Aprotinin

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Aprotinin
Aprotinin.png
Clinical data
Other namesTrasylol, bovine pancreatic trypsin inhibitor
AHFS/Drugs.com Monograph
Pregnancy
category
  • X
Dependence
liability 		None
Routes of
administration 		Intravenous
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 100% (intravenous)
Identifiers
  • Aprotinin
CAS Number
IUPHAR/BPS
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
ECHA InfoCard 100.029.983 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C284H432N84O79S7
Molar mass 6511.51 g·mol−1
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The drug aprotinin (Trasylol, previously Bayer and now Nordic Group pharmaceuticals), is a small protein bovine pancreatic trypsin inhibitor (BPTI), or basic trypsin inhibitor of bovine pancreas, which is an antifibrinolytic molecule that inhibits trypsin and related proteolytic enzymes. Under the trade name Trasylol, aprotinin was used as a medication administered by injection to reduce bleeding during complex surgery, such as heart and liver surgery. Its main effect is the slowing down of fibrinolysis, the process that leads to the breakdown of blood clots. The aim in its use was to decrease the need for blood transfusions during surgery, as well as end-organ damage due to hypotension (low blood pressure) as a result of marked blood loss. The drug was temporarily withdrawn worldwide in 2007 after studies suggested that its use increased the risk of complications or death; [1] this was confirmed by follow-up studies. Trasylol sales were suspended in May 2008, except for very restricted research use. In February 2012 the European Medicines Agency (EMA) scientific committee reverted its previous standpoint regarding aprotinin, and has recommended that the suspension be lifted. [2] Nordic became distributor of aprotinin in 2012. [3]

Contents

Chemistry

Bovine pancreatic trypsin inhibitor
BPTI seq ribbon sticks.jpg
BPTI sequence, with its folded 3D structure represented by a ribbon for the secondary structure and a stick model (gray) for the backbone and sidechains.
Identifiers
Organism Bos taurus (domestic cow)
SymbolPTI
Entrez 404172
PDB 4PTI More structures
RefSeq (mRNA) NM_001001554
RefSeq (Prot) NP_001001554
UniProt P00974
Other data
Chromosome 13: 75.02 - 75.03 Mb
Search for
Structures Swiss-model
Domains InterPro

Aprotinin is a monomeric (single-chain) globular polypeptide derived from bovine lung tissue. It has a molecular weight of 6512 Da and consists of 16 different amino acid types arranged in a chain 58 residues long [4] [5] that folds into a stable, compact tertiary structure of the 'small SS-rich" type, containing 3 disulfides, a twisted β-hairpin and a C-terminal α-helix. [6]

The amino acid sequence for bovine BPTI is RPDFC LEPPY TGPCK ARIIR YFYNA KAGLC QTFVY GGCRA KRNNF KSAED CMRTC GGA. [7] There are 10 positively charged lysine (K) and arginine (R) side chains and only 4 negative aspartate (D) and glutamates (E), making the protein strongly basic, which accounts for the basic in its name. (Because of the usual source organism, BPTI is sometimes referred to as bovine pancreatic trypsin inhibitor.)[ citation needed ]

The high stability of the molecule is due to the 3 disulfide bonds linking the 6 cysteine members of the chain (Cys5-Cys55, Cys14-Cys38 and Cys30-Cys51). [8] The long, basic lysine 15 side chain on the exposed loop (at top left in the image) binds very tightly in the specificity pocket at the active site of trypsin and inhibits its enzymatic action. BPTI is synthesized as a longer, precursor sequence, which folds up and then is cleaved into the mature sequence given above.[ citation needed ]

BPTI is the classic member of the protein family of Kunitz-type serine protease inhibitors. Its physiological functions include the protective inhibition of the major digestive enzyme trypsin when small amounts are produced, by cleavage of the trypsinogen precursor during storage in the pancreas.[ citation needed ]

Mechanism of drug action

Aprotinin is a competitive inhibitor of several serine proteases, specifically trypsin, chymotrypsin and plasmin at a concentration of about 125,000 IU/ml, and kallikrein at 300,000 IU/ml. [5] Its action on kallikrein leads to the inhibition of the formation of factor XIIa. As a result, both the intrinsic pathway of coagulation and fibrinolysis are inhibited. Its action on plasmin independently slows fibrinolysis. [4]

Drug efficacy

In cardiac surgery with a high risk of significant blood loss, aprotinin significantly reduced bleeding, mortality and hospital stay. [5] Beneficial effects were also reported in high-risk orthopedic surgery. [5] In liver transplantation, initial reports of benefit were overshadowed by concerns about toxicity. [9]

In a meta-analysis performed in 2004, transfusion requirements decreased by 39% in coronary artery bypass graft (CABG) surgery. [10] In orthopedic surgery, a decrease of blood transfusions was likewise confirmed. [11]

Drug safety

There have been concerns about the safety of aprotinin. [5] Anaphylaxis (a severe allergic reaction) occurs at a rate of 1:200 in first-time use, but serology (measuring antibodies against aprotinin in the blood) is not carried out in practice to predict anaphylaxis risk because the correct interpretation of these tests is difficult. [5]

Thrombosis, presumably from overactive inhibition of the fibrinolytic system, may occur at a higher rate, but until 2006 there was limited evidence for this association. [5] [10] Similarly, while biochemical measures of renal function were known to occasionally deteriorate, there was no evidence that this greatly influenced outcomes. [5] A study performed in cardiac surgery patients reported in 2006 showed that there was indeed a risk of acute renal failure, myocardial infarction and heart failure, as well as stroke and encephalopathy. [12] The study authors recommend older antifibrinolytics (such as tranexamic acid) in which these risks were not documented. [12] The same group updated their data in 2007 and demonstrated similar findings. [13]

In September 2006, Bayer A.G. was faulted by the FDA for not revealing during testimony the existence of a commissioned retrospective study of 67,000 patients, 30,000 of whom received aprotinin and the rest other anti-fibrinolytics. The study concluded aprotinin carried greater risks. The FDA was alerted to the study by one of the researchers involved. Although the FDA issued a statement of concern they did not change their recommendation that the drug may benefit certain subpopulations of patients. [14] In a Public Health Advisory Update dated October 3, 2006, the FDA recommended that "physicians consider limiting Trasylol use to those situations in which the clinical benefit of reduced blood loss is necessary to medical management and outweighs the potential risks" and carefully monitor patients. [15]

On October 25, 2007, the FDA issued a statement regarding the "Blood conservation using antifibrinolytics" (BART) randomized trial in a cardiac surgery population. The preliminary findings suggest that, compared to other antifibrinolytic drugs (epsilon-aminocaproic acid and tranexamic acid) aprotinin may increase the risk of death. [16] On October 29, 2006 the Food and Drug Administration issued a warning that aprotinin may have serious kidney and cardiovascular toxicity. The producer, Bayer, reported to the FDA that additional observation studies showed that it may increase the chance for death, serious kidney damage, congestive heart failure and strokes. FDA warned clinicians to consider limiting use to those situations where the clinical benefit of reduced blood loss is essential to medical management and outweighs the potential risks. [17] On November 5, 2007, Bayer announced that it was withdrawing Aprotinin because of a Canadian study that showed it increased the risk of death when used to prevent bleeding during heart surgery. [18]

Two studies published in early 2008, both comparing aprotinin with aminocaproic acid, found that mortality was increased by 32 [19] and 64%, [20] respectively. One study found an increased risk in need for dialysis and revascularisation. [20]

No cases of bovine spongiform encephalopathy transmission by aprotinin have been reported, although the drug was withdrawn in Italy due to fears of this. [5]

In vitro use

Small amounts of aprotinin can be added to tubes of drawn blood to enable laboratory measurement of certain rapidly degraded proteins such as glucagon.[ citation needed ]

In cell biology aprotinin is used as an enzyme inhibitor to prevent protein degradation during lysis or homogenization of cells and tissues.[ citation needed ]

Aprotinin can be labelled with fluorescein isothiocyanate. The conjugate retains its antiproteolytic and carbohydrate-binding properties [21] and has been used as a fluorescent histochemical reagent for staining glycoconjugates (mucosubstances) that are rich in uronic or sialic acids. [22]

History

Initially named "kallikrein inactivator", aprotinin was first isolated from cow parotid glands in 1930. [23] and independently as a trypsin inhibitor from bovine pancreas in 1936. [24] It was purified from bovine lung in 1964. [25] As it inhibits pancreatic enzymes, it was initially used in the treatment for acute pancreatitis, in which destruction of the gland by its own enzymes is thought to be part of the pathogenesis. [26] Its use in major surgery commenced in the 1960s. [27]

BPTI is one of the most thoroughly studied proteins in terms of structural biology, experimental and computational dynamics, mutagenesis, and folding pathway. It was one of the earliest protein crystal structures solved, in 1970 in the laboratory of Robert Huber, [28] and it's substrate-like interaction mode deciphered in the context of the bovine trypsin complex in 1974. [29] It later also became famous being the first protein to have its structure determined by NMR spectroscopy, in the laboratory of Kurt Wuthrich at the ETH in Zurich in the early 1980s. [30] [31]

Because it is a small, stable protein whose structure had been determined at high resolution by 1975, [32] it was the first macromolecule of scientific interest to be simulated using molecular dynamics computation, in 1977 by J. Andrew McCammon and Bruce Gelin, in the Karplus group at Harvard. [33] That study confirmed the then-surprising fact found in the NMR work [34] that even well-packed aromatic sidechains in the interior of a stable protein can flip over rather rapidly (microsecond to millisecond time scale). Rate constants were determined by NMR for the hydrogen exchange of individual peptide NH groups along the chain, ranging from too fast to measure on the most exposed surface to many months for the most buried hydrogen-bonded groups in the center of the β sheet, and those values also correlate fairly well with degree of motion seen in the dynamics simulations.

BPTI was important in the development of knowledge about the process of protein folding, the self-assembly of a polypeptide chain into a specific arrangement in 3D. The problem of achieving the correct pairings among the 6 Cys sidechains was shown to be especially difficult for the two buried, close-together SS near the BPTI chain termini, requiring a non-native intermediate for folding the mature sequence in vitro (it was later discovered that the precursor sequence folds more easily in vivo). BPTI was the cover image on a protein folding compendium volume by Thomas Creighton in 1992. [35]

Current findings

One scientific study in rats reported that treatment with aprotinin prevents disruption of the blood–brain barrier during the C. neoformans infection. [36] Another study in cell cultures suggests that the drug inhibits SARS-CoV-2 Replication. [37]

Related Research Articles

<span class="mw-page-title-main">Trypsin</span> Family of digestive enzymes

Trypsin is an enzyme in the first section of the small intestine that starts the digestion of protein molecules by cutting long chains of amino acids into smaller pieces. It is a serine protease from the PA clan superfamily, found in the digestive system of many vertebrates, where it hydrolyzes proteins. Trypsin is formed in the small intestine when its proenzyme form, the trypsinogen produced by the pancreas, is activated. Trypsin cuts peptide chains mainly at the carboxyl side of the amino acids lysine or arginine. It is used for numerous biotechnological processes. The process is commonly referred to as trypsinogen proteolysis or trypsinization, and proteins that have been digested/treated with trypsin are said to have been trypsinized. Trypsin was discovered in 1876 by Wilhelm Kühne and was named from the Ancient Greek word for rubbing since it was first isolated by rubbing the pancreas with glycerin.

<span class="mw-page-title-main">Pancreatitis</span> Inflammation of the pancreas

Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types: acute pancreatitis, and chronic pancreatitis.

<span class="mw-page-title-main">Oligopeptide</span>

An oligopeptide, often just called peptide, consists of two to twenty amino acids and can include dipeptides, tripeptides, tetrapeptides, and pentapeptides. Some of the major classes of naturally occurring oligopeptides include aeruginosins, cyanopeptolins, microcystins, microviridins, microginins, anabaenopeptins, and cyclamides. Microcystins are best studied, because of their potential toxicity impact in drinking water. A review of some oligopeptides found that the largest class are the cyanopeptolins (40.1%), followed by microcystins (13.4%).

<span class="mw-page-title-main">Alpha-1 antitrypsin</span> Mammalian protein found in Homo sapiens

Alpha-1 antitrypsin or α1-antitrypsin is a protein belonging to the serpin superfamily. It is encoded in humans by the SERPINA1 gene. A protease inhibitor, it is also known as alpha1–proteinase inhibitor (A1PI) or alpha1-antiproteinase (A1AP) because it inhibits various proteases. In older biomedical literature it was sometimes called serum trypsin inhibitor, because its capability as a trypsin inhibitor was a salient feature of its early study. As a type of enzyme inhibitor, it protects tissues from enzymes of inflammatory cells, especially neutrophil elastase, and has a reference range in blood of 0.9–2.3 g/L, but the concentration can rise manyfold upon acute inflammation.

<span class="mw-page-title-main">Digestive enzyme</span> Class of enzymes

Digestive enzymes are a group of enzymes that break down polymeric macromolecules into their smaller building blocks, in order to facilitate their absorption into the cells of the body. Digestive enzymes are found in the digestive tracts of animals and in the tracts of carnivorous plants, where they aid in the digestion of food, as well as inside cells, especially in their lysosomes, where they function to maintain cellular survival. Digestive enzymes of diverse specificities are found in the saliva secreted by the salivary glands, in the secretions of cells lining the stomach, in the pancreatic juice secreted by pancreatic exocrine cells, and in the secretions of cells lining the small and large intestines.

Trypsinogen is the precursor form of trypsin, a digestive enzyme. It is produced by the pancreas and found in pancreatic juice, along with amylase, lipase, and chymotrypsinogen. It is cleaved to its active form, trypsin, by enteropeptidase, which is found in the intestinal mucosa. Once activated, the trypsin can cleave more trypsinogen into trypsin, a process called autoactivation. Trypsin cleaves the peptide bond on the carboxyl side of basic amino acids such as arginine and lysine.

<span class="mw-page-title-main">Pancreatic enzymes (medication)</span> Amylase, lipase, and protease mixture.

Pancreatic enzymes, also known as pancreases or pancrelipase and pancreatin, are commercial mixtures of amylase, lipase, and protease. They are used to treat malabsorption syndrome due to certain pancreatic problems. These pancreatic problems may be due to cystic fibrosis, surgical removal of the pancreas, long term pancreatitis, pancreatic cancer, or MODY 5, among others. The preparation is taken by mouth.

<span class="mw-page-title-main">Tranexamic acid</span> Chemical compound

Tranexamic acid (TXA) is a medication used to treat or prevent excessive blood loss from major trauma, postpartum bleeding, surgery, tooth removal, nosebleeds, and heavy menstruation. It is also used for hereditary angioedema. It is taken either orally or by injection into a vein.

<span class="mw-page-title-main">Enteropeptidase</span> Class of enzymes

Enteropeptidase is an enzyme produced by cells of the duodenum and is involved in digestion in humans and other animals. Enteropeptidase converts trypsinogen into its active form trypsin, resulting in the subsequent activation of pancreatic digestive enzymes. Absence of enteropeptidase results in intestinal digestion impairment.

Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein has no known paralogue, while tissue kallikrein-related peptidases (KLKs) encode a family of fifteen closely related serine proteases. These genes are localised to chromosome 19q13, forming the largest contiguous cluster of proteases within the human genome. Kallikreins are responsible for the coordination of various physiological functions including blood pressure, semen liquefaction and skin desquamation.

<span class="mw-page-title-main">Plasma kallikrein</span>

Plasma kallikrein is an enzyme. This enzyme catalyses the following chemical reaction

Pancreatic elastase is a form of elastase that is produced in the acinar cells of the pancreas, initially produced as an inactive zymogen and later activated in the duodenum by trypsin. Elastases form a subfamily of serine proteases, characterized by a distinctive structure consisting of two beta barrel domains converging at the active site that hydrolyze amides and esters amongst many proteins in addition to elastin, a type of connective tissue that holds organs together. Pancreatic elastase 1 is a serine endopeptidase, a specific type of protease that has the amino acid serine at its active site. Although the recommended name is pancreatic elastase, it can also be referred to as elastase-1, pancreatopeptidase, PE, or serine elastase.

<span class="mw-page-title-main">Pancreatic ribonuclease family</span> Class of enzymes

Pancreatic ribonuclease family is a superfamily of pyrimidine-specific endonucleases found in high quantity in the pancreas of certain mammals and of some reptiles.

<span class="mw-page-title-main">SPINK1</span> Protein-coding gene in the species Homo sapiens

Pancreatic secretory trypsin inhibitor (PSTI) also known as serine protease inhibitor Kazal-type 1 (SPINK1) or tumor-associated trypsin inhibitor (TATI) is a protein that in humans is encoded by the SPINK1 gene.

Ecallantide is a drug used for the treatment of hereditary angioedema (HAE) and in the prevention of blood loss in cardiothoracic surgery. It is an inhibitor of the protein kallikrein and a 60-amino acid polypeptide which was developed from a Kunitz domain through phage display to mimic antibodies inhibiting kallikrein.

<span class="mw-page-title-main">Kunitz STI protease inhibitor</span>

Kunitz soybean trypsin inhibitor is a type of protein contained in legume seeds which functions as a protease inhibitor. Kunitz-type Soybean Trypsin Inhibitors are usually specific for either trypsin or chymotrypsin. They are thought to protect seeds against consumption by animal predators.

The fibrinolysis system is responsible for removing blood clots. Hyperfibrinolysis describes a situation with markedly enhanced fibrinolytic activity, resulting in increased, sometimes catastrophic bleeding. Hyperfibrinolysis can be caused by acquired or congenital reasons. Among the congenital conditions for hyperfibrinolysis, deficiency of alpha-2-antiplasmin or plasminogen activator inhibitor type 1 (PAI-1) are very rare. The affected individuals show a hemophilia-like bleeding phenotype. Acquired hyperfibrinolysis is found in liver disease, in patients with severe trauma, during major surgical procedures, and other conditions. A special situation with temporarily enhanced fibrinolysis is thrombolytic therapy with drugs which activate plasminogen, e.g. for use in acute ischemic events or in patients with stroke. In patients with severe trauma, hyperfibrinolysis is associated with poor outcome. Moreover, hyperfibrinolysis may be associated with blood brain barrier impairment, a plasmin-dependent effect due to an increased generation of bradykinin.

<span class="mw-page-title-main">Kunitz domain</span> InterPro Domain

Kunitz domains are the active domains of proteins that inhibit the function of protein degrading enzymes or, more specifically, domains of Kunitz-type are protease inhibitors. They are relatively small with a length of about 50 to 60 amino acids and a molecular weight of 6 kDa. Examples of Kunitz-type protease inhibitors are aprotinin, Alzheimer's amyloid precursor protein (APP), and tissue factor pathway inhibitor (TFPI). Kunitz STI protease inhibitor, the trypsin inhibitor initially studied by Moses Kunitz, was extracted from soybeans.

CU-2010 and CU-2020 are synthetic compounds that act as serine protease inhibitors. These were developed in 2010 to replace the use of aprotinin during and after cardiac surgery, including surgeries with cardiopulmonary bypass which cause blood loss and hemorrhagic complications. CU-2010 and CU-2020 were developed to avoid many issues associated with the use of aprotinin, including the risk of an allergic reaction and infection. Since the isolation of aprotinin is expensive, a drug with a simpler synthesis was desired.

References

  1. ↑ "Bayer Temporarily Suspends Global Trasylol Marketing" (PDF) (Press release). Trasylol.com. 2007-11-05. Archived from the original (PDF) on 2011-07-17. Retrieved 2007-12-03.
  2. ↑ "European Medicines Agency recommends lifting suspension of aprotinin". European Medicines Agency. 2012-02-17. Archived from the original on 2014-02-18. Retrieved 2012-02-22.
  3. ↑ "The Nordic Group acquires rights to Trasylol® from Bayer HealthCare". The Nordic Group B.V. Archived from the original on 1 February 2014. Retrieved 28 January 2014.
  4. 1 2 Mannucci PM (July 1998). "Hemostatic drugs". The New England Journal of Medicine. 339 (4): 245–53. doi:10.1056/NEJM199807233390407. PMID   9673304.
  5. 1 2 3 4 5 6 7 8 9 Mahdy AM, Webster NR (December 2004). "Perioperative systemic haemostatic agents". British Journal of Anaesthesia. 93 (6): 842–58. doi: 10.1093/bja/aeh227 . PMID   15277296.
  6. ↑ Richardson JS (1981). "The anatomy and taxonomy of protein structure". Advances in Protein Chemistry Volume 34. Advances in Protein Chemistry. Vol. 34. pp. 167–339. doi:10.1016/S0065-3233(08)60520-3. ISBN   978-0-12-034234-1. PMID   7020376.
  7. ↑ Kassell B, Radicevic M, Ansfield MJ, Laskowski M (January 1965). "The basic trypsin inhibitor of bovine pancreas. IV. The linear sequence of the 58 amino acids". Biochemical and Biophysical Research Communications. 18 (2): 255–8. doi:10.1016/0006-291X(65)90749-7. PMID   14282026.
  8. ↑ Kassell B, Laskowski M (August 1965). "The basic trypsin inhibitor of bovine pancreas. V. The disulfide linkages". Biochemical and Biophysical Research Communications. 20 (4): 463–8. doi:10.1016/0006-291X(65)90601-7. PMID   5860161.
  9. ↑ Xia VW, Steadman RH (January 2005). "Antifibrinolytics in orthotopic liver transplantation: current status and controversies". Liver Transplantation. 11 (1): 10–8. doi: 10.1002/lt.20275 . PMID   15690531.
  10. 1 2 Sedrakyan A, Treasure T, Elefteriades JA (September 2004). "Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials". The Journal of Thoracic and Cardiovascular Surgery. 128 (3): 442–8. doi: 10.1016/j.jtcvs.2004.03.041 . PMID   15354106.
  11. ↑ Shiga T, Wajima Z, Inoue T, Sakamoto A (December 2005). "Aprotinin in major orthopedic surgery: a systematic review of randomized controlled trials". Anesthesia and Analgesia. 101 (6): 1602–7. doi: 10.1213/01.ANE.0000180767.50529.45 . PMID   16301226. S2CID   33762135.
  12. 1 2 Mangano DT, Tudor IC, Dietzel C (January 2006). "The risk associated with aprotinin in cardiac surgery". The New England Journal of Medicine. 354 (4): 353–65. doi: 10.1056/NEJMoa051379 . PMID   16436767.
  13. ↑ Mangano DT, Miao Y, Vuylsteke A, Tudor IC, Juneja R, Filipescu D, et al. (February 2007). "Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery". JAMA. 297 (5): 471–9. doi:10.1001/jama.297.5.471. PMID   17284697.
  14. ↑ Harris G (2006-09-30). "F.D.A. Says Bayer Failed to Reveal Drug Risk Study - New York Times". The New York Times. Retrieved 2007-11-05.
  15. ↑ "Facts & Comparisons: Trasylol Public Health Advisory Update". Archived from the original on 2012-07-22. Retrieved 2007-11-05.
  16. ↑ "Early Communication about an Ongoing Safety Review Aprotinin Injection (marketed as Trasylol)". Food and Drug Administration . Archived from the original on 2007-10-30. Retrieved 2007-10-28.
  17. ↑ "Information for Healthcare Professionals; Aprotinin (marketed as Trasylol)". Food and Drug Administration . Archived from the original on 2006-10-10. Retrieved 2006-10-30.
  18. ↑ Harris G (2007-11-05). "Bayer Withdraws Heart Surgery Drug". The New York Times. Retrieved 2007-11-05.
  19. ↑ Shaw AD, Stafford-Smith M, White WD, Phillips-Bute B, Swaminathan M, Milano C, et al. (February 2008). "The effect of aprotinin on outcome after coronary-artery bypass grafting". The New England Journal of Medicine. 358 (8): 784–93. doi: 10.1056/NEJMoa0707768 . PMID   18287601.
  20. 1 2 Schneeweiss S, Seeger JD, Landon J, Walker AM (February 2008). "Aprotinin during coronary-artery bypass grafting and risk of death". The New England Journal of Medicine. 358 (8): 771–83. doi: 10.1056/NEJMoa0707571 . PMID   18287600.
  21. ↑ Stoddart RW, Kernan JA (March 1973). "Aprotinin, a carbohydrate-binding protein". Histochemie. Histochemistry. Histochimie. 34 (4): 275–80. doi:10.1007/BF00306299. PMID   4266832. S2CID   44549220.
  22. ↑ Kiernan JA, Stoddart RW (1973). "Fluorescent-labelled aprotinin: a new reagent for the histochemical detection of acid mucosubstances". Histochemistry. 34 (1): 77–84. doi:10.1007/BF00304309. PMID   4119444. S2CID   32032724.
  23. ↑ Kraut H, Frey EK, Bauer E (1930). "Über die Inaktivierung des kallikreins". Hoppe-Seyler's Z Physiol Chem (in German). 192: 1–21. doi:10.1515/bchm2.1930.192.1-3.1.
  24. ↑ Kunitz M, Northrop JH (July 1936). "Isolation from beef pancreas of crystalline trypsinogen, trypsin, trypsin inhibitor, and an inhibitor trypsin compound". The Journal of General Physiology. 19 (6): 991–1007. doi:10.1085/jgp.19.6.991. PMC   2141477 . PMID   19872978.
  25. ↑ Kraut H, Bhargava N (1964). "Versuche zur Isolierung des Kallikrein-Inaktivators aus Rinderlunge and seine Identifizierung mit dem Inaktivator aus Rinderparotis" [Experiments on the Isolation of the Kallikrein Inactivator. V. The Isolation of a Kallikrein Inactivator From the Bovine Lung and Its Identification With the Inhibitor From the Bovine Parotid Gland]. Hoppe-Seyler's Zeitschrift für Physiologische Chemie (in German). 338: 231–7. doi:10.1515/bchm2.1964.338.1-2.231. PMID   14330402.
  26. ↑ Nugent FW, Warren KW, Jonasson H, Garciadeparedes G (November 1964). "Early Experience With Trasylol in the Treatment of Acute Pancreatitis". Southern Medical Journal. 57 (11): 1317–21. doi:10.1097/00007611-196411000-00012. PMID   14195953. S2CID   5286289.
  27. ↑ Tice DA, Worth MH, Clauss RH, Reed GH (July 1964). "The Inhibition of Trasylol of Fibrinolytic Activity Associated With Cardiovascular Operations". Surgery, Gynecology & Obstetrics. 119: 71–4. PMID   14179354.
  28. ↑ Huber R, Kukla D, Rühlmann A, Epp O, Formanek H (August 1970). "The basic trypsin inhibitor of bovine pancreas. I. Structure analysis and conformation of the polypeptide chain". Die Naturwissenschaften. 57 (8): 389–92. Bibcode:1970NW.....57..389H. doi:10.1007/BF00599976. PMID   5447861. S2CID   6261274.
  29. ↑ Huber R, Kukla D, Bode W, Schwager P, Bartels K, Deisenhofer J, Steigemann W (October 1974). "Structure of the complex formed by bovine trypsin and bovine pancreatic trypsin inhibitor. II. Crystallographic refinement at 1.9 A resolution". Journal of Molecular Biology. 89 (1): 73–101. doi:10.1016/0022-2836(74)90163-6. PMID   4475115.
  30. ↑ Wagner G, Wüthrich K (March 1982). "Sequential resonance assignments in protein 1H nuclear magnetic resonance spectra. Basic pancreatic trypsin inhibitor". Journal of Molecular Biology. 155 (3): 347–66. doi:10.1016/0022-2836(82)90009-2. PMID   6176717.
  31. ↑ Havel TF, Wüthrich K (March 1985). "An evaluation of the combined use of nuclear magnetic resonance and distance geometry for the determination of protein conformations in solution". Journal of Molecular Biology. 182 (2): 281–94. doi:10.1016/0022-2836(85)90346-8. PMID   2582141.
  32. ↑ Deisenhofer J, Steigemann W (1975). "Crystallographic Refinement of the Structure of Bovine Pancreatic Trypsin Inhibitor at 1.5 Angstroms Resolution" (PDF). Acta Crystallographica B. 31: 238. doi:10.1107/S0567740875002415.
  33. ↑ McCammon JA, Gelin BR, Karplus M (June 1977). "Dynamics of folded proteins". Nature. 267 (5612): 585–90. Bibcode:1977Natur.267..585M. doi:10.1038/267585a0. PMID   301613. S2CID   4222220.
  34. ↑ Wüthrich K, Wagner G (February 1975). "NMR investigations of the dynamics of the aromatic amino acid residues in the basic pancreatic trypsin inhibitor". FEBS Letters. 50 (2): 265–8. doi:10.1016/0014-5793(75)80504-7. PMID   234403. S2CID   46084481.
  35. ↑ Creighton TE (1992). Protein Folding. W. H. Freeman. ISBN   978-0-7167-7027-5.
  36. ↑ Xu CY, Zhu HM, Wu JH, Wen H, Liu CJ (February 2014). "Increased permeability of blood-brain barrier is mediated by serine protease during Cryptococcus meningitis". The Journal of International Medical Research. 42 (1): 85–92. doi: 10.1177/0300060513504365 . PMID   24398759.
  37. ↑ Bojkova D, Bechtel M, McLaughlin KM, McGreig JE, Klann K, Bellinghausen C, et al. (October 2020). "Aprotinin Inhibits SARS-CoV-2 Replication". Cells. 9 (11): 2377. doi: 10.3390/cells9112377 . PMC   7692688 . PMID   33143316.
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