Targeting Dual Points of Entry

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LifeGuide
[Treatment Horizons]

Two Birds, One Stone
Researchers make advances with agents that can target dual points of entry
by Mariel Selbovitz, MPH

two-doors

Drug discovery and early to mid-stage drug development for HIV primarily takes place at academic institutions and small biotechnology companies. At the Frontiers in Developing Antiretroviral Therapy Conference (HIV DART 2014), which took place from December 9–12 in Miami, Florida, there were numerous presentations on promising new treatments for HIV being researched by academic institutions. One project that particularly stood out involved the development of early stage, dual-tropic HIV entry inhibitors that also inhibit HIV reverse transcriptase.

HIV entry into immune cells involves an initial interaction between the viral surface receptor, gp120, and the human cell surface receptor, CD4. This is followed by a subsequent interaction with one of two human cell surface co-receptors: CCR5 or CXCR4. CCR5 is the “entryway” for M-tropic viruses and CXCR4 is the “entryway” for T-tropic viruses. Tropism simply refers to the type of cell that HIV infects, and thus characterizes different HIV strains. R5 (M-tropic) viruses can infect macrophages, dendritic cells, and CD4 T cells. X4 (T-tropic) viruses primarily infect CD4 T cells and are associated with rapid disease progression. Drugs that inhibit binding by these co-receptors are called entry inhibitors.

Entry inhibitors are key to controlling HIV because, once the virus has successfully entered an immune cell, it becomes much more difficult to control its proliferation. The overwhelming majority of antiretroviral agents (ARVs) function after viral entry by inhibiting key viral proteins, including reverse transcriptase, integrase, and protease. While inhibition of these targets can be quite effective at reducing viral load, this approach inevitably results in a variety of complications and side effects.

There are two entry inhibitors currently on the market, each inhibiting a different point of entry: Fuzeon, which blocks virion/immune cell membrane fusion, and Selzentry, which blocks the binding of the CCR5 co-receptor to the gp120/CD4 complex. Both of these drugs have seen only modest use. In the case of Fuzeon, immunogenic reactions on the skin at the site of injection limit its long-term use. Extended dosing with Selzentry can result in a viral tropism shift, i.e., initially dual-tropic virus and eventually to the more virulent T-tropic virus, which renders the drug ineffective.

But what if one drug had the capacity to inhibit both points of entry? The target would not be one or the other—X4 and R5-tropic viruses—but both: dual-tropic, in other words.

Under the leadership of Dennis Liotta, PhD, Executive Director, Emory Institute of Drug Development, researchers at Emory University have been working on the development of a novel class of entry inhibitors that work on all types of immune cells. Throughout the last two decades, Dr. Liotta’s lab has discovered several of the ARVs presently being taken by people with HIV. Previously, Dr. Liotta, along with his Emory colleague, Dr. Raymond Schinazi, co-invented lamivudine and emtricitabine, which are key components of ten FDA approved combination therapies including Epivir, Combivir, Trizivir, Epzicom, Epivir-HBV, Emtriva, Truvada, Atripla, Complera and Stribild.

Dr. Liotta’s team has now identified several dual-tropic entry inhibitors that simultaneously block the binding of CXCR4 and CCR5, to the gp120/CD4 complex.

The team identified an apparent common binding region in the backbones of CCR5 and CXCR4. Dr. Liotta’s lab then used virtual screening techniques to evaluate the binding of millions of commercially available chemicals searching for those with the greatest potential. They then purchased the top ranked compounds and evaluated them using HIV-infected cells that expressed either CCR5 or CXCR4 surface receptors. Using this approach, they were able to identify one compound that inhibited both CCR5- and CXCR4-mediated entry by binding to this common region.

One of the chemists on the team made over fifty analogs of the original structure, several of which had improved activity/toxicity profiles. Subsequently, with the help of virologists at Bristol-Myers Squibb, the team was able to demonstrate that the compounds also have activity against HIV reverse transcriptase. Thus, in a little over a year, Dr. Liotta and his team had identified an initial dual-tropic “hit” and, through a series of structural modifications, increased the potency of what can be considered their lead drug candidate. In addition, they also dramatically improved the efficiency of the synthetic route used to prepare this novel class of compounds. They estimate that it will likely take another eighteen to twenty-four months before a compound with suitable properties can be evaluated in clinical trials.

If this development project is successful, it could dramatically enhance the scope and effectiveness of HIV combination therapy. First, twenty-four of the more than thirty approved HIV drugs target viral proteins, which mutate much more rapidly than their human counterparts (potentially resulting in drug resistance). It follows that a drug that simultaneously inhibits the binding of CCR5 and CXCR4 should exhibit a high barrier to the development of resistance when compared with drugs that target viral proteins. In addition, combining this drug with pairs of existing HIV drugs should result in the creation of several new combination therapies. Importantly, in resource-challenged environments the combination of a dual-tropic entry inhibitor with selected pairs of antiretroviral agents could improve the effectiveness and substantially reduce the cost of the regimens used in these settings. While all of this remains to be seen, the principles underlying these attributes are all well precedented from the past twenty-five years of HIV research.

Mariel Selbovitz, MPH, serves as the Chair of the Cornell ACTG Community Advisory Board and has authored over thirty abstracts and articles.