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        1. 浙江省科技型企業---加速您的多肽研究
          首頁 >多肽產品 >線粒體靶向抗氧化劑SS-31:DArg-Dmt-Lys-Phe-NH2/依拉瑞肽/MTP-131

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          736992-21-5\1606994-55-1\線粒體靶向抗氧化劑SS-31\H2N-D-Arg-Dmt-Lys-Phe-NH2\依拉瑞肽\Elamipretide\MTP-131,杭州專肽生物的產品

          線粒體靶向抗氧化劑SS-31:DArg-Dmt-Lys-Phe-NH2/依拉瑞肽/MTP-131

          SS-31肽是一種心磷脂過氧化物酶抑制劑和線粒體靶向肽。它可以改善左心室和線粒體功能。SS-31肽可減輕人小梁網狀細胞中的線粒體功能障礙和氧化損傷。它可以防止iHTM和GTM(3)細胞受到H2O2誘導的持續氧化應激。治療慢性心力衰竭和線粒體肌病的II期臨床試驗正在進行中。

          編號:144820

          CAS號:736992-21-5/1606994-55-1/1849610-71-4

          單字母:H2N-r-Dmt-KF-NH2

          糾錯
          • 編號:144820
            中文名稱:線粒體靶向抗氧化劑SS-31:DArg-Dmt-Lys-Phe-NH2/依拉瑞肽/MTP-131
            英文名:Elamipretide
            英文同義詞:MTP-131
            CAS號:736992-21-5,醋酸體鹽
            1606994-55-1,TFA鹽
            1849610-71-4,3醋酸分子
            單字母:H2N-r-Dmt-KF-NH2
            三字母:H2N

            N端氨基

            -DArg

            D型精氨酸

            -Dmt

            2,6-二甲基酪氨酸

            -Lys

            賴氨酸

            -Phe

            苯丙氨酸

            -NH2

            C端酰胺化

            氨基酸個數:4
            分子式:C32H49N9O5
            平均分子量:639.79
            精確分子量:639.39
            等電點(PI):-
            pH=7.0時的凈電荷數:2.97
            平均親水性:1.1666666666667
            疏水性值:-1.87
            外觀與性狀:白色粉末狀固體
            消光系數:-
            來源:人工化學合成,僅限科學研究使用,不得用于人體。
            純度:98%
            生成周期:現貨
            儲存條件:負80℃至負20℃
            標簽:氨基酸衍生物肽    靶向多肽    D型氨基酸肽    抑制劑相關肽(Inhibitor Peptide)    現貨多肽   

            InChI:(2R)-5-amino-2-[[2-[[(2S)-6-amino-2-[[(2R)-4-amino-2-[[(2R)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-3-methylbutanoyl]pyrrolidine-2-carbonyl]amino]-3-methylpentanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]-4-carboxybutanoyl]amino]-4-methylpentanoyl]amino]-5-oxopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-4-methylpentanoyl]amino]-5-oxopentanoyl]amino]-4-carboxybutanoyl]amino]hexanoyl]amino]-4-carboxybutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-4-oxobutanoyl]amino]hexanoyl]amino]acetyl]amino]-5-oxopentanoic acid
            IUPAC Name:H-Phe-Val-Pro-Ile-Phe-Thr-Tyr-Gly-Glu-Leu-Gln-Arg-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Lys-Gly-Gln-OH; L-phenylalanyl-L-valyl-L-prolyl-L-isoleucyl-L-phenylalanyl-L-threonyl-L-tyrosyl-glycyl-L-alpha-glutamyl-L-leucyl-L-glutaminyl-L-arginyl-L-leucyl-L-glutaminyl-L-alpha-glutamyl-L-lysyl-L-alpha-glutamyl-D-arginyl-D-asparagyl-L-lysyl-glycyl-D-glutamine; Motilin (swine), 13-L-leucine-
          • SS-31肽是一種心磷脂過氧化物酶抑制劑和線粒體靶向肽。它可以改善左心室和線粒體功能。SS-31肽可減輕人小梁網狀細胞中的線粒體功能障礙和氧化損傷。它可以防止iHTM和GTM(3)細胞受到H2O2誘導的持續氧化應激。治療慢性心力衰竭和線粒體肌病的II期臨床試驗正在進行中。
            H-Dmt-D-Arg-Phe-Lys-NH2 (Dmt:2,6-dimethyl-L-tyrosine) 是衍生與皮啡肽的阿片肽,它具有很強的鎮痛作用和良好的細胞膜通過能力,在對其進行深入的機制研究后發現了線粒體靶向抗氧化肽SS-31 (H-D-Arg-Dmt-Lys-Phe-NH2). SS-31對缺血再灌注損傷、神經退行性疾病、心力衰竭、肌肉老化等和自由基有關的疾病具有治療效果。SS-31 是一種針對線粒體的分子。它與心磷脂相互作用以重新激活缺血線粒體。同時SS-31也是一種細胞穿膜肽。

            依拉瑞肽(MTP-131;D-Arg-DMT-Lys-Phe-NH2;其中DMT是2,6-二甲基-L-Tyr)是具有治療缺血-再灌注損傷(例如,心臟缺血-再灌注損傷)和心肌梗塞的治療潛力的線粒體靶向化合物。這種化合物的類似物可具有改善的治療特征譜,包括改善的代謝性質、選擇性或效力。

            Elamipretide是一條由四個氨基酸組成的小分子多肽,在生物體內Elamipretide以線粒體內膜為靶點,能夠預防神經細胞和其他細胞類型的氧化損傷;防止線粒體去極化,減少胰島細胞凋亡,增加胰島細胞產量,改善移植后功能。以Elamipretide為主要原料的藥物已經進入臨床三期。

            Elamidetide is a small peptide composed of four amino acids, including one unnatural amino acid. In vivo, elamipretide can prevent oxidative damage of nerve cells and other cell types by targeting mitochondrial inner membrane, prevent mitochondrial depolarization, reduce apoptosis of islet cells, increase islet cell production, and improve the function after transplantation. The drugs with elamipretide as the main raw material have entered the third phase of clinical practice.

            Elamipretide triacetate是一種芳香陽離子四肽,靶向線粒體內膜,是心磷脂過氧化物酶的抑制劑。它很容易穿透細胞膜,并已用于研究Leber遺傳性視神經病變的治療試驗。

            Elamipretide triacetate is an aromatic-cationic tetrapeptide that targets the mitochondrial intima and is an inhibitor of cardiolipin peroxidase. It easily penetrates cell membranes and has been used in therapeutic trials investigating Leber's Hereditary Optic Neuropathy.

            靶向多肽可以根據其功能和用途分為不同的類別。在PDC(多肽偶聯藥物)中,靶向多肽通常被分為細胞穿透肽和細胞靶向肽兩大類。

            細胞穿透肽:這類多肽能夠跨越細胞膜,轉運具有生物活性的大分子物質,如多肽、蛋白質、核酸等化學藥物,使其順利進入細胞。一些常見的細胞穿透肽包括Pep-1、Pentratin、PepFact14、Transportan等。

            細胞靶向肽:這類多肽的作用主要是引導化學藥物或生物活性分子與特定類型的細胞結合,以提高其靶向性和治療效率。常見的細胞靶向肽包括PEGA、生長激素抑制素類似物、蛙皮素類似物、RGD肽類等。

            很多蛋白在細胞中非常容易被降解,或被標記,進而被選擇性地破壞。但含有部分D型氨基酸的多肽則顯示了很強的抵抗蛋白酶降解能力。

            定義
            酶是用于生化反應的非常有效的催化劑。它們通過提供較低活化能的替代反應途徑來加快反應速度。酶作用于底物并產生產物。一些物質降低或什至停止酶的催化活性被稱為抑制劑。
            發現
            1965年,Umezawa H分析了微生物產生的酶抑制劑,并分離出了抑制亮肽素和抗痛藥的胰蛋白酶和木瓜蛋白酶,乳糜蛋白酶抑制的胰凝乳蛋白酶,胃蛋白酶抑制素抑制胃蛋白酶,泛磷酰胺抑制唾液酸酶,烏藤酮抑制酪氨酸羥化酶,多巴汀抑制多巴胺3-羥硫基嘧啶和多巴胺3-羥色胺酶酪氨酸羥化酶和多巴胺J3-羥化酶。最近,一種替代方法已應用于預測新的抑制劑:合理的藥物設計使用酶活性位點的三維結構來預測哪些分子可能是抑制劑1。已經開發了用于識別酶抑制劑的基于計算機的方法,例如分子力學和分子對接。
            結構特征
            已經確定了許多抑制劑的晶體結構。已經確定了三種與凝血酶復合的高效且選擇性的低分子量剛性肽醛醛抑制劑的晶體結構。這三種抑制劑全部在P3位置具有一個新的內酰胺部分,而對胰蛋白酶選擇性最高的兩種抑制劑在P1位置具有一個與S1特異性位點結合的胍基哌啶基。凝血酶的抑制動力學從慢到快變化,而對于胰蛋白酶,抑制的動力學在所有情況下都快。根據兩步機理2中穩定過渡態絡合物的緩慢形成來檢驗動力學。
            埃米爾•菲舍爾(Emil Fischer)在1894年提出,酶和底物都具有特定的互補幾何形狀,彼此恰好契合。這稱為“鎖和鑰匙”模型3。丹尼爾·科什蘭(Daniel Koshland)提出了誘導擬合模型,其中底物和酶是相當靈活的結構,當底物與酶4相互作用時,活性位點通過與底物的相互作用不斷重塑。
            在眾多生物活性肽的成熟過程中,需要由其谷氨酰胺(或谷氨酰胺)前體形成N末端焦谷氨酸(pGlu)。游離形式并與底物和三種咪唑衍生抑制劑結合的人QC的結構揭示了類似于兩個鋅外肽酶的α/β支架,但有多個插入和缺失,特別是在活性位點區域。幾種活性位點突變酶的結構分析為針對QC相關疾病5的抑制劑的合理設計提供了結構基礎。
            作用方式
            酶是催化化學反應的蛋白質。酶與底物相互作用并將其轉化為產物。抑制劑的結合可以阻止底物進入酶的活性位點和/或阻止酶催化其反應。抑制劑的種類繁多,包括:非特異性,不可逆,可逆-競爭性和非競爭性??赡嬉种苿?nbsp;以非共價相互作用(例如疏水相互作用,氫鍵和離子鍵)與酶結合。非特異性抑制方法包括最終使酶的蛋白質部分變性并因此不可逆的任何物理或化學變化。特定抑制劑 對單一酶發揮作用。大多數毒藥通過特異性抑制酶發揮作用。競爭性抑制劑是任何與底物的化學結構和分子幾何結構非常相似的化合物。抑制劑可以在活性位點與酶相互作用,但是沒有反應發生。非競爭性抑制劑是與酶相互作用但通常不在活性位點相互作用的物質。非競爭性抑制劑的凈作用是改變酶的形狀,從而改變活性位點,從而使底物不再能與酶相互作用而產生反應。非競爭性抑制劑通常是可逆的。不可逆抑制劑與酶形成牢固的共價鍵。這些抑制劑可以在活性位點附近或附近起作用。
            功能
            工業應用中, 酶在商業上被廣泛使用,例如在洗滌劑,食品和釀造工業中。蛋白酶用于“生物”洗衣粉中,以加速蛋白質在諸如血液和雞蛋等污漬中的分解。商業上使用酶的問題包括:它們是水溶性的,這使得它們難以回收,并且一些產物可以抑制酶的活性(反饋抑制)。
            藥物分子,許多藥物分子都是酶抑制劑,藥用酶抑制劑通常以其特異性和效力為特征。高度的特異性和效力表明該藥物具有較少的副作用和較低的毒性。酶抑制劑在自然界中發現,并且也作為藥理學和生物化學的一部分進行設計和生產6。
            天然毒物 通常是酶抑制劑,已進化為保護植物或動物免受天敵的侵害。這些天然毒素包括一些已知最劇毒的化合物。
            神經氣體( 例如二異丙基氟磷酸酯(DFP))通過與絲氨酸的羥基反應生成酯,從而抑制了乙酰膽堿酯酶的活性位點。
            參考
            1、Scapin G (2006). Structural biology and drug discovery. Curr. Pharm. Des.,      12(17):2087–2097.
            2、Krishnan R, Zhang E, Hakansson K, Arni RK, Tulinsky A, Lim-Wilby MS, Levy OE, Semple JE, Brunck TK (1998). Highly selective mechanism-based thrombin inhibitors:  structures of thrombin and trypsin inhibited with rigid peptidyl aldehydes. Biochemistry, 37 (35):12094-12103.
            3、Fischer E (1894). Einfluss der configuration auf die wirkung der enzyme. Ber. Dt. Chem. Ges., 27:2985–2993.
            4、Koshland DE (1958). Application of a theory of enzyme specificity to protein synthesis. PNAS., 44 (2):98–104.
            5、Huang KF, Liu YL, Cheng WJ, Ko TP, Wang AH (2005). Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation. PNAS., 102(37):13117-13122.
            6、Holmes CF, Maynes JT, Perreault KR, Dawson JF, James MN (2002). Molecular enzymology underlying regulation of protein phosphatase-1 by natural toxins. Curr Med Chem., 9(22):1981-1989.

             

            Definition
            Enzymes are very efficient catalysts for biochemical reactions. They speed up reactions by providing an alternative reaction pathway of lower activation energy. Enzyme acts on substrate and gives rise to a product. Some substances reduce or even stop the catalytic activities of enzymes are called inhibitors.

            Discovery
            In 1965, Umezawa H analysed enzyme inhibitors produced by microorganisms and isolated leupeptin and antipain inhibiting trypsin and papain, chymostatin inhibiting chymotrypsin, pepstatin inhibiting pepsin, panosialin inhibiting sialidases, oudenone inhibiting tyrosine hydroxylase, dopastin inhibiting dopamine 3-hydroxylase, aquayamycin and chrothiomycin inhibiting tyrosine hydroxylase and dopamine J3-hydroxylase . Recently, an alternative approach has been applied to predict new inhibitors: rational drug design uses the three-dimensional structure of an enzyme's active site to predict which molecules might be inhibitors 1. Computer-based methods for identifying inhibitor for an enzyme have been developed, such as molecular mechanics and molecular docking.

            Structural Characteristics
            The crystal structures of many inhibitors have been determined. The crystal structures of three highly potent and selective low-molecular weight rigid peptidyl aldehyde inhibitors complexed with thrombin have been determined. All the three inhibitors have a novel lactam moiety at the P3 position, while the two with greatest trypsin selectivity have a guanidinopiperidyl group at the P1 position that binds in the S1 specificity site. The kinetics of inhibition vary from slow to fast with thrombin and are fast in all cases with trypsin. The kinetics are examined in terms of the slow formation of a stable transition-state complex in a two-step mechanism 2.

            Emil Fischer in 1894 suggested that both the enzyme and the substrate possess specific complementary geometric shapes that fit exactly into one another.This is known as "the lock and key" model 3. Daniel Koshland suggested induced fit model where substrate and enzymes are rather flexible structures, the active site is continually reshaped by interactions with the substrate as the substrate interacts with the enzyme 4.

            N-terminal pyroglutamate (pGlu) formation from its glutaminyl (or glutamyl) precursor is required in the maturation of numerous bioactive peptides. The structure of human QC in free form and bound to a substrate and three imidazole-derived inhibitors reveals an alpha/beta scaffold akin to that of two-zinc exopeptidases but with several insertions and deletions, particularly in the active-site region. The structural analyses of several active-site-mutant enzymes provide a structural basis for the rational design of inhibitors against QC-associated disorders 5.

            Mode of Action
            Enzymes are proteins that catalyze chemical reactions. Enzymes interact with substrate and convert them into products. Inhibitor binding can stop a substrate from entering the enzyme's active site and/or hinder the enzyme from catalyzing its reaction. There are a variety of types of inhibitors including: nonspecific, irreversible, reversible - competitive and noncompetitive. Reversible inhibitors bind to enzymes with non-covalent interactions like hydrophobic interactions, hydrogen bonds, and ionic bonds. Non-specific methods of inhibition include any physical or chemical changes which ultimately denature the protein portion of the enzyme and are therefore irreversible. Specific Inhibitors exert their effects upon a single enzyme. Most poisons work by specific inhibition of enzymes. A competitive inhibitor is any compound which closely resembles the chemical structure and molecular geometry of the substrate. The inhibitor may interact with the enzyme at the active site, but no reaction takes place. A noncompetitive inhibitor is a substance that interacts with the enzyme, but usually not at the active site.  The net effect of a non competitive inhibitor is to change the shape of the enzyme and thus the active site, so that the substrate can no longer interact with the enzyme to give a reaction. Non competitive inhibitors are usually reversible. Irreversible Inhibitors form strong covalent bonds with an enzyme.  These inhibitors may act at, near, or remote from the active site .

            Functions
            Industrial application, enzymes are widely used commercially, for example in the detergent, food and brewing industries. Protease enzymes are used in 'biological' washing powders to speed up the breakdown of proteins in stains like blood and egg. Problems using enzymes commercially include: they are water soluble which makes them hard to recover and some products can inhibit the enzyme activity (feedback inhibition) .

            Drug molecules, many drug molecules are enzyme inhibitors and a medicinal enzyme inhibitor is usually characterized by its specificity and its potency. A high specificity and potency suggests that a drug will have fewer side effects and less toxic. Enzyme inhibitors are found in nature and are also designed and produced as part of pharmacology and biochemistry 6.

            Natural poisons are often enzyme inhibitors that have evolved to defend a plant or animal against predators. These natural toxins include some of the most poisonous compounds known.

            Nerve gases such as diisopropylfluorophosphate (DFP) inhibit the active site of acetylcholine esterase by reacting with the hydroxyl group of serine to make an ester.

            References

            Scapin G (2006). Structural biology and drug discovery. Curr. Pharm. Des.,      12(17):2087–2097.

            Krishnan R, Zhang E, Hakansson K, Arni RK, Tulinsky A, Lim-Wilby MS, Levy OE, Semple JE, Brunck TK (1998). Highly selective mechanism-based thrombin inhibitors:  structures of thrombin and trypsin inhibited with rigid peptidyl aldehydes. Biochemistry, 37 (35):12094-12103.

            Fischer E (1894). Einfluss der configuration auf die wirkung der enzyme. Ber. Dt. Chem. Ges., 27:2985–2993.

            Koshland DE (1958). Application of a theory of enzyme specificity to protein synthesis. PNAS., 44 (2):98–104.

            Huang KF, Liu YL, Cheng WJ, Ko TP, Wang AH (2005). Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation. PNAS., 102(37):13117-13122.

            Holmes CF, Maynes JT, Perreault KR, Dawson JF, James MN (2002). Molecular enzymology underlying regulation of protein phosphatase-1 by natural toxins. Curr Med Chem., 9(22):1981-1989.

          • DOI名稱
            10.1111/cbdd.12003Superior Analgesic Effect of H-Dmt-D-Arg-Phe-Lys-NH2 ([Dmt1]DALDA), a Multifunctional Opioid Peptide, Compared to Morphine in a Rat Model of Neuropathic Pain下載
            10.1111_1440-1681.13484SS-31 protect retinal pigment epithelial cells from H2O2- induced cell injury by reducing apoptosis下載
            10.1111_acel.13213SS-31 and NMN: Two paths to improve metabolism and function in aged hearts下載
            10.1111_acel.12731Treatment with the mitochondrial-targeted antioxidant peptide SS-31 rescues neurovascular coupling responses and cerebrovascular endothelial function and improves cognition in aged mice下載
            10.1111_bph.12468Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis下載
            10.1155/2022/1295509SS-31, a Mitochondria-Targeting Peptide, Ameliorates Kidney Disease下載
            10.1161/CIRCHEARTFAILURE.115.002206Chronic Therapy With Elamipretide (MTP-131), a Novel Mitochondria-Targeting Peptide, Improves Left Ventricular and Mitochondrial Function in Dogs With Advanced Heart Failure下載
          • 暫時沒有數據
          • 編號名稱CAS號
            432781Cys-SS-31
            H2N-Cr-Dmt-KF-NH2
            SS-31的N端添加半胱氨酸,引入巰基
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