| Synthesis, modification and reduction of primary structure of hypotensive peptides present in scorpion venom for optimizing their use as a hypotensive medicament -> Monitor Keywords |
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  Synthesis, modification and reduction of primary structure of hypotensive peptides present in scorpion venom for optimizing their use as a hypotensive medicamentUSPTO Application #: 20070275901Title: Synthesis, modification and reduction of primary structure of hypotensive peptides present in scorpion venom for optimizing their use as a hypotensive medicament Abstract: The present invention relates to synthetic and recombinant peptide primary structures including an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 12, wherein the primary structure includes an +aa-Pro-Pro amino acid in which “+aa” is Lys, Arg, His or a modified amino acid having a positive charge at physiological pH. The present invention also relates to a pharmaceutical composition including at least one peptide having a primary structure as defined above. (end of abstract) Agent: Caesar, Rivise, Bernstein, Cohen & Pokotilow, Ltd. - Philadelphia, PA, US Inventors: Maria Elena de Lima PEREZ-GARCIA, Carlos Ribeiro DINIZ, Maria da Conceicao Vasconcellos Ribeiro Diniz, Robson Augusto Souza DOS SANTOS, Pierre Edouard BOUGIS, Marie France EAUCLAIRE, Adriano Monteiro de Castro PIMENTA, Thiago Verano BRAGA USPTO Applicaton #: 20070275901 - Class: 514015000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 9 To 11 Peptide Repeating Units In Known Peptide Chain The Patent Description & Claims data below is from USPTO Patent Application 20070275901. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] The present invention relates to the synthesis, modification and reduction of the primary structure of arterial hypotension inducing peptides (hypotensive peptides) named Tityus serrulatus Hypotensins I to IV found in yellow scorpion Tityus serrulatus. BACKGROUND OF THE INVENTION [0002] Hypertension is an important challenge for the international public health authorities due to its high occurrence in modern society, in addition to the cardiovascular and renal risks derived therefrom. It is estimated that approximately 26% of the world population, that is, 972 million people suffered from hypertension in year 2000. [0003] Blood pressure, or arterial pressure, is measured as systolic (pressure of the blood in the arteries when the ventricular systoles occurs) and diastolic (when diastole occurs). According to World Health Organization (WHO) the optimal blood pressure is less than 120 systolic and 80 diastolic (120/80 mmHg). High blood pressure, or hypertension, is considered to be a pressure greater than or equal to 140/90 mmHg and "high normal" blood pressure is between 130/85 and 140/90 mmHg (Bulletin of the World Health Organization, 1999). [0004] Hypertension may be classified as primary and secondary. Primary or essential hypertension does not have a specific cause, being the most common form of hypertension and being presented by 95% of the patients. Genetic factors seem to be one of the major causes of this kind of hypertension. [0005] The causes of secondary hypertension are known and pregnancy, cirrhosis and renal disorders may contribute for a temporary hypertensive condition. Some medicaments such as cortisone and estrogen may also temporarily increase the blood pressure. Prolonged use of anti-inflammatory drugs (NSAIDs) such as aspirin may cause renal disorders and can also affect the treatment of individuals suffering from hypertension who make use of anti-hypertensive drugs such as .beta.-blockers and diuretics. It is known that cocaine causes acute hypertension conditions although apparently it does not cause a chronic condition. A study shows that about 10% of the cases related to hypertension are caused by the abuse of alcohol ingestion. Caffeine causes a temporary increase of blood pressure. However, studies show that its regular consumption increases the risks of heart diseases in health individuals. The dangers associated with caffeine, however, cannot be compared to smoking, which may increase the risk of death by cardiomyopathy and hypertension. Blood pressure may also temporarily increase due to stress or physical activities. [0006] At the present time, five classes of drugs are recognized as efficient for hypertensive treatment: diuretics, alpha-blockers, beta-blockers, angiotensin converting enzyme (ACE) inhibitors, calcium antagonists, and angiotensin II antagonists. [0007] Diuretics cause the body to excrete water and salt, thus decreasing the blood plasma volume and, consequently, decreasing the blood pressure. ACE inhibitors reduce the production of angiotensin-II and reduce the degradation of bradykinin. Beta-blockers inhibit the increase of the heart rate caused by the exciting effect of noradrenaline. Vasodilators expand blood vessels and calcium channel blockers help decrease the contractions of the heart. [0008] All drugs used for hypertension have side effects and, therefore, there is still a need for novel anti-hypertensive drug classes. [0009] The use of peptides as active ingredients for medicaments is a promising application of biotechnology. The major advantages rely on the selectivity and affinity of those molecules, as well as on the possible decrease of side effects and toxicity that result from chemical intermediates and/or metabolites. There are, on the other hand, important drawbacks that must be overcome for using those molecules such as their size that has influence on their absorption and distribution, as well as the resistance thereof against enzymatic hydrolysis and degradation in vivo. [0010] Presently known anti-hypertensive peptides are isolated from animal venoms and have a primary structure comprising from 5 to 13 amino acid residues. Such peptides have anti-hypertensive activity based on the inhibition of angiotensin converting enzyme (ACE) that prevents the hydrolysis of bradykinin (a hypotensive agent) and the synthesis of angiotensin-II (a hypertensive agent), thereby acting as anti-hypertensive peptides. [0011] Scorpion Hypotensive Peptides (SHptP) named TsHpt-I, TsHpt-II, TsHpt-III and TsHpt-IV, which are disclosed in patent application U.S. Ser. No. 10/517,097 refer to novel anti-hypertensive peptides found in animal origin venom. They i) consist of 24 to 25 amino acid residues, not crosslinked by disulfide bridges (absence of cysteine) and having molecular weights in the range of 2500 to 3000 Da; ii) have a molecular signature with amino acid residues Pro-Pro or Pro-Pro-Ala in their carboxy-terminal ends; and iii) induce a potent, long and sustained arterial hypotension, with one of the action mechanisms thought to be the potentialization of bradykinin occurring independently from the inhibition of the angiotensin converting enzyme. SUMMARY OF THE INVENTION [0012] The present invention relates to synthetic peptide primary structures comprising an amino acid sequence selected from the group of SEQ ID NOs:1 to 12, wherein said primary structure comprises an +aa-Pro-Pro amino acid in which "+aa" is Lys, Arg, His or any other modified amino acid that has a positive charge at physiological pH. [0013] In another embodiment, the present invention also relates to a recombinant peptide primary structure as defined above prepared by recombinant techniques in heterologous expression systems such as viral systems, bacterial systems, fungal systems or in any other expression systems in eukaryotic or prokaryotic cells, or combinations thereof. [0014] Still in accordance with another embodiment the present invention relates to a pharmaceutical composition comprising at least one peptide having a primary structure as defined above. [0015] The present invention also relates to a method for treating hypertension, comprising administering to an animal at least one peptide of the invention. BRIEF DESCRIPTION OF THE DRAWINGS [0016] The invention will be described in conjunction with the following drawings wherein: [0017] FIG. 1.1 is a graph showing the effect on blood pressure of the injection in bolus (i.v.) of TsHpt-I (35 .mu.g/Kg) (grey bar), the injection in bolus (i.v.) of 1 .mu.g of bradykinin (BK) (black bars), and 2 .mu.g of BK (white bar) (n=5; *P<0.05); [0018] FIG. 1.2 is a graph showing the effect on blood pressure of the injection in bolus (i.v.) of TsHpt.sub.17-25 (37 .mu.g/Kg) (grey bar), the injection in bolus (i.v.) of 1 .mu.g of BK (black bars) and 2 .mu.g of BK (white bar) (n=5; *P<0.05); [0019] FIG. 1.3 is a graph showing the effect on blood pressure of the injection in bolus (i.v.) of TsHpt.sub.ac17-25am peptide with a N-terminal acetylation and C-terminal amidation (43 .mu.g/Kg) (grey bar), the injection in bolus (i.v.) of 1 .mu.g of BK (black bars) and 2 .mu.g of BK (white bar) (n=4; *P<0.05); [0020] FIG. 1.4 is a graph showing the effect on blood pressure of the injection in bolus (i.v.) of TsHpt.sub.22-25 (37 .mu.g/Kg) (grey bar), the injection in bolus (i.v.) of 1 .mu.g of BK (black bars) and 2 .mu.g of BK (white bar) (n=4; *P<0.05); Continue reading... 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