Maraviroc

Tanjila

Acquired immunodeficiency syndrome (AIDS) was recognized as a disease in 1981 due to human immunodeficiency virus 1 (HIV-1). Soon, AIDS became a worldwide the biggest infectious disease globally due to its high progressive nature and lethality. For treatment, the first approach was nucleoside reverse transcriptase inhibitors, (NRTIs), then came the non-nucleoside reverse transcriptase inhibitors (NNRTIs), and in the mid-1990s, the first HIV-1 protease inhibitors. The highly active antiretroviral therapy (HAART) combination dosing regimens came that currently includes oral antiretroviral agents targeting host CD4 T-cells after HIV infection, the replication of HIV and the assembly stages. The recent development in HIV research is drugs targeting virus before the entry into the host cell, in attachment, fusion and penetration stages. Maraviroc is the drug preventing HIV1 from entry into the host cell, introducing a new class of drug therapy called chemokine co receptor antagonist or entry inhibitor.

During research work of HIV, scientists tried to find drugs targeting HIV entry to host cell.

The first licensed drug in this class, enfuvirtide, acted by binding to the viral envelope protein gp41 and preventing a post attachment of the viral entry. The drug had excellent efficacy in treatment experienced patients, but the mode of administration and cost of goods associated with a complex peptide drug had restricted its use.

Efforts had focused on small-molecule HIV-1 entry disrupters to enable oral delivery. It included the discovery of gp120-CD4-binding inhibitors and blockade of CXCR4 via antagonism but met challenges in efficacy and significant side effects, respectively.

The greatest success in targeting HIV-1 entry as a new mechanism has been developed as chemokine co receptor CCR5 antagonist.  

The chemokine receptors most commonly utilized by HIV-1 are CCR5 and/or CXCR4, with CCR5 being almost exclusively the essential and sole co receptor for infection of a person previously uninfected.

In 1996, CCR5 was identified as the predominant and essential coreceptor for HIV-1 cell entry, thereby triggering a widespread search for finding new therapeutic agents that targeted a host rather than a viral factor. The rationale for targeting viral entry as a novel approach to HIV therapy arose from the discovery of commonly occurring CCR5 mutation known as delta 32 mutation on chromosome 3.

Each CCR5 mutated gene results in the production of non-functional CCR5 co receptors (known as delta 32 homozygotes) that are not susceptible to HIV1 infection like typical CCR5 receptors. Delta 32 heterozygotes can be affected but the disease progression in delayed than normal CCR5 co receptors.

A decade later, CCR5 antagonist drug class included a number of investigational agents. The most advanced of these is Maraviroc, discovered in 2005 by Pfizer team and received approval by EMA in 2007 for treating CCR5 tropic HIV1 patients.

After 2 years, it was approved by FDA and current research is ongoing to develop Maraviroc related analogs with improved pharmacokinetics.

Amide substituent interacts with the predominantly lipophilic binding site on CCR5 and cyclobutyl amide analog was the most potent of the series.

Further studies established that S enantiomer of the cyclobutyl amide was the active isomer.

By keeping cyclobutyl substituent constant, piperadine analogs were studied, among them, tropane derivatives were highly potent inhibitors.

Cyclohexyl group and difluoro moiety give potent antiviral profile with lack affinity to hERG channel, resulting Maraviroc.

Maraviroc contains tertiary amine, two hydrophobic groups, one heteroaryl group, these are main elements of CCR5 antagonists.

The chemokine co receptors of the host cell are of g-protein coupled receptor (GPCR) super family. They are mainly of 2 variants, for interacting with HIV 1 variant – CCR5 and CXCR4. Some HIV variant selectively binds to CCR5 (CCR5 tropic variant), some use CXCR4 (CXCR4 tropic variant) and some use both (dual-tropic strain) to infect the host.

To inhibit the interaction of HIV with the host cell, CCR5 antagonist needs to bind specifically to the CCR5 molecule of the host. So bound CCR5 is blocked from binding the viral gp120 that prevents the conformational change of gp41, which prevents viral particle entry to the host cell. Without penetration, HIV can’t replicate and infect the host.  

Unlike reverse transcriptase inhibitor and protease inhibitors, co receptor antagonists act outside the infected cell. They are unique because they target host cells like T cell or macrophages rather than viral component having clinical advantages. Maraviroc is the only HIV-1 CCR5-based entry inhibitor to date approved by FDA and research and development of other CCR5 inhibitors are going on.

Tanjila Islam is a graduated pharmacist from East West University, Dhaka, Bangladesh. She can be reached at tanjila1524@gmail.com

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