Function of enfuvirtide in HIV-1 infection

2018-09-21

Introduction 

Enfuvirtide, also named pentafuside, is an HIV fusion inhibitor originated at Duke University, where researchers formed a pharmaceutical company known as Trimeris. It was approved by U.S. food and drug administration (FDA) on March 13, 2003 as the first novel class of antiretroviral drugs used in combination therapy for the treatment of HIV-1 infection. It's a linear 36-amino-acid polypeptide chain with acetylation at the N-terminal and carboxyamide at the C-terminal. The product of enfuvirtide is a white or gray-white amorphous solid insoluble in pure water, while the solubility is 82-142 g/ml in the buffer solution of pH 7.5.

Pharmacologic action

A biomimetic peptide, enfuvirtide is a synthetic peptide HIV fusion inhibitor, which can bind to viral envelope glycoprotein and prevent the conformation change necessary for virus fusion with cell membrane, thus inhibiting the replication of HIV-1. In more detail, it's derives from a natural amino acid sequence in the HR2 domain of GP41 by simulating the activity of the HR2 domain and competing bind with the HR1 domain of GP41 to prevent the interaction between HR1 and HR2 and the configuration change of GP41, and then stop the virus from fusion with the host cells.

Function

This product is a HIV fusion inhibitor, a synthetic peptide derived from highly conserved sequence of HIV-1 transmembrane fusion protein GP41, can prevent virus fusion and entry into cells. It can be combined with the first seven repeat sequences (HRI) on the GP4l subunit of viral envelope glycoprotein to prevent the necessary conformation changes of virus and cell membrane fusion. In vitro experiments showes that this product can inhibit the activity of HIV-1 (80 ng/ml can inhibit its infectivity) and reduce the replication of HIV-1.

Pharmacokinetics and metabolism

Studies on biological distribution in rodents show that enfuvirtide easily enter the lymphatic system and reach the maximum concentration in lymphoid node 30 min after intravenous injection. In the circulatory system, the half-life of the drug is 2.4 h and the drug concentration above IC 50 can be sustained for 6 hours. The plasma clearance of this drug followed a double exponential process. The phase half-life of subcutaneous and intramuscular administration is 15 min and the elimination half-life is about 2.5 h. Clinical studies also provide pharmacokinetic information about the product in humans. The drug is given intravenously twice a day for 14 days, reaching the maximum detectable concentration, maximum theoretical concentration and area under the curve, and increasing with the increase of dosage. The median half-life of circulatory system is 1.83 h, and there is no significant difference between single dose and continuous administration. The pharmacokinetic study of children ages from 3 to 12 years shows that the plasma drug concentration can be maintained at a low level above 1 μ g/ml (this is considered necessary to effectively suppress the virus) for 12 hours after subcutaneous administration for 60 mg/m2.

References:

1. Wild, C. T., Shugars, D. C., Greenwell, T. K., Mcdanal, C. B., & Matthews, T. J. (1994). Peptides corresponding to a predictive α-helical domain of human immunodeficiency virus type 1 gp41 are potent inhibitors of virus infection. Proc Natl Acad Sci U S A, 91(21), 9770-9774.

2. Chowdhury S, Roy P K, Smith R J. Mathematical Modelling of Enfuvirtide and Protease Inhibitors as Combination Therapy for HIV [J]. International Journal of Nonlinear Sciences & Numerical Simulation, 2016, 17(6):259-275.

3. Cheng S, Wang Y, Zhang Z, et al. Enfuvirtide-PEG conjugate: A potent HIV fusion inhibitor with improved pharmacokinetic properties [J]. European Journal of Medicinal Chemistry, 2016, 121:232.

4. Cooper D A, Lange J M. Peptide inhibitors of virus-cell fusion: enfuvirtide as a case study in clinical discovery and development [J]. Lancet Infectious Diseases, 2004, 4(7):426.

5. Zhu X, Zhu Y, Ye S, et al. Improved Pharmacological and Structural Properties of HIV Fusion Inhibitor AP3 over Enfuvirtide: Highlighting Advantages of Artificial Peptide Strategy [J]. Scientific Reports, 2015, 5:13028.

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