**39. Maraviroc**

A success story has been the introduction CCR5 antagonist, Maraviroc, trade name Selzentry or Celsentri into clinical practice. Maraviroc is a non-competitive CCR5 antagonist that selectively binds to the human CCR5, present on the cell membrane, preventing the interaction with HIV-1 env gp 120. CCR5 is necessary for CCR5-tropic HIV-1 to enter cells. It is metabolized in the liver. Drug plasma concentrations are likely to be increased in patients with hepatic impairment. Route of metabolism is through Cytochrome P450 3A4 (CYP3A). The drug has shown potent activity against multidrug-resistance CCR5-tropic HIV-1 strains. It has antiviral activity *in vitro* against CCR5 tropic HIV-1 isolates from various subtypes. However, Maraviroc has no activity against CXCR4-tropic and dual tropic HIV-1. It has been found to be effective, efficient and safe to use in combination with other antiretroviral agents such as with lopinavir/ritonavir plus efavirenz or saquinavir/ritonavir plus efavirenz in adult patients with exclusive CCR5 tropic HIV-1 isolates. Maraviroc was developed by Pfizer Inc. (Kent, UK).

**Figure 5.** Structure of Maraviroc adopted from chemicalbook.com

Maraviroc inhibit CCR5 binding and signaling at nanomolar (nM) concentrations (IC90 of 2 nM). It is well tolerated with most common mild to moderate side-effects including headache, asthenia, dizziness, gingivitis and nausea. It is known that before starting on a coreceptor antagonist, patients need to determine their viral tropism. The introduction of the CCR5 antagonist, maraviroc for HIV-1 therapy has increased the research interest in the epidemiology of tropism and its relationship with HIV-1 subtype. A greater understanding of the tropism of non-B subtypes is key for the optimal use of CCR5 antagonists in the treatment of these infections in the developing world and HIV-1 prevention strategies. There is no food effect as it can be taken with or without food and can be stored at room temperature. Hence it is very suitable for resource poor settings which also bear the brunt of the HIV scourge with predominant R5 variants.

**Figure 6.** Mode of action of maraviroc, adopted from Qian K, 2008.

#### **40. Challenges of CCR5 antagonists**

254 Immunodeficiency

**39. Maraviroc** 

Tak-652, spirodiketopiperazine derivatives such as E913 and SCH-C/SCH-351125. Spirodiketopiperazine derivatives have been associated with severe hepatotoxicity, leading to the cancellation of their development. SCH351125 or SCH-C was the first CCR5 antagonist to enter clinical efficacy studies but has been dropped out due to variable antiviral effect and provocation of prolonged QTc interval. To counter these setbacks Vicriviroc was developed

Two agents, maraviroc and vicriviroc, are the agents within this family that have passed the final stages of clinical development. These agents have their scientific names ending in "– viroc", to denote their action of "viral receptor occupancy". Since these drugs show activity against R5 viruses only, viral tropism testing should be made before their prescription and eventually during treatment in order to exclude the presence of X4 viruses. They are less expensive to produce and have good oral bioavailability. Their half maximal inhibitory

A success story has been the introduction CCR5 antagonist, Maraviroc, trade name Selzentry or Celsentri into clinical practice. Maraviroc is a non-competitive CCR5 antagonist that selectively binds to the human CCR5, present on the cell membrane, preventing the interaction with HIV-1 env gp 120. CCR5 is necessary for CCR5-tropic HIV-1 to enter cells. It is metabolized in the liver. Drug plasma concentrations are likely to be increased in patients with hepatic impairment. Route of metabolism is through Cytochrome P450 3A4 (CYP3A). The drug has shown potent activity against multidrug-resistance CCR5-tropic HIV-1 strains. It has antiviral activity *in vitro* against CCR5 tropic HIV-1 isolates from various subtypes. However, Maraviroc has no activity against CXCR4-tropic and dual tropic HIV-1. It has been found to be effective, efficient and safe to use in combination with other antiretroviral agents such as with lopinavir/ritonavir plus efavirenz or saquinavir/ritonavir plus efavirenz in adult patients with exclusive CCR5 tropic HIV-1 isolates. Maraviroc was developed by Pfizer Inc. (Kent, UK).

Maraviroc inhibit CCR5 binding and signaling at nanomolar (nM) concentrations (IC90 of 2 nM). It is well tolerated with most common mild to moderate side-effects including

which was much more potent than SCH-C, safer and better oral bioavailability.

concentrations (IC50) are in the nanomolar ranges.

**Figure 5.** Structure of Maraviroc adopted from chemicalbook.com

The CCR5-to-CXCR4 switch represents a concern because while CCR5 inhibitors suppress R5 viruses they may allow the emergence of CXCR4-tropic viruses. Efforts to develop HIV entry inhibitors are hampered by problems associated with rapid evolution of the virus, leading to drug resistance. Blocking only one of the pathways for HIV entry into cells has resulted in the opening of the other pathways potentially accelerating disease progression by promoting the evolution of more virulent CXCR4-dependent variants. In this view, AnorMED Company has announced the discovery and development of a joint CXCR4/CCR5 antagonist although little is known about the binding mechanism at this time.

#### **41. Future of coreceptor antagonists**

There have been speculations that new, safe and effective chemokine receptor inhibitors should facilitate CCR5 and CXCR4 internalization independent of the cellular signaling. The most anticipated eventual combination of CXCR4 and CCR5 inhibitors would be beneficial,

since selective pressure could direct the virus to use less productive coreceptors, avoiding the progression of the disease. In addition leveraging new technologies capable of detecting low-level minority species may provide the most significant advances in ensuring that individuals with low levels of dual/mixed tropic virus are not inadvertently prescribed CCR5 antagonists.

Coreceptor Usage in HIV Infection 257

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