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Enfuvirtide

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Enfuvirtide
Clinical data
Trade namesFuzeon
AHFS/Drugs.comMonograph
MedlinePlusa603023
License data
Pregnancy
category
Routes of
administration
Subcutaneous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability84.3% (SC)
Protein binding92%
MetabolismLiver
Elimination half-life3.8 hours
Excretionunknown
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard100.169.201 Edit this at Wikidata
Chemical and physical data
FormulaC204H301N51O64
Molar mass4491.945 g·mol−1
3D model (JSmol)
  • CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](Cc1c[nH]c2c1cccc2)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc3c[nH]c4c3cccc4)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](Cc5c[nH]c6c5cccc6)C(=O)N[C@@H](Cc7ccccc7)C(=O)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](Cc8cnc[nH]8)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](Cc9ccc(cc9)O)NC(=O)C
  • 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 checkY
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Enfuvirtide (INN), sold under the brand name Fuzeon, is an HIV fusion inhibitor, the first of a class of antiretroviral drugs used in combination therapy for the treatment of AIDS/HIV.

Medical uses

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Enfuvirtide is indicated for the treatment of HIV-1 infection, in combination therapy with other antiretrovirals, in people where all other treatments have failed.[2]

Adverse effects

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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 anaphylaxisrechallenge is not recommended.[2]

Pharmacology

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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.[citation needed]

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.[3]

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).[4] The physiological significance of this activation is unknown.[citation needed]

Microbiology

[edit]

Enfuvirtide is considered to be active against HIV-1 only. Low activity against HIV-2 isolates has been demonstrated in vitro.[5]

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.[6]

Structural formula

[edit]

Enfuvirtide is a 36-amino acid peptide with the following sequence:[7][8]

CH3CO-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 (Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-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 13 March 2003[9] as the first HIV fusion inhibitor, 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.[citation needed]

References

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  1. ^ a b "Product". guildlink.com.au. Archived from the original on 8 January 2023. Retrieved 8 January 2023.
  2. ^ a b Rossi S, ed. (2006). Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd. ISBN 0-9757919-2-3.
  3. ^ Lalezari JP, Eron JJ, Carlson M, Cohen C, DeJesus E, Arduino RC, et al. (March 2003). "A phase II clinical study of the long-term safety and antiviral activity of enfuvirtide-based antiretroviral therapy". AIDS. 17 (5): 691–8. doi:10.1097/00002030-200303280-00007. PMID 12646792. S2CID 32014873.
  4. ^ Su SB, Gong WH, Gao JL, Shen WP, Grimm MC, Deng X, et al. (June 1999). "T20/DP178, an ectodomain peptide of human immunodeficiency virus type 1 gp41, is an activator of human phagocyte N-formyl peptide receptor". Blood. 93 (11): 3885–92. doi:10.1182/blood.V93.11.3885. PMID 10339497.
  5. ^ Roche Products Pty Ltd. Fuzeon (Australian Approved Product Information). Dee Why (NSW): Roche; 2005.
  6. ^ Greenberg ML, Cammack N (August 2004). "Resistance to enfuvirtide, the first HIV fusion inhibitor". The Journal of Antimicrobial Chemotherapy. 54 (2): 333–40. doi:10.1093/jac/dkh330. PMID 15231762.
  7. ^ Wild C, Greenwell T, Shugars D, Rimsky-Clarke L, Matthews T (1995). "The Inhibitory Activity of an HIV Type 1 Peptide Correlates with Its Ability to Interact with a Leucine Zipper Structure". AIDS Research and Human Retroviruses. 11 (3): 323–25. doi:10.1089/aid.1995.11.323. PMID 7786578.
  8. ^ De Clercq E (July 1995). "Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention with HIV Infections". Journal of Medicinal Chemistry. 38 (14): 2491–2517. doi:10.1021/jm00014a001. PMID 7543152.
  9. ^ "Drugs@FDA: FDA Approved Drug Products – Fuzeon (Click on 'Approval Date(s) and History, Letters, Labels, Reviews for NDA 021481')". accessdata.fda.gov. United States Food and Drug Administration. Archived from the original on 28 June 2017. Retrieved 6 January 2019.