Enfuvirtide

Base Information

• Chemical Name: Enfuvirtide
• CAS No.: 159519-65-0
• Deprecated CAS: 262434-79-7
• Molecular Formula: C204H301N51O64
• Molecular Weight: 4491.90
• Hs Code.: 3504009000
• European Community (EC) Number: 641-385-0
• UNII: 19OWO1T3ZE
• ChEMBL ID: CHEMBL525076
• DSSTox Substance ID: DTXSID20166672
• NCI Thesaurus Code: C2105
• RXCUI: 139896
• Wikipedia: Enfuvirtide
• Mol file: 159519-65-0.mol

Synonyms:DP 178;DP-178;DP178;enfuvirtide;Fuzeon;pentafuside;peptide T20;T20 peptide;T20, Peptide

Chemical Property of Enfuvirtide

Chemical Property:

• Appearance/Colour: White to off-white amorphous solid
• PSA: 1902.89000
• Density: 1.59g/cm3
• LogP: 5.69700
• Storage Temp.: ?20°C
• XLogP3: -14.7
• Hydrogen Bond Donor Count: 63
• Hydrogen Bond Acceptor Count: 67
• Rotatable Bond Count: 151
• Exact Mass: 4491.1933541
• Heavy Atom Count: 319
• Complexity: 11200

Purity/Quality:

98% ^*data from raw suppliers

Enfuvirtide acetate salt ≥95% (HPLC) ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Drug Classes: Antiviral Agents
• Canonical 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(CC1=CNC2=CC=CC=C21)C(=O)NC(C)C(=O)NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC3=CNC4=CC=CC=C43)C(=O)NC(CC(=O)N)C(=O)NC(CC5=CNC6=CC=CC=C65)C(=O)NC(CC7=CC=CC=C7)C(=O)N)NC(=O)C(CC(C)C)NC(=O)C(CO)NC(=O)C(CC8=CN=CN8)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(CC9=CC=C(C=C9)O)NC(=O)C
• Isomeric SMILES: 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](CC1=CNC2=CC=CC=C21)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](CC3=CNC4=CC=CC=C43)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC5=CNC6=CC=CC=C65)C(=O)N[C@@H](CC7=CC=CC=C7)C(=O)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CC8=CN=CN8)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](CC9=CC=C(C=C9)O)NC(=O)C
• Recent ClinicalTrials: Optimized Antiretroviral Therapy During Allogeneic Hematopoietic Stem Cell Transplantation in HIV-1 Individuals
• Recent EU Clinical Trials: Studio PKCT - Pharmacokinetics of chemotherapy when given concurrently with antiretroviral (Protocol no. CSL01).
• Description: 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. 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 (Kd = 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.
• Uses: Antiviral (blockade of gp-41 mediated membrane fusion). Fuzeon (Roche) [Note—The trivial name, pentafuside, has appeared in literature.
• 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.
• 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
• Drug interactions: Potentially hazardous interactions with other drugs Orlistat: absorption possibly reduced by orlistat.