Энфувиртид

Описание

Enfuvirtide is a biomimetic peptide inhibitor of HIV-1 fusion with CD4⁺ cells. It inhibits HIV-1 infectivity of HeLa cells stably expressing CD4 by the HXB2 strain (IC₅₀ = 692 pM) and by clinical isolates (IC₉₀s = 6.1-61 nM) in a single-cycle infectivity assay. It also inhibits genomic integration of HIV-1 into human intraepithelial vaginal cells and peripheral blood mononuclear cells (PBMCs; IC₅₀s = 51.2 and 13.58 μM, respectively). Enfuvirtide binds to a recombinant molecular mimic of HIV-1 glycoprotein gp41 that contains three N-terminal heptad and two C-terminal heptad repeat regions (K_d = 32 nM). It also binds to recombinant formyl peptide receptors (FPR) expressed in rat basophilic leukemia cells (IC₅₀ = 5 nM) and attracts and activates human peripheral blood phagocytes, but not T lymphocytes, in vitro when used at a concentration of 100 nM. Formulations containing enfuvirtide have been used in combination therapy for the treatment of HIV-1/AIDS.

Использование

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

Определение

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.

Биологические функции

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.

Приобретенная устойчивость

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.

Общее описание

Enfuvirtide acetate salt is a linear synthetic peptide made of 36 amino acids. It has an acetylated N-terminus and a carboxamide C-terminus. Enfuvirtide is catabolized with the help of proteolytic enzymes.

Фармацевтические приложения

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.

Фармакокине?тика

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.

Клиническое использование

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

Побочные эффекты

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.