Medical Pharmacology: Antiviral Drugs

→Entry Inhibitors: The drug enfuvirtide, derived from gp41, binds to gp41 in a way that prevents the structural change needed for fusion (see previous page).

Another drug, maraviroc, inhibits viral entry by binding to one of the chemokine HIV co-receptors, CCR5, thus inhibiting interaction with gp120 and inhibiting fusion initiation.¹

Maraviroc (Selzentry, Celsentri)

In 2007 the US FDA approved the first member of a new group of antiretroviral drugs used for treating HIV-1 infection.²

This agent, Maraviroc (Selzentry, Celsentri) acts by interfering with the interaction between HIV-1 gp120 protein and the chemokine co-receptor CCR5.
Maraviroc was FDA approved for use in those patients experiencing virologic failure secondary to resistance to other antiviral medications.²

**HIV Entry and Locations of Different Entry Inhibitor Sites of Action⁸**

"A schematic illustration of HIV entry in the steps presented by different entry inhibitors. "HIV entry can be divided into 3 discrete steps: Attachment of the viral glycoprotein (gp120) to the CD4 receptor, followed by subtle conformational changes in gp120 which expose structural elements on the v3 loop that bind to co-receptor, either CCR5 or CXCR4. This induces a structural rearrangement in gp41 which inserts a hydrophobic fusion peptide region into the target cell membrane. This brings the virus and cell membrane in close apposition to initiate fusion and ultimately entry of the virus into the target cell. HIV entry inhibitors can be thought of as 3 distinct subclasses, each targeting one of the 3 previous steps."

Studies about 30 years ago identified the CD4 receptor as the principal target for HIV-1 binding to CD4⁺ cells.

Experiments using hybrid mouse cells expressing human CD4⁺ indicated that CD4⁺ binding by itself is insufficient to cause viral entry.

Subsequently, two co-receptors were discovered.

These co-receptors were CCR5 (C-C chemokine Receptor type 5)and CXCR4 and were chemokine receptors which were also necessary for viral entry, along with the CD4⁺ receptor.

CCR5 is associated with naturally occurring ligands:

Such as macrophage inflammatory protein (MIP) 1α and 1β i.e. MIP1α and MIP1β (also known as CCL3 and CCL4) and
RANTES, which is a chemotactic protein also known as CCL5.

**Membrane Associated CCR5 (RANTES)⁵**

CCR5 receptor is depicted as yellow with the cell membrane gray

**CCL5 (RANTES) Structure⁴**

"The beta-chemokines include RANTES (Regulated upon Activation, Normal T-cell Expressed and Secreted) as well as macrophage inflammatory protein-1 (MIP-1) α and β, and interleukin-8...."³ Here, the structure of RANTES is shown (Chung et al. Biochemistry 34:9307, 1995). It is a small (8 kDa (kilodalton)) dimeric protein that is highly basic (pI 9.5) in which is made up of two identical subunits of 68 amino acids each. The two monomers are shown."³

**Ligand Binding Domain between CCR5 and Maraviroc¹³**

Top view of the ligand-binding pocking in CCR5 (blue) and the antiretroviral drug Maraviroc (Orange) Attribution: Figure 3 A from reference (13); Tan et al., 2013.

These HIV-1 co-receptors, CXCR4 and CCR5, are part of the G protein-coupled receptor superfamily described in earlier sections.⁶
- These G proteins systems have been identified as important pharmacological therapeutic targets in a variety of diseases.
- CCR5 is considered an especially important therapeutic target since genetic absence of surface expression of this protein confers nearly complete resistance to HIV-1 infection.⁷

Maraviroc (Selzentry, Celsentri) Pharmacology

Introduction:
- Maraviroc inhibits association between gp120, HIV outer envelope protein, and the CCR5 chemokine receptor.⁸
  - Maraviroc activity is limited to those HIV strains expressing CCR5 and therefore exhibits no activity against those HIV strains which are either CXCR4 expressing or which express both CCR5 and CXCR4 co-receptors.
  - As a result of this focused mechanism of action, Maraviroc has the advantage of retaining antiretroviral efficacy even when HIV strains exhibit resistance to other antiretroviral drugs.⁸

Drug Resistance:²

Resistance to the antiretroviral activity of Maraviroc appears to occur in either of two mechanisms.²

The first mechanism involves a change in tropism such that the HIV-1 strain becomes able to use the CXCR4 chemokine co-receptor.
The second mechanism allows HIV-1 to continue to use the CCR5 co-receptor even though it is being blocked by Maraviroc.
Of these two mechanisms of resistance development, the change in tropism may be of particular clinical concern since virus that can use the CXCR4 co-receptor may be associated with a more rapid decline in CD4⁺ lymphocyte count and disease progression.¹⁰

However, the main mechanism of Maraviroc resistance is likely the ability of HIV-1 to use Maraviroc-associated CCR5 co-receptors.

This mutation appears to depend on multiple mutations in the V3 loop of gp120.²

V3 Loop of HIV Envelop Protein gp120¹¹

The HIV-V3 loop of the gp120 envelope glycoprotein consists of 35 amino acids with a disulfide bond. This region forms 3 helices, 5 beta turns and 1 gamma turn.¹¹

In this setting increasing concentrations of Maraviroc does not result in increased viral inhibition. Intrinsic resistance to Maraviroc appears limited and cross-resistance with the fusion inhibitor enfuvirtide has not been observed.²

Pharmacokinetics:⁹
- The dose-dependent oral bioavailability of Maraviroc is about 20%-30%.
  - Food decreases bioavailability as much as 50% in this agent exhibits protein binding in human plasma in the range of about 75%.
- The P450 microsomal metabolizing system is responsible for biotransformation and supports Maraviroc elimination with a half-life of about 10 hours.
  - The P450 isozyme primarily implicated in elimination is CYP3A4.²
- Pharmakokinetics of Maraviroc may be affected by agents that inhibit CYP3A.
  - For example, itraconozole, lopinavir, lopinavir plus ratonavir, ratonavir, saquinavir and ataznavir increase maximal plasma concentration of Maraviroc as well as increasing the area under the curve (AUC).²

Clinical/Therapeutic Uses:⁹

Maraviroc (Selzentry, Celsentri) is FDA approved for use in HIV-infected patients (adults) whose HIV infection consists mainly of the CCR5-tropic virus.
The addition of Maraviroc to patients receiving optimal, typically multidrug antiviral treatment but with documented multidrug resistant HIV-1 appears clinically beneficial.
- For example, after about six months of Maraviroc treatment, 44% of patients resistant to multidrug antivirals, exhibit undetectable (<50 copies/ml) plasma HIV-1 RNA following Maraviroc treatment.
- The value of 44% is compared with 17% achieving this level of HIV-1 plasma on multidrug treatment.
- Maraviroc-treated individuals also showed a higher mean CD4 lymphocyte count compared to patients on other multidrug antivirals (120 cells/ml versus 61 cell/ml).

**Maraviroc with darunavir/ritonavir Combination Therapy: Analysis¹⁴**

Attribution: Stellbrink HJ Pulik P Szlavic J Murphy D Lazzarin A Portilla J Rinehart A Le Fevre E Fang A Valluri S Mukwaya G Heera J Maraviroc (MVC) Once Daily with Darunavir/Ritonavir (DRV/r) Compared to Tenofovir/Emtricitabine (TDF/FTC) With DRV/r: 48 Week Results from MODERN (Study A4001095) https://www.youtube.com/watch?v=JMMqkXx4YrU (7/2014) International AIDS Conference YouTube Channel: https://www.youtube.com/channel/UCBBhpWA2uqSzk2lfFig-7JQ

Noting that Maraviroc adminstration results in limited to no therapeutic effectiveness in those patients whose HIV-1 strain exhibits CXCR4 or dual/mixed CCR5 + CXCR4 chemokine co-receptors, Maraviroc cost-effectiveness may be limited due to the need for phenotype testing.⁹