Entry and fusion inhibitors

crop_square Key points

  • check_circle Diverse class of drugs most of which prevent HIV-1 from cell entry
  • check_circle Various drug targets including CCR5 and CXCR4 co-receptors
  • check_circle Bulevirtide is an entry inhibitor against hepatitis B and D cell entry

crop_square Background and biochemistry

Entry and membrane fusion inhibitors are primarily used for treatment of HIV-1. This is a diverse class of drugs targeting various receptors and coreceptors essential for viral cell entry. Enfuvirtide was the first anti-HIV-1 fusion inhibitor approved by the FDA in 2003. HIV-1 cell entry depends on the interactions between the viral transmembrane protein env (glycoprotein 160) and host cells. Post-translational cleavage of the gp160 polyprotein creates glycoprotein 41 (gp41) and glycoprotein 120 (gp120). The first step of HIV-1 cell entry is the attachment of gp120 to the human immune cell’s CD4+ receptor. Bulevirtide is a recently approved drug (2021) for the treatment of chronic hepatitis D.

crop_square Mechanism of action

Fostemsavir is a prodrug (active metabolite temsavir) that binds to gp120 preventing attachment to the CD4+ receptor. C-C chemokine receptor type 5 (CCR5) and C-X-C chemokine receptor type 4 (CXCR-4) are expressed on the surface of human immune cells and serve as essential co-receptors for HIV-1 gp120 mediated viral cell entry. This interaction is blocked by CCR5 receptor antagonists such as Maraviroc. Ibalizumab is a monoclonal antibody which binds to the CD4+ receptor causing conformational changes to the CD4+/gp120 complex which subsequently blocks the attachment of gp120 to co-receptors (CCR5/CXCR4). Enfuvirtide binds to gp41 which prevents conformational changes necessary for the fusion of viral and cellular membranes. is a recently approved drug that inactivates the sodium/bile acid cotransporter (Na+-taurocholate cotransporting polypeptide - NTCP) expressed on human hepatocytes blocking the entry of hepatitis B and hepatitis D virions.

crop_square Drugs and spectrum of activity

drug name drug target antiviral spectrum
Fostemsavir gp120
Maraviroc CCR5
Ibalizumab CD4+/gp120
Enfuvirtide gp41
Bulevirtide NTCP

All HIV entry and fusion inhibitors listed above are only used in combination with antiretroviral drugs of other classes. HIV-2 is intrinsically resistant to enfuvirtide. Fostemsavir is not active against HIV-2. There is a lack of clinical data on the use of maraviroc and ibalizumab in HIV-2.

crop_square Pharmacokinetics

Both fostemsavir and maraviroc show low bioavailability of around 30% following oral administration. Fostemsavir is rapidly metabolised to its active metabolite temsavir and undergoes further complex hepatic metabolization. Maraviroc is primarily metabolised by CYP3A4 and mostly eliminated through faeces. Fostemsavir metabolites are primarily excreted in the urine. Ibalizumab is administered through the vein, like many monoclonal antibodies. Enfuvirtide and bulevirtide are given subcutaneously only. Proteins (monoclonal antibodies like Ibalizumab) and peptide chains (enfuvirtide and bulevirtide) are not hepatically metabolised or eliminated in the urine. They are catabolised to amino acid residues.

crop_square Adverse drug effects

Entry and fusion inhibitor adverse drug affects vary considerably. Maraviroc and fostemsavir are known to cause gastrointestinal symptoms. Maraviroc may rarely cause osteonecrosis. Ibalizumab is generally well-tolerated but may cause severe allergic reactions like other monoclonal anitbodies. Enfuvirtide therapy commonly causes diarrhoea, nausea and fatigue. Bulevirtide is generally well-tolerated.