a rare disease called Hereditary Angioedema, also known as Hereditary Angio-Neurotic Edema10. 

Some analogs of bradykinin have been found to have prolonged hypotensive action compared to bradykinin (Eg: beta-H-Pro-bradykinin)3.  Some analogs have relative or even lower potencies compared to bradykinin (Eg: HArg1-Bradykinin and HArg9 Bradykinin)7.  Other analogs have been studied for their potential of finding bradykinin antagonists that might be useful in the treatment of angio-neurotic edema.  

References

1.     Partridge, SM (1948). (Title or abstract not available), Biochem. J., 42, 238.

2.     Allen PK, Kusumam J, Yoji S, Yoshitaka N, Berhane G, Sesha R and Michael S (1998). Bradykinin formation: Plasma and tissue pathways and cellular interactions. Clinical reviews in allergy and immunology, 16, 4, 403-429.

3.     Ondetti MA, Engel SL (1975). Bradykinin analogs containing beta.-homoamino acid, J. Med. Chem.,18 (7), 761–763.

4.     Roseli A, Gomes S, Jair RC, Luis J and Valdemar H (1996). Met-Lys-Bradykinin-Ser, the kinin released from human kininogen by human pepsin. Immunopharmacology, 32, 76-79.

5.    Peter GM, Amrita A, and Mauro P (2000). Association between Kinin B1 Receptor Expression and Leukocyte Trafficking across Mouse Mesenteric Postcapillary Venules. J Exp. Med., 192, 367-380.

6.     Duchene J, Lecomte F, Ahmed S, Cayla C, Pesquero J, Bader M, Perretti M and Ahluwalia A, (2007). A Novel Inflammatory Pathway Involved in Leukocyte Recruitment: Role for the Kinin B1 Receptor and the Chemokine CXCL5. J Immunol., 179, 4849-4856.

7.     Max ES, Phyllis AL (1974). Synthesis and pharmacology of homoarginine bradykinin analog. J. Med. Chem., 17 (11), pp 1227–1228.

8.     Dendorfer A, Wolfrum S, Wagemann M, Qadri F, Dominiak P, (2001). Pathways of bradykinin degradation in blood and plasma of normotensive and hypertensive rats. Am J Physiol Heart Circ Physiol., 280:H2182

9.     Kuoppala A, Lindstedt KA, Saarinen J, Kovanen PT, Kokkonen JO (2000). Inactivation of bradykinin by angiotensin-converting enzyme and by carboxypeptidase N in human plasma. Am J Physiol Heart Circ Physiol, 278(4):H1069-74.

10.   Bas M, Adams V, Suvorava T, Niehues T, Hoffmann TK, Kojda G (2007). Nonallergic angioedema: role of bradykinin. Allergy, 62(8):842-56.

多肽H2N-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-COOH的合成步骤：

1、合成CTC树脂：称取2.0g CTC Resin（如初始取代度约为0.43mmol/g）和1.03mmol Fmoc-Arg(Pbf)-OH于反应器中，加入适量DCM溶解氨基酸（需要注意，此时CTC树脂体积会增大好几倍，避免DCM溶液过少），再加入2.58mmol DIPEA（Mw：129.1,d：0.740g/ml），反应2-3小时后，可不抽滤溶液，直接加入1ml的HPLC级甲醇，封端半小时。依次用DMF洗涤2次，甲醇洗涤1次，DCM洗涤一次，甲醇洗涤一次，DCM洗涤一次，DMF洗涤2次（这里使用甲醇和DCM交替洗涤，是为了更好地去除其他溶质，有利于后续反应）。得到  Fmoc-Arg(Pbf)-CTC Resin。结构图如下：

2、脱Fmoc：加3倍树脂体积的20%Pip/DMF溶液，鼓氮气30分钟，然后2倍树脂体积的DMF 洗涤5次。得到 H2N-Arg(Pbf)-CTC Resin 。（此步骤脱除Fmoc基团，茚三酮检测为蓝色，Pip为哌啶）。结构图如下：

3、缩合：取2.58mmol Fmoc-Phe-OH 氨基酸，加入到上述树脂里，加适当DMF溶解氨基酸，再依次加入5.16mmol DIPEA，2.45mmol HBTU。反应30分钟后，取小样洗涤，茚三酮检测为无色。用2倍树脂体积的DMF 洗涤3次树脂。（洗涤树脂，去掉残留溶剂，为下一步反应做准备）。得到Fmoc-Phe-Arg(Pbf)-CTC Resin。氨基酸：DIPEA：HBTU：树脂=3：6：2.85：1（摩尔比）。结构图如下：

4、依次循环步骤二、步骤三，依次得到

H2N-Phe-Arg(Pbf)-CTC Resin

Fmoc-Pro-Phe-Arg(Pbf)-CTC Resin

H2N-Pro-Phe-Arg(Pbf)-CTC Resin

Fmoc-Ser(tBu)-Pro-Phe-Arg(Pbf)-CTC Resin

H2N-Ser(tBu)-Pro-Phe-Arg(Pbf)-CTC Resin

Fmoc-Phe-Ser(tBu)-Pro-Phe-Arg(Pbf)-CTC Resin

H2N-Phe-Ser(tBu)-Pro-Phe-Arg(Pbf)-CTC Resin

Fmoc-Gly-Phe-Ser(tBu)-Pro-Phe-Arg(Pbf)-CTC Resin

H2N-Gly-Phe-Ser(tBu)-Pro-Phe-Arg(Pbf)-CTC Resin

Fmoc-Pro-Gly-Phe-Ser(tBu)-Pro-Phe-Arg(Pbf)-CTC Resin

H2N-Pro-Gly-Phe-Ser(tBu)-Pro-Phe-Arg(Pbf)-CTC Resin

Fmoc-Pro-Pro-Gly-Phe-Ser(tBu)-Pro-Phe-Arg(Pbf)-CTC Resin

以上中间结构，均可在专肽生物多肽计算器-多肽结构计算器中，一键画出。

最后再经过步骤二得到 H2N-Pro-Pro-Gly-Phe-Ser(tBu)-Pro-Phe-Arg(Pbf)-CTC Resin，结构如下：

5、切割：6倍树脂体积的切割液（或每1g树脂加8ml左右的切割液），摇床摇晃 2小时，过滤掉树脂，用冰无水乙醚沉淀滤液，并用冰无水乙醚洗涤沉淀物3次，最后将沉淀物放真空干燥釜中，常温干燥24小试，得到粗品H2N-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-COOH。结构图见产品结构图。

切割液选择：1）TFA：H2O=95%：5%、TFA：H2O=97.5%：2.5%

2）TFA：H2O：TIS=95%：2.5%：2.5%

3）三氟乙酸：茴香硫醚：1，2-乙二硫醇：苯酚：水=87.5%：5%：2.5%：2.5%：2.5%

（前两种适合没有容易氧化的氨基酸，例如Trp、Cys、Met。第三种适合几乎所有的序列。）

6、纯化冻干：使用液相色谱纯化，收集目标峰液体，进行冻干，获得蓬松的粉末状固体多肽。不过这时要取小样复测下纯度 是否目标纯度。

7、最后总结：

杭州专肽生物技术有限公司（ALLPEPTIDE https://www.allpeptide.com）主营定制多肽合成业务，提供各类长肽，短肽，环肽，提供各类修饰肽，如：荧光标记修饰（CY3、CY5、CY5.5、CY7、FAM、FITC、Rhodamine B、TAMRA等），功能基团修饰肽（叠氮、炔基、DBCO、DOTA、NOTA等），同位素标记肽（N15、C13），订书肽（Stapled Peptide）,脂肪酸修饰肽（Pal、Myr、Ste），磷酸化修饰肽（P-Ser、P-Thr、P-Tyr），环肽（酰胺键环肽、一对或者多对二硫键环），生物素标记肽，PEG修饰肽，甲基化修饰肽

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