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Enfuvirtide (INN) is an HIV fusion inhibitor, the first of a novel class of antiretroviral drugs used in combination therapy for the treatment of HIV-1 infection. It is marketed under the trade name Fuzeon (Roche).

Enfuvirtide therapy costs an estimated US$25,000 per year in the United States. Its cost and inconvenient dosing regimen are factors behind its use as a reserve, for salvage therapy in patients with multi-drug resistant HIV.

Structural formula[edit]

Ac-Tyr-Thr-Ser-Leu-Ile-His-Ser-Leu-Ile-Glu-Glu-Ser-Gln-Asn-Gln-Gln-Glu-Lys-Asn-Glu-Gln-Glu-Leu-Leu-Glu-Leu-Asp-Lys-Trp-Ala-Ser-Leu-Trp-Asn-Trp-Phe-NH₂

History[edit]

Enfuvirtide originated at Duke University, 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 to complete the development of the drug. It was approved by the U.S. Food and Drug Administration (FDA) on March 13, 2003 as the first HIV fusion inhibitor, a new class of antiretroviral drugs. It was approved on the basis of two studies (TORO 1 and TORO 2) which compared the effect of optimized regimens of antiretroviral medication with and without the addition of enfuvirtide on serum viral load.

Pharmacology[edit]

Mechanism of action[edit]

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, enfuvirtide was designed to mimic components of the HIV-1 fusion machinery and displace them, preventing normal fusion. Drugs that disrupt fusion of virus and target cell are termed entry inhibitors or fusion inhibitors.

HIV binds to the host CD4+ cell receptor via the viral protein gp120; gp41, a viral transmembrane protein, then undergoes a conformational change 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.^[1]

Microbiology[edit]

Enfuvirtide is considered to be active against HIV-1 only. Low activity against HIV-2 isolates has been demonstrated in vitro.^[2]

Variable susceptibility to enfuvirtide has been observed in clinical isolates, with acquired resistance the result of a mutated 10 amino acid motif in viral gp41. Primary resistance, however, has yet to be observed.^[3]

Clinical use[edit]

Indications[edit]

Enfuvirtide is indicated for the treatment of HIV-1 infection, in combination therapy with other antiretrovirals, in patients where all other treatments have failed.^[4]

Dosage forms[edit]

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. 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.^[5]

Adverse effects[edit]

Common adverse drug reactions (≥1% of patients) associated with enfuvirtide therapy include: injection site reactions (pain, hardening of skin, erythema, nodules, cysts, itch; experienced by nearly all patients, particularly in the first week), peripheral neuropathy, insomnia, depression, cough, dyspnoea, anorexia, arthralgia, infections (including bacterial pneumonia) and/or eosinophilia. Various hypersensitivity reactions occur infrequently (0.1–1% of patients), symptoms of which include rash, fever, nausea, vomiting, chills, rigors, hypotension, elevated hepatic transaminases; and possibly more severe reactions including respiratory distress, glomerulonephritis and/or anaphylaxis – rechallenge is not recommended.^[4]

References[edit]

^ Lalezari, JP; Eron, JJ; Carlson, M; Cohen, C; Dejesus, E; Arduino, RC; Gallant, JE; Volberding, P et al. (2003). "A phase II clinical study of the long-term safety and antiviral activity of enfuvirtide-based antiretroviral therapy". AIDS (London, England) 17 (5): 691–8. doi:10.1097/01.aids.0000050825.06065.84. PMID 12646792. |displayauthors= suggested (help)
^ Roche Products Pty Ltd. Fuzeon (Australian Approved Product Information). Dee Why (NSW): Roche; 2005.
^ Greenberg, ML; Cammack, N (2004). "Resistance to enfuvirtide, the first HIV fusion inhibitor". Journal of antimicrobial chemotherapy 54 (2): 333–40. doi:10.1093/jac/dkh330. PMID 15231762.
^ ^a ^b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
^ Klein, Richard (13 March 2003). "FDA approves Fuzeon". fda.gov. Retrieved 2 July 2011.

UpToDate Contents

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1. HIV療法に失敗した治療歴のあるHIV感染患者のための抗レトロウイルス療法の選択 selecting an antiretroviral regimen for treatment experienced hiv infected patients who are failing therapy
2. HIV感染症の治療に用いる抗レトロウイルス薬の概要 overview of antiretroviral agents used to treat hiv
3. 未治療HIV感染患者のための抗レトロウイルス療法の選択 selecting antiretroviral regimens for the treatment naive hiv infected patient
4. Interpretation of HIV drug resistance testing
5. HIV-2感染の治療 treatment of hiv 2 infection

English Journal

Development of Small-molecule HIV Entry Inhibitors Specifically Targeting gp120 or gp41.

Lu L, Yu F, Cai L, Debnath AK, Jiang S1.
Current topics in medicinal chemistry.Curr Top Med Chem.2015 Sep 1. [Epub ahead of print]
Human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein surface subunit gp120 and transmembrane subunit gp41 play important roles in HIV-1 entry, thus serving as key targets for the development of HIV-1 entry inhibitors. T20 peptide (enfuvirtide) is the first U.S. FDA-approved HIV en
PMID 26324044

The N-Terminal T-T Motif of a Third-Generation HIV-1 Fusion Inhibitor Is Not Required for Binding Affinity and Antiviral Activity.

Chong H1, Qiu Z1, Su Y1, He Y1.
Journal of medicinal chemistry.J Med Chem.2015 Aug 27;58(16):6378-88. doi: 10.1021/acs.jmedchem.5b00109. Epub 2015 Aug 17.
The highlighted next-generation HIV-1 fusion inhibitor peptide 1 is capped by two threonines. Here, we generated peptide 2 by deleting the T-T motif and compared their structural and antiviral properties. Significantly, two peptides showed similar helical and oligomeric states in solution, comparabl
PMID 26256053

Protein/peptide-based entry/fusion inhibitors as anti-HIV therapies: challenges and future direction.

Fumakia M1, Yang S1, Gu J1, Ho EA1.
Reviews in medical virology.Rev Med Virol.2015 Aug 26. doi: 10.1002/rmv.1853. [Epub ahead of print]
The failures of several first-generation and second-generation small molecule drug-based anti-HIV therapies in various stages of clinical trials are an indication that there is a need for a paradigm shift in the future designs of anti-HIV therapeutics. Over the past several decades, various anti-HIV
PMID 26308574

Japanese Journal

インテグラーゼ阻害薬,ケモカインレセプター阻害薬、融合阻害薬 (特集 HIV/AIDS--最新の治療研究の進歩) -- (抗HIV薬・ワクチン研究の進歩)

潟永博之
日本臨床 68(3), 520-524, 2010-03
NAID 40016975407

Affinity selection and sequence-activity relationships of HIV-1 membrane fusion inhibitors directed at the drug-resistant variants

Oishi Shinya,Watanabe Kentaro,Ito Saori,Tanaka Michinori,Nishikawa Hiroki,Ohno Hiroaki,Shimane Kazuki,Izumi Kazuki,Sakagami Yasuko,Kodama Eiichi N.,Matsuoka Masao,Asai Akira,Fujii Nobutaka
MedChemComm 1(4), 276-281, 2010
… Enfuvirtide is the first approved membrane fusion inhibitor against HIV-1. … Although this drug is effective against multi-drug resistant strains, the emergence of enfuvirtide-resistant strains has been reported in patients who have received an enfuvirtide-containing regimen. …
NAID 120002484932

Electrostatically constrained α-helical peptide inhibits replication of HIV-1 resistant to enfuvirtide.

Nishikawa Hiroki,Nakamura Shota,Kodama Eiichi,Ito Saori,Kajiwara Keiko,Izumi Kazuki,Sakagami Yasuko,Oishi Shinya,Ohkubo Tadayasu,Kobayashi Yuji,Otaka Akira,Fujii Nobutaka,Matsuoka Masao
The international journal of biochemistry & cell biology 41(4), 891-899, 2009-04
… Alpha-helical peptides, such as T-20 (enfuvirtide) and C34, derived from the gp41 carboxyl-terminal heptad repeat (C-HR) of HIV-1, inhibit membrane fusion of HIV-1 and the target cells. …
NAID 120002790064

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★リンクテーブル★

リンク元	「エンフビルチド」「エンフュヴィルタイド」「エンフュービルタイド」

「エンフビルチド」

Enfuvirtide
Systematic (IUPAC) name
	Acetyl-??-amide
Clinical data
Trade names	Fuzeon
AHFS/Drugs.com	monograph
Pregnancy cat.	B2 (Au), B (U.S.)
Legal status	S4 (Au), POM (UK), ℞-only (U.S.)
Routes	Subcutaneous (SC)
Pharmacokinetic data
Bioavailability	84.3% (SC)
Protein binding	92%
Metabolism	Hepatic
Half-life	3.8 hours
Excretion	unknown
Identifiers
CAS number	159519-65-0
ATC code	J05AX07
PubChem	CID 16130199
DrugBank	DB00109
ChemSpider	16743716
UNII	19OWO1T3ZE
KEGG	D02499
ChEBI	CHEBI:608828
ChEMBL	CHEMBL525076
NIAID ChemDB	059486
Chemical data
Formula	C202H298N50O64
Mol. mass	4492.1 g/mol
	SMILES CCC(C)C(C(=O)NC(CCC(=O)O)C(=O)NC(CCC(=O)O)C(=O)NC(CO)C(=O)NC(CCC(=O)N)C(=O)NC(CC(=O)N)C(=O)NC(CCC(=O)N)C(=O)NC(CCC(=O)N)C(=O)NC(CCC(=O)O)C(=O)NC(CCCCN)C(=O)NC(CC(=O)N)C(=O)NC(CCC(=O)O)C(=O)NC(CCC(=O)N)C(=O)NC(CCC(=O)O)C(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)NC(CCC(=O)O)C(=O)NC(CC(C)C)C(=O)NC(CC(=O)O)C(=O)NC(CCCCN)C(=O)NC(Cc1c[nH]c2c1cccc2)C(=O)NC(C)C(=O)NC(CO)C(=O)NC(CC(C)C)C(=O)NC(Cc3c[nH]c4c3cccc4)C(=O)NC(CC(=O)N)C(=O)NC(Cc5c[nH]c6c5cccc6)C(=O)NC(Cc7ccccc7)C(=O)N)NC(=O)C(CC(C)C)NC(=O)C(CO)NC(=O)C(Cc8cnc[nH]8)NC(=O)C(C(C)CC)NC(=O)C(CC(C)C)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C(Cc9ccc(cc9)O)NC(=O)C;
	InChI InChI=1S/C204H301N51O64/c1-20-102(15)166(253-195(310)137(75-100(11)12)239-200(315)150(93-258)251-190(305)143(82-112-90-215-95-219-112)248-203(318)167(103(16)21-2)254-196(311)138(76-101(13)14)240-201(316)151(94-259)252-204(319)168(105(18)260)255-197(312)139(221-106(19)261)78-108-45-47-113(262)48-46-108)202(317)233-131(58-68-164(280)281)178(293)228-130(57-67-163(278)279)182(297)250-149(92-257)198(313)232-125(52-62-155(210)266)179(294)245-145(84-157(212)268)191(306)229-124(51-61-154(209)265)175(290)224-122(49-59-152(207)263)173(288)226-126(53-63-159(270)271)176(291)222-120(43-31-33-69-205)172(287)244-144(83-156(211)267)192(307)231-127(54-64-160(272)273)177(292)225-123(50-60-153(208)264)174(289)227-128(55-65-161(274)275)180(295)235-134(72-97(5)6)185(300)237-133(71-96(3)4)184(299)230-129(56-66-162(276)277)181(296)236-135(73-98(7)8)187(302)247-147(86-165(282)283)194(309)223-121(44-32-34-70-206)171(286)241-140(79-109-87-216-117-40-28-25-37-114(109)117)183(298)220-104(17)170(285)249-148(91-256)199(314)238-136(74-99(9)10)186(301)242-142(81-111-89-218-119-42-30-27-39-116(111)119)189(304)246-146(85-158(213)269)193(308)243-141(80-110-88-217-118-41-29-26-38-115(110)118)188(303)234-132(169(214)284)77-107-35-23-22-24-36-107/h22-30,35-42,45-48,87-90,95-105,120-151,166-168,216-218,256-260,262H,20-21,31-34,43-44,49-86,91-94,205-206H2,1-19H3,(H2,207,263)(H2,208,264)(H2,209,265)(H2,210,266)(H2,211,267)(H2,212,268)(H2,213,269)(H2,214,284)(H,215,219)(H,220,298)(H,221,261)(H,222,291)(H,223,309)(H,224,290)(H,225,292)(H,226,288)(H,227,289)(H,228,293)(H,229,306)(H,230,299)(H,231,307)(H,232,313)(H,233,317)(H,234,303)(H,235,295)(H,236,296)(H,237,300)(H,238,314)(H,239,315)(H,240,316)(H,241,286)(H,242,301)(H,243,308)(H,244,287)(H,245,294)(H,246,304)(H,247,302)(H,248,318)(H,249,285)(H,250,297)(H,251,305)(H,252,319)(H,253,310)(H,254,311)(H,255,312)(H,270,271)(H,272,273)(H,274,275)(H,276,277)(H,278,279)(H,280,281)(H,282,283)/t102-,103-,104-,105+,120-,121-,122-,123-,124-,125-,126-,127-,128-,129-,130-,131-,132-,133-,134-,135-,136-,137-,138-,139-,140-,141-,142-,143-,144-,145-,146-,147-,148-,149-,150-,151-,166-,167-,168-/m0/s1 ; Key:PEASPLKKXBYDKL-FXEVSJAOSA-N ;
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