An endopeptidase inhibitor is a drug that

inhibit Inhibitor or inhibition may refer to: In biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...

s one or more endopeptidase

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

s. Endopeptidases are one of two types of

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...

s (enzymes that break down

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

s and

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

s), the other being exopeptidases. Endopeptidases cleave

peptide bond In organic chemistry, a peptide bond is an amide type of covalent chemical bond linking two consecutive alpha-amino acids from C1 (carbon number one) of one alpha-amino acid and N2 (nitrogen number two) of another, along a peptide or protein cha ...

s of non-terminal

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

s (that is, they cut proteins/peptides into two chains), whereas exopeptidases break terminal bonds, resulting in the release of a single amino acid or

dipeptide A dipeptide is an organic compound derived from two amino acids. The constituent amino acids can be the same or different. When different, two isomers of the dipeptide are possible, depending on the sequence. Several dipeptides are physiologicall ...

from the peptide chain.

Examples of endopeptidase inhibitors

Some examples of endopeptidase inhibitors include the following: *

Neprilysin Neprilysin (), also known as membrane metallo-endopeptidase (MME), neutral endopeptidase (NEP), cluster of differentiation 10 (CD10), and common acute lymphoblastic leukemia antigen (CALLA) is an enzyme that in humans is encoded by the ''MME'' ge ...

inhibitors ** Selective

neprilysin Neprilysin (), also known as membrane metallo-endopeptidase (MME), neutral endopeptidase (NEP), cluster of differentiation 10 (CD10), and common acute lymphoblastic leukemia antigen (CALLA) is an enzyme that in humans is encoded by the ''MME'' ge ...

inhibitors *** Candoxatril -

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

to candoxatrilat *** Candoxatrilat -

active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

of candoxatril *** Dexecadotril (retorphan) - (''R'')-

enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...

racecadotril Racecadotril, also known as acetorphan, is an antidiarrheal medication which acts as a peripheral enkephalinase inhibitor. Unlike other opioid medications used to treat diarrhea, which reduce intestinal motility, racecadotril has an antisecretor ...

; prodrug to (''R'')-thiorphan *** Ecadotril (sinorphan) - (''S'')-enantiomer of racecadotril; prodrug to (''S'')-thiorphan ***

Racecadotril Racecadotril, also known as acetorphan, is an antidiarrheal medication which acts as a peripheral enkephalinase inhibitor. Unlike other opioid medications used to treat diarrhea, which reduce intestinal motility, racecadotril has an antisecretor ...

(acetorphan) - racemic form of dexecadotril and ecadotril; prodrug to

thiorphan Thiorphan is the active metabolite of the antidiarrheal racecadotril (acetorphan). It prevents the degradation of endogenous enkephalin An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are t ...

***

Sacubitril Sacubitril (; INN) 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 w ...

- prodrug to

sacubitrilat Sacubitrilat ( INN; or LBQ657) is the active metabolite of the antihypertensive drug sacubitril, which is used in the treatment of heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of s ...

***

Sacubitrilat Sacubitrilat ( INN; or LBQ657) is the active metabolite of the antihypertensive drug sacubitril, which is used in the treatment of heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of s ...

- active metabolite of sacubitril ***

Thiorphan Thiorphan is the active metabolite of the antidiarrheal racecadotril (acetorphan). It prevents the degradation of endogenous enkephalin An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are t ...

- active metabolite of racecadotril ***

UK-414,495 UK-414,495 is a drug developed by Pfizer for the treatment of female sexual arousal disorder. UK-414,495 acts as a potent, selective inhibitor of the enzyme neutral endopeptidase, which normally serves to break down the neuropeptide VIP. The con ...

** Non-selective neprilysin inhibitors *** Aladotril - also inhibits angiotensin converting enzyme (ACE) (an exopeptidase) *** Alatriopril - also inhibits ACE *** Daglutril - also inhibits

endothelin converting enzyme converting enzyme 1, also known as ECE1, is an enzyme which in humans is encoded by the ''ECE1'' gene. Function Endothelin-converting enzyme-1 is involved in the proteolytic processing of endothelin-1 (EDN1), -2 ( EDN2), and -3 (EDN3 Endoth ...

(ECE) (an exopeptidase) *** Fasidotril - also inhibits ACE *** Gemopatrilat - also inhibits ACE *** Ilepatril - also inhibits ACE *** Ketalorphan - also inhibits APN, ACE, and dipeptidyl-peptidase 3 (DPP-3) (an exopeptidase) ***

Omapatrilat Omapatrilat (INN, proposed trade name Vanlev) is an experimental antihypertensive agent that was never marketed. It inhibits both neprilysin (neutral endopeptidase, NEP) and angiotensin-converting enzyme (ACE). NEP inhibition results in elevated ...

- also inhibits ACE ***

Phosphoramidon Phosphoramidon is a chemical compound derived from cultures of '' Streptomyces tanashiensis''. It is an inhibitor of the enzyme thermolysin, of the membrane metallo-endopeptidase,neprilysin Neprilysin (), also known as membrane metallo-endopeptidase (MME), neutral endopeptidase (NEP), cluster of differentiation 10 (CD10), and common acute lymphoblastic leukemia antigen (CALLA) is an enzyme that in humans is encoded by the ''MME'' ge ...

and

thermolysin Thermolysin (, ''Bacillus thermoproteolyticus neutral proteinase'', ''thermoase'', ''thermoase Y10'', ''TLN'') is a thermostable neutral metalloproteinase enzyme produced by the Gram-positive bacteria ''Bacillus thermoproteolyticus''. It requires ...

; also inhibits ECE ***

RB-101 RB-101 is a drug that acts as an enkephalinase inhibitor, which is used in scientific research. RB-101 is a prodrug which acts by splitting at the disulfide bond once inside the brain, to form two selective enzyme inhibitors and blocking both ty ...

- also inhibits

aminopeptidase N Membrane alanyl aminopeptidase () also known as alanyl aminopeptidase (AAP) or aminopeptidase N (AP-N) is an enzyme that in humans is encoded by the ANPEP gene. Function Aminopeptidase N is located in the small-intestinal and renal microvilla ...

(APN) (an exopeptidase) *** Sampatrilat *** Spinorphan - also inhibits APN, ACE, and DPP-3 *** Tynorphin - also inhibits APN, ACE, and DPP-3 *

Trypsin inhibitor A trypsin inhibitor (TI) is a protein and a type of serine protease inhibitor (serpin) that reduces the biological activity of trypsin by controlling the activation and catalytic reactions of proteins. Trypsin is an enzyme involved in the breakdown ...

s/others **

Aloxistatin Aloxistatin (loxistatin, E-64d, EST) is a drug which acts as a cysteine protease inhibitor and has anticoagulant effects. It is a synthetic analogue of E-64, a natural product derived from fungi. It was researched for the treatment of muscular dys ...

- inhibitor of

cysteine protease Cysteine proteases, also known as thiol proteases, are hydrolase enzymes that degrade proteins. These proteases share a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic triad or dyad. Discovered by Gopal Chund ...

s **

Camostat Camostat is a serine protease inhibitor. Serine protease enzymes have a variety of functions in the body, and so camostat has a diverse range of uses. Camostat is approved in Japan for the treatment of chronic pancreatitis and postoperative reflu ...

- inhibitor of trypsin and various other

s ** Ecallantide -

kallikrein Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein (encoded by ''KLKB1 gene'') has no known paralogue, while tissue kallikrein-related peptidases (''KLKs'') encode a f ...

inhibitor **

Leupeptin Leupeptin, also known as ''N''-acetyl-L-leucyl-L-leucyl-L-argininal, is a naturally occurring protease inhibitor that can inhibit cysteine, serine and threonine peptidases. It is often used during ''in vitro'' experiments when a specific enzymati ...

- non-selective inhibitor of cysteine,

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...

, and

threonine protease Threonine proteases are a family of proteolytic enzymes harbouring a threonine (Thr) residue within the active site. The prototype members of this class of enzymes are the catalytic subunits of the proteasome, however the acyltransferases converg ...

s **

Nafamostat Nafamostat mesylate (INN), a synthetic serine protease inhibitor, it is a short-acting anticoagulant, and is also used for the treatment of pancreatitis. It also has some potential antiviral and anti-cancer properties. Nafamostat is a fast-acting p ...

- inhibitor of trypsin, tryptase, and various other serine proteases **

Pacifastin Pacifastin is a family of serine proteinase inhibitors found in arthropods. Pacifastin inhibits the serine peptidases trypsin and chymotrypsin. All pacifastin members that have been characterized at the molecular level are precursor peptides co ...

s - trypsin and chymotrypsin inhibitor ** Patamostat - trypsin inhibitor **

Pepstatin Pepstatin is a potent inhibitor of aspartyl proteases. It is a hexa-peptide containing the unusual amino acid statine (Sta, (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid), having the sequence Isovaleryl-Val-Val-Sta-Ala-Sta (Iva-Val-Val-Sta-Al ...

- inhibitor of

renin Renin (etymology and pronunciation), also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body's renin–angiotensin–aldosterone system (RAAS)—also known as the r ...

and various aspartyl proteases ** Sepimostat - inhibitor of serine proteases **

Sivelestat Sivelestat ( INN, research name ONO 5046, marketed as Elaspol) is an inhibitor of human neutrophil elastase. It is used in the treatment of acute respiratory failure Respiratory failure results from inadequate gas exchange by the respiratory s ...

- inhibitor of

neutrophil elastase Neutrophil elastase (, ''leukocyte elastase'', ''ELANE'', ''ELA2'', ''elastase 2'', ''neutrophil'', ''elaszym'', ''serine elastase'', subtype ''human leukocyte elastase (HLE)'') is a serine proteinase in the same family as chymotrypsin and has br ...

Talopeptin Talopeptin is a chemical compound derived from cultures of '' Streptomyces''. It is a known reversible inhibitor of thermolysin and is expected to inhibit other metalloproteinases. Chemically, talopeptin differs from its closely related peptida ...

- inhibitor of

and other

metalloprotease A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myogen ...

s ** Ulinastatin - inhibitor of trypsin and various other proteases ** Upamostat - serine protease inhibitor *

Renin inhibitor Renin inhibitors are pharmaceutical drugs inhibiting the activity of renin that is responsible for hydrolyzing angiotensinogen to angiotensin I, which in turn reduces the formation of angiotensin II that facilitates blood pressure. Renin inhibit ...

s **

Aliskiren Aliskiren (brand names Tekturna and Rasilez) is the first in a class of drugs called direct renin inhibitors. It is used for essential (primary) hypertension. While used for high blood pressure, other better studied medications are typically reco ...

** Ciprokiren ** Ditekiren ** Enalkiren **

** Remikiren ** Terlakiren ** Zankiren

References

Protease inhibitors {{pharmacology-stub

Examples of endopeptidase inhibitors

See also

References