Enfuvirtide ( INN) is an HIV

fusion inhibitor Entry inhibitors, also known as fusion inhibitors, are a class of antiviral drugs that prevent a virus from entering a cell, for example, by blocking a receptor. Entry inhibitors are used to treat conditions such as HIV and hepatitis D. HIV entry ...

, the first of a class of

antiretroviral drug The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multi ...

s used in

combination therapy Combination therapy or polytherapy is therapy that uses more than one medication or modality. Typically, the term refers to using multiple therapies to treat a ''single'' disease, and often all the therapies are pharmaceutical (although it can al ...

for the treatment of HIV-1 infection. It is marketed under the trade name Fuzeon (

Roche F. Hoffmann-La Roche AG, commonly known as Roche, is a Swiss multinational healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX ...

Structural formula

Enfuvirtide is a 36-amino acid peptide with the following sequence: CH₃CO- Tyr- Thr- Ser-

Leu Leu may refer to: Businesses and organisations * LEU, NYSE American stock symbol for Centrus Energy Corp. * London Ecology Unit, a former body (1986-2000) which advised London boroughs on environmental matters * Free and Equal (''LeU - Liberi e ...

Ile Ile may refer to: * iLe, a Puerto Rican singer * Ile District (disambiguation), multiple places * Ilé-Ifẹ̀, an ancient Yoruba city in south-western Nigeria * Interlingue (ISO 639:ile), a planned language * Isoleucine, an amino acid * Another ...

- His-Ser-Leu-Ile- Glu-Glu-Ser-

Gln Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral, ...

- Asn-Gln-Gln-Glu- Lys-Asn-Glu-Gln-Glu-Leu-Leu-Glu-Leu- Asp- Lys- Trp- Ala-Ser-Leu-Trp- Asn-Trp- Phe- NH₂ (Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH₂)

History

Enfuvirtide originated at

Duke University Duke University is a private research university in Durham, North Carolina. Founded by Methodists and Quakers in the present-day city of Trinity in 1838, the school moved to Durham in 1892. In 1924, tobacco and electric power industrialist Jam ...

, where researchers formed a pharmaceutical company known as Trimeris. Trimeris began development on enfuvirtide in 1996 and initially designated it T-20. In 1999, Trimeris entered into partnership with

Hoffmann-La Roche F. Hoffmann-La Roche AG, commonly known as Roche, is a Swiss multinational healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX ...

to complete the development of the drug. It was approved by the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(FDA) on March 13, 2003 as the first HIV

, a new class of antiretroviral drugs. It was approved on the basis of two studies which compared the effect of optimized regimens of antiretroviral medication with and without the addition of enfuvirtide on serum viral load.

Pharmacology

Mechanism of action

Enfuvirtide works by disrupting the HIV-1 molecular machinery at the final stage of fusion with the target cell, preventing uninfected cells from becoming infected. A biomimetic

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. ...

, enfuvirtide was designed to mimic components of the HIV-1 fusion machinery and displace them, preventing normal fusion. Drugs that disrupt fusion of

virus A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsk ...

and target cell are termed entry inhibitors or

s. HIV binds to the host CD4+ cell receptor via the viral protein gp120; gp41, a viral

transmembrane protein A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequent ...

, then undergoes a

conformational change In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors. A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or oth ...

that assists in the fusion of the viral membrane to the host cell membrane. Enfuvirtide binds to gp41 preventing the creation of an entry pore for the capsid of the virus, keeping it out of the cell. Enfuvirtide is also an activator of the chemotactic factor receptor, formyl peptide receptor 1, and thereby activates phagocytes and presumably other cells bearing this receptor (see formyl peptide receptors). The physiological significance of this activation is unknown.

Microbiology

Enfuvirtide is considered to be active against HIV-1 only. Low activity against HIV-2 isolates has been demonstrated ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology a ...

''.Roche Products Pty Ltd. Fuzeon (Australian Approved Product Information). Dee Why (NSW): Roche; 2005. Variable susceptibility to enfuvirtide has been observed in clinical isolates, with acquired resistance the result of a mutated 10

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 ...

motif in viral gp41. Primary resistance, however, has yet to be observed.

Clinical use

Indications

Enfuvirtide is indicated for the treatment of HIV-1 infection, in

with other antiretrovirals, in patients where all other treatments have failed.

Dosage forms

By virtue of its peptide nature, enfuvirtide is marketed in injectable form. The lyophilised enfuvirtide powder must be reconstituted by the patient and administered twice daily by

subcutaneous injection Subcutaneous administration is the insertion of medications beneath the skin either by injection or infusion. A subcutaneous injection is administered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis, c ...

. Due to the chronic nature of this kind of therapy, this dosage form may be a major problem for the patient's adherence to this drug regimen.

Adverse effects

Common

adverse drug reaction An adverse drug reaction (ADR) is a harmful, unintended result caused by taking medication. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs. The meaning of this term ...

s (≥1% of patients) associated with enfuvirtide therapy include: injection site reactions (pain, hardening of skin,

erythema Erythema (from the Greek , meaning red) is redness of the skin or mucous membranes, caused by hyperemia (increased blood flow) in superficial capillaries. It occurs with any skin injury, infection, or inflammation. Examples of erythema not asso ...

, nodules,

cyst A cyst is a closed sac, having a distinct envelope and division compared with the nearby tissue. Hence, it is a cluster of cells that have grouped together to form a sac (like the manner in which water molecules group together to form a bubble) ...

s, itch; experienced by nearly all patients, particularly in the first week),

peripheral neuropathy Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

, depression, cough, dyspnoea, anorexia, arthralgia, infections (including bacterial

pneumonia Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severit ...

) and/or

eosinophilia Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds . Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 x 109/ L (i.e. 1,500/ μL). The hypereosinophilic sy ...

. Various

hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune ...

reactions occur infrequently (0.1–1% of patients), symptoms of which include

rash A rash is a change of the human skin which affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, c ...

fever Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenter ...

chills Chills is a feeling of coldness occurring during a high fever, but sometimes is also a common symptom which occurs alone in specific people. It occurs during fever due to the release of cytokines and prostaglandins as part of the inflammatory ...

, rigors,

hypotension Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the di ...

, elevated hepatic

transaminase Transaminases or aminotransferases are enzymes that catalyze a transamination reaction between an amino acid and an α- keto acid. They are important in the synthesis of amino acids, which form proteins. Function and mechanism An amino acid ...

s; and possibly more severe reactions including

respiratory distress Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing disc ...

, glomerulonephritis and/or

anaphylaxis Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follo ...

– rechallenge is not recommended.

References

External links

* {{Portal bar , Medicine , Viruses Entry inhibitors Hepatotoxins Peptides Hoffmann-La Roche brands Genentech brands