159519-65-0 Usage
Description
Enfuvirtide, also known as Fuzeon, is a synthetic 36-amino acid peptide and the first of a new class of HIV therapeutics. It functions as an HIV fusion inhibitor, interfering with the entry of HIV-1 by inhibiting the fusion of viral and cellular membranes. Enfuvirtide binds to the first heptad-repeat (HR1) in the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for fusion with cell membranes. It is prepared by chemical synthesis and is catabolized with the help of proteolytic enzymes.
Uses
Used in Pharmaceutical Industry:
Enfuvirtide is used as an antiviral agent for the treatment of HIV-1/AIDS. It is particularly effective due to its unique mechanism of action, which does not show cross-resistance to NRTI, NNRTI, and PIs. Enfuvirtide is used in combination therapy, providing a new approach to treating HIV-1 infections, especially in heavily pretreated patients.
Enfuvirtide is used as a biomimetic peptide inhibitor for preventing HIV-1 infectivity in HeLa cells stably expressing CD4 and inhibiting genomic integration of HIV-1 into human intraepithelial vaginal cells and peripheral blood mononuclear cells (PBMCs). It is also used to bind to a recombinant molecular mimic of HIV-1 glycoprotein gp41, as well as to recombinant formyl peptide receptors (FPR) expressed in rat basophilic leukemia cells, attracting and activating human peripheral blood phagocytes in vitro.
In clinical studies, Enfuvirtide has demonstrated a dose-dependent decrease in viral load and has shown synergistic effects when combined with conventional antiretroviral agents, enhancing chemo-sensitivity and efficacy in resistant cases. It is administered twice per day by subcutaneous injection and is highly plasma protein bound.
Originator
Duke University (US)
Biological Functions
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.
Acquired resistance
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.
Pharmaceutical Applications
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.
Biochem/physiol Actions
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.
Pharmacokinetics
Subcutaneous absorption c. 84.3%
Cmax 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.
Clinical Use
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
Side effects
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.
Drug interactions
Potentially hazardous interactions with other drugs
Orlistat: absorption possibly reduced by orlistat.
Metabolism
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.
Check Digit Verification of cas no
The CAS Registry Mumber 159519-65-0 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,5,9,5,1 and 9 respectively; the second part has 2 digits, 6 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 159519-65:
(8*1)+(7*5)+(6*9)+(5*5)+(4*1)+(3*9)+(2*6)+(1*5)=170
170 % 10 = 0
So 159519-65-0 is a valid CAS Registry Number.
InChI:InChI=1/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)
