159519-65-0

N-acetyl-L-tyrosyl-L-threonyl-L-seryl-L-leucyl-L-isoleucyl-L-histidyl-L-seryl-Lleucyl- L-isoleucyl-L-glutamyl-L-glutamyl-L-seryl-L-glutaminyl-L-asparaginyl-Lglutaminyl- L-glutaminyl-L-glutamy-L-lysyl-L-asparaginyl-L-glutamyl-L-glutaminyl- L-glutamyl-L-leucyl-L-leucyl-L-glutamyl-L-leucyl-L-aspartyl-L-lysyl-L-tryptophyl- L-alanyl-L-seryl-L-leucyl-L-tryptophyl-L-asparaginyl-L-tryptophyl-L-phenylalaninamide Enfuvirtide is the first of a new class of HIV therapeutics that interferes with the entry of HIV-1 by inhibiting fusion of viral and cellular membranes. It binds to the first heptad-repeat (HR1) in ghe gp41 subunit of the viral envelope glycoprotein and prevents the conformational changes required for the fusion with cell membranes, thus representing a new mechanism. It is a potent inhibitor of this binding with an IC₅₀ in laboratory and primary isolates (HIV-1 clades A–G) ranging from 4 to 280 nM (18–1260 ng/mL), but has virtually no activity against HIV-2. Due to its unique mechanism, it does not show cross-resistance to NRTI, NNRTI and PIs. It is prepared by chemical synthesis, using a combination of solution and solid phase steps. The solid phase steps utilize fmoc protection and the acid sensitive 2- chlorotrityl chloride resin to produce peptides of lengths ranging from nine to sixteen amino acids. These amino acids are subsequently coupled to form the full-length peptide followed by side-chain deprotection and column chromatography. In the HuPBMC-SCID mouse model of HIV-1 infection enfuvirtide showed a dosedependent decrease in viral load. At doses of 200 mg/kg/day, it decreased the RNA levels to 8.2 copies/1 million cells compared to 17 million copies/1 million cells in the saline-treated group. In a clinical study involving 78 heavily pretreated patients (plasma HIV RNA＞5000 copies/mL), enfuvirtide dosing of 12.5–200 mg/day by b.i.d. subcutaneous injection resulted in a dose-dependent decrease in viral load (plasma HIV RNA 0.3–1.6 log 10 copies/mL). In a combination drug study where all patients received an optimized retroviral regimen with or without enfuvirtide, it was found that, at week 24, the enfuvirtide group had a 4.5 fold-relative drop in HIV RNA copies/mL relative to the standard treatment group. Subjects received 3–5 antiretroviral agents with or without enfuvirtide. In clinical trials, HIV-1 isolates from 185 patients using enfuvirtide in a cocktail with other antiretroviral agents showed 4 to 422-fold decrease in sensitivity to this drug. These more resistant types had changes in the gp41 amino acids 36–45. Enfuvirtide is dosed twice per day (90 mg) by subcutaneous injection and has an elimination half-life of about 3.8 h. It is highly plasma protein bound (92%) and has a Vdss is 5.5 L. Local injection site irritation (98% had at least one reaction), diarrhea (26.8%), nausea (20.1%), and fatigue (16.1%) were the most common adverse events.

Duke University (US)

Antiviral (blockade of gp-41 mediated membrane fusion). Fuzeon (Roche) [Note—The trivial name, pentafuside, has appeared in literature.

ChEBI: A synthetic 36-amino acid peptide consisting of N-acetyltyrosyl, threonyl, seryl, leucyl, isoleucyl, histidyl, seryl, leucyl, isoleucyl, alpha-glutamyl, alpha-glutamyl, seryl, glutaminyl, asparaginyl, glutaminyl, glutamin l, alpha-glutamyl, lysyl, asparaginyl, alpha-glutamyl, alpha-glutamyl, alpha-glutamyl, leucyl, leucyl, alpha-glutamyl, leucyl, alpha-aspartyl, lysyl, tryp ophyl, alanyl, seryl, leucyl, tryptophyl, asparaginyl, tryptophyl, and phenylalaninamide residues joined in sequence. An HIV fusion inhibitor, it was the first of a novel class of antiretroviral drugs used in combination therapy for the treatment of HIV-1 nfection. It interferes with entry of HIV into cells by binding to the gp41 sub-unit of the viral envelope glycoprotein, so inhibiting fusion of viral and cellular membranes.

Fuzeon

Enfuvirtide is used in combination with other antiretrovirals and works against a variety of HIV-1 variants, but it is not active against HIV-2. Resistance to enfuvirtide can develop when the virus produces changes in a 10-amino-acid domain between residues 36 to 45 in the gp41 HIV surface glycoprotein.

Resistance is mediated by amino acid substitutions within the first heptad repeat region of gp41 at amino acids 36–45. Resistance emerges fairly rapidly in patients experiencing virological failure with an enfuvirtide-containing antiretroviral regimen, and is associated with the return of the plasma HIV load toward baseline within a few weeks.

A linear 36-amino acid synthetic peptide with an acetylated N-terminus and a carboxamide C-terminus. It is formulated as a lyophilized powder to be reconstituted for subcutaneous injection.

Enfuvirtide is an HIV fusion inhibitor used to patients with multi-drug resistant HIV. Enfuvirtide binds to gp41 preventing the creation of an entry pore for the HIV-1 virus.

Subcutaneous absorption c. 84.3%
C_max 90 mg s/c twice daily c. 4.59 mg/L
Plasma half-life c. 3.8 h
Volume of distribution 5.5 L
Plasma protein binding c. 92%
Absorption and distribution
Absorption of the 90 mg dose is comparable when injected into the subcutaneous tissue of the abdomen, thigh or arm. It does not penetrate the CSF or semen. Distribution into breast milk has not been described.
Metabolism and excretion
It probably undergoes catabolism to its constituent amino acids, with subsequent recycling of the amino acids in the body pool.

Treatment of HIV infection (in combination with other antiretroviral drugs) in adults and children older than 6 years who show evidence of HIV-1 replication despite ongoing antiretroviral therapy

It does not seem to have any long-term toxicities (including the HIV lipodystrophy syndrome) associated with other commonly used antiretrovirals. Reaction at the injection site, variously characterized by local pain, erythema, pruritus, induration, ecchymosis, nodules or cysts, is experienced by more than 90% of patients and may lead to treatment fatigue.

Potentially hazardous interactions with other drugs Orlistat: absorption possibly reduced by orlistat.

As a peptide, enfuvirtide is expected to undergo catabolism to its constituent amino acids, with subsequent recycling of the amino acids in the body pool. In vitro human microsomal studies and in vivo studies indicate that enfuvirtide is not an inhibitor of CYP450 enzymes. In in vitro human microsomal and hepatocyte studies, hydrolysis of the amide group of the C-terminus amino acid, phenylalanine results in a deamidated metabolite. Mass balance studies to determine elimination pathway(s) of enfuvirtide have not been performed in humans.

[1] PAOLO INGALLINELLA. Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency.[J]. Proceedings of the National Academy of Sciences of the United States of America, 2009, 106 14: 5801-5806. DOI: 10.1073/pnas.0901007106
[2] M JULIANA MCELRATH. Ex vivo comparison of microbicide efficacies for preventing HIV-1 genomic integration in intraepithelial vaginal cells.[J]. Antimicrobial Agents and Chemotherapy, 2010, 54 2: 763-772. DOI: 10.1128/aac.00891-09
[3] KELLY CHAMPAGNE  Michael J R  Akira Shishido. Interactions of HIV-1 inhibitory peptide T20 with the gp41 N-HR coiled coil.[J]. The Journal of Biological Chemistry, 2009, 284 6: 3619-3627. DOI: 10.1074/jbc.m809269200
[4] S B SU. T20/DP178, an ectodomain peptide of human immunodeficiency virus type 1 gp41, is an activator of human phagocyte N-formyl peptide receptor.[J]. Blood, 1999, 93 11: 3885-3892.