Teprotide

Last updated
Teprotide
Teprotide.svg
Names
IUPAC name
5-oxo-L-prolyl-L-tryptophyl-L-prolyl-N5-(diaminomethylidene)-L-ornithyl-L-prolyl-L-glutaminyl-L-isoleucyl-L-prolyl-L-proline
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
PubChem CID
UNII
  • InChI=1S/C53H76N14O12/c1-3-29(2)43(51(77)66-25-9-16-39(66)50(76)67-26-10-17-40(67)52(78)79)63-45(71)34(18-20-41(54)68)60-46(72)37-14-7-23-64(37)48(74)35(13-6-22-57-53(55)56)61-47(73)38-15-8-24-65(38)49(75)36(62-44(70)33-19-21-42(69)59-33)27-30-28-58-32-12-5-4-11-31(30)32/h4-5,11-12,28-29,33-40,43,58H,3,6-10,13-27H2,1-2H3,(H2,54,68)(H,59,69)(H,60,72)(H,61,73)(H,62,70)(H,63,71)(H,78,79)(H4,55,56,57)/t29-,33-,34-,35-,36-,37-,38-,39-,40-,43-/m0/s1 Yes check.svgY
    Key: UUUHXMGGBIUAPW-CSCXCSGISA-N Yes check.svgY
  • InChI=1S/C53H76N14O12/c1-3-29(2)43(51(77)66-25-9-16-39(66)50(76)67-26-10-17-40(67)52(78)79)63-45(71)34(18-20-41(54)68)60-46(72)37-14-7-23-64(37)48(74)35(13-6-22-57-53(55)56)61-47(73)38-15-8-24-65(38)49(75)36(62-44(70)33-19-21-42(69)59-33)27-30-28-58-32-12-5-4-11-31(30)32/h4-5,11-12,28-29,33-40,43,58H,3,6-10,13-27H2,1-2H3,(H2,54,68)(H,59,69)(H,60,72)(H,61,73)(H,62,70)(H,63,71)(H,78,79)(H4,55,56,57)/t29-,33-,34-,35-,36-,37-,38-,39-,40-,43-/m0/s1
  • O=C(O)[C@H]7N(C(=O)[C@H]6N(C(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]5N(C(=O)[C@@H](NC(=O)[C@H]4N(C(=O)[C@@H](NC(=O)[C@H]1NC(=O)CC1)Cc3c2ccccc2[nH]c3)CCC4)CCC/N=C(\N)N)CCC5)CCC(=O)N)[C@@H](C)CC)CCC6)CCC7
Properties
C53H76N14O12
Molar mass 1101.257
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Teprotide is nonapeptide which has been isolated from the snake Bothrops jararaca . It is an angiotensin converting enzyme inhibitor (ACE inhibitor) which inhibits the conversion of angiotensin I to angiotensin II and may potentiate some of the pharmacological actions of bradykinin. It has a molecular formula of C53H76N14O12 and has been investigated as an antihypertension agent.

Contents

Isolation and synthesis

The antihypertensive effects of teprotide were first observed by Sergio Ferreira in 1965 [1] and it was first isolated by Ferreira et al. [2] along with eight other peptides in 1970. Teprotide was synthesized in 1970 by Ondetti et al. [3] and from there its antihypertensive properties were studied more closely.

Medical use

Teprotide was chosen as a lead because of its long-lasting in vivo activity. This was demonstrated by Bianchi et al. [4] by administering teprotide to dogs and rats and observing that it inhibited the vasopressor response induced by angiotensin I. Teprotide was shown to be an effective antihyperension agent but it had limited use because of its expense and lack of oral activity. It was found that teprotide inhibits the enzyme that converts angiotensin I to angiotensin II. From this researchers conducted structure-activity studies which allowed them to identify the active binding site of the ACE which allowed for the development of antihypertension drugs to be developed. Captopril was the first antihypertension drug developed by Ondetti and Cushman. [5] Many ACE inhibitors have been developed since this time but this was the start of them.

Related Research Articles

ACE inhibitor Class of medications used primarily to treat high blood pressure

Angiotensin-converting-enzyme inhibitors are a class of medication used primarily for the treatment of high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease in blood volume, which leads to lower blood pressure and decreased oxygen demand from the heart.

Renin–angiotensin system Hormone system

The renin–angiotensin system (RAS), or renin–angiotensin–aldosterone system (RAAS), is a hormone system that regulates blood pressure, fluid and electrolyte balance, and systemic vascular resistance.

Bradykinin Chemical compound

Bradykinin (BK) is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor and makes veins constrict, via prostaglandin F2, thereby leading to leakage into capillary beds, due to the increased pressure in the capillaries. Bradykinin is a physiologically and pharmacologically active peptide of the kinin group of proteins, consisting of nine amino acids.

Captopril Chemical compound

Captopril, sold under the brand name Capoten among others, is an angiotensin-converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first oral ACE inhibitor found for the treatment of hypertension. It does not cause fatigue as associated with beta-blockers. Due to the adverse drug event of causing hyperkalemia, as seen with most ACE Inhibitors, the medication is usually paired with a diuretic.

Angiotensin-converting enzyme Mammalian protein found in Homo sapiens

Angiotensin-converting enzyme, or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasoconstrictor angiotensin II. Therefore, ACE indirectly increases blood pressure by causing blood vessels to constrict. ACE inhibitors are widely used as pharmaceutical drugs for treatment of cardiovascular diseases.

Lisinopril Medication used to treat high blood pressure and heart failure

Lisinopril is a medication of the angiotensin-converting enzyme (ACE) inhibitor and is used to treat high blood pressure, heart failure, and after heart attacks. For high blood pressure it is usually a first-line treatment. It is also used to prevent kidney problems in people with diabetes mellitus. Lisinopril is taken by mouth. Full effect may take up to four weeks to occur.

Maurício Oscar da Rocha e Silva was a Brazilian physician, biomedical scientist and pharmacologist. He discovered bradykinin, an endogenous polypeptide involved in the physiology, pharmacology and pathology of blood pressure control and many other phenomena related to the contraction of smooth muscles.

Sérgio Henrique Ferreira was a Brazilian physician and pharmacologist noted for the discovery of the bradykinin potentiating factor, which led to new and widely used anti-hypertension drugs — the ACE inhibitors.

Gastão Rosenfeld, was a Brazilian physician and biomedical scientist, one of the co-discoverers of bradykinin, together with Maurício Rocha e Silva and Wilson Teixeira Beraldo, in 1949.

Miguel Angel Ondetti was an Argentine-born American chemist who first synthesized captopril, the first ACE inhibitor that was used to treat heart disease. With his co-worker, David Cushman, he won the 1999 Lasker Award for: "developing an innovative approach to drug design based on protein structure and using it to create the ACE inhibitors, powerful oral agents for the treatment of high blood pressure, heart failure, and diabetic kidney disease".

The bradykinin receptor family is a group of G-protein coupled receptors whose principal ligand is the protein bradykinin.

<i>Bothrops jararaca</i> Species of snake

Bothrops jararaca — known as the jararaca or yarara — is a highly venomous pit viper species endemic to South America in southern Brazil, Paraguay, and northern Argentina. The specific name, jararaca, is derived from the Tupi words yarará and ca, which mean "large snake". Within its geographic range, it is often abundant and is an important cause of snakebite. No subspecies are currently recognized.

David Cushman was born in Indianapolis, Indiana. He was the son of Wayne B. and Mildred M. and married to Linda L. Kranch. They have two children together named Michael and Laura Cushman. Dr. Cushman was an American chemist who co-invented captopril, the first of the ACE inhibitors used in the treatment of cardiovascular disease. With Miguel A. Ondetti, he won the 1999 Lasker Award for: "developing an innovative approach to drug design based on protein structure and using it to create the ACE inhibitors, powerful oral agents for the treatment of high blood pressure, heart failure, and diabetic kidney disease."

Omapatrilat

Omapatrilat is an experimental antihypertensive agent that was never marketed. It inhibits both neprilysin and angiotensin-converting enzyme (ACE). NEP inhibition results in elevated natriuretic peptide levels, promoting natriuresis, diuresis, vasodilation, and reductions in preload and ventricular remodeling.

Lewis Joel Greene is an American Brazilian biochemist, scientist, university professor and editor of the Brazilian Journal of Medical and Biological Research.

Bradykinin receptor B<sub>2</sub> Protein-coding gene in the species Homo sapiens

Bradykinin receptor B2 is a G-protein coupled receptor for bradykinin, encoded by the BDKRB2 gene in humans.

The discovery of an orally inactive peptide from snake venom established the important role of angiotensin converting enzyme (ACE) inhibitors in regulating blood pressure. This led to the development of Captopril, the first ACE inhibitor. When the adverse effects of Captopril became apparent new derivates were designed. Then after the discovery of two active sites of ACE: N-domain and C-domain, the development of domain-specific ACE inhibitors began.

Moexipril

Moexipril an angiotensin converting enzyme inhibitor used for the treatment of hypertension and congestive heart failure. Moexipril can be administered alone or with other antihypertensives or diuretics.

Sacubitril Chemical compound

Sacubitril is an antihypertensive drug used in combination with valsartan. The combination drug sacubitril/valsartan, known during trials as LCZ696 and marketed under the brand name Entresto, is a treatment for heart failure. It was approved under the FDA's priority review process for use in heart failure on July 7, 2015.

Venom in medicine is the medicinal use of venoms for therapeutic benefit in treating diseases.

References

  1. Ferreira, Sergio (February 1965). "A bradykinin-potentiating factor (bpf) present in the venom of bothrops jararaca". British Journal of Pharmacology. 24: 169–169. doi:10.1111/j.1476-5381.1965.tb02091.x. PMC   1704050 . PMID   14302350.
  2. Ferreira, Sergio H.; Diana C. Bartelt; Lewis J. Greene (June 1970). "Isolation of bradykinin-potentiating peptides from Bothrops jararaca venom". Biochemistry. 9 (13): 2583–2593. doi:10.1021/bi00815a005. PMID   4317874.
  3. Ondetti, Miguel A.; Nina J. Wiliams; Emily F. Sabo; Josip Pluscec; Eugene R. Weaver; Octavian Kocy (October 1971). "Angiotensin-converting enzyme inhibitors from the venom of bothrops jararaca. Isolation, elucidation of structure, and synthesis". Biochemistry. 10 (22): 4033–4039. doi:10.1021/bi00798a004. PMID   4334402.
  4. Bianchi, A.; D.B. Evans; M. Cobb; M.T. Peschka; T.R. Schaeffer; R.J. Laffan (July 1973). "Inhibition by SQ 20881 of vasopressor response to angiotensin I in conscious animals". European Journal of Pharmacology. 23 (2): 90–96. doi:10.1016/0014-2999(73)90248-3. PMID   4354808.
  5. Cushman, D.W.; M.A. Ondetti (April 1991). "History of the design of captopril and related inhibitors of angiotensin converting enzyme". Hypertension. 17 (4): 589–592. doi: 10.1161/01.hyp.17.4.589 . PMID   2013486.