Saucy solution: HIV antivirals

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  • Published: May 15, 2014
  • Author: David Bradley
  • Channels: NMR Knowledge Base
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Most efficacious

Effects of Substitutions at the 4= and 2 Positions on the Bioactivity of 4=-Ethynyl-2-Fluoro-2=-Deoxyadenosine

US researchers are using nuclear magnetic resonance spectroscopy to help inform their virology efforts in the hope of develop new, potent antiviral agents for the treatment of HIV, human immunodeficiency virus.

Virologist Stefan Sarafianos and his colleagues at the Christopher S. Bond Life Sciences Center, at the University of Missouri, in Columbia recently demonstrated that EFdA - 4'-ethynyl-2-fluoro-2'-deoxyadenosine - a compound that can stop HIV in its tracks has seventy times the efficacy against resistant strains than one of the most commonly used AIDS drugs Tenofovir. The demonstration could thus herald a new generation of anti-AIDS medications that can put paid to drug resistance in this lethal disease for the time being.

Sarafianos explains that HIV in patients treated with Tenofovir usually evolves and develops a K65R RT mutation that causes the drug to stop working as the first line of defence. In contrast, EFdA works well against resistant HIV and is even ten times more effective against "wild-type" HIV that is yet to mutate into the Tenofovir-resistant form. The researchers found that EFdA is activated by cells more readily than Tenofovir and is not broken down at a rate even close to the rate at which similar existing antiviral drugs are eradicated from the body

Molecular spanner in the works

Sarafianos points out that these two factors - the ready activation and the robust nature of the compound against hepatic metabolism make it more potent than other drugs. "Our task now is to look at the structural features that make it such a fantastic drug," he explains.

EFdA has a rather unusual history for a pharmaceutical. Rather than it being identified through molecular modelling, theoretical structure-activity relationships or through assaying of known herbal remedies, it was first identified in 2001 by a Japanese soy sauce company, Yamasa. At the time, the company was simply trying to find a way to improve the taste of its products. This compound, a nucleoside analogue, was among several potential flavour-enhancing compounds. Of course, the chemists at Yamasa were well aware that its structure resembled several antiviral compounds that had been discovered or synthesised in the preceding decade, including existing anti-HIV agents. Such antiviral drugs generally work by inhibiting the replication of the viral genetic material by mimicking the natural nucleosides used by the viral machinery - specifically the enzyme reverse transcriptase to build DNA in the host white blood cells from its RNA. They are slotted into the growing genetic material, but put a metaphorical spanner in the works because their non-natural unrecognised structure halts further processing.

Assays on the compound, EFdA, showed it to be quite the tough "spanner" and so its discovery initiated more than a decade of research to pinpoint what makes it particularly special in blocking the genetic duplication machinery. “Nucleoside reverse transcriptase inhibitors (NRTIs) are called chain terminators because they stop the copying of the DNA chain, and once incorporated it's like a dead end," Sarafianos explains.

The team is working closely with University of Pittsburgh biochemist Michael Parniak and the National Institutes of Health’s Hiroaki Mitsuya to explore the potential of EDfA, or a derivative, in being developed as an anti-HIV drug. Mitsuya was involved in the original discoveries of the first three drugs for treating HIV and Parniak is an expert in evaluating HIV treatments using cultured white blood cells. Sarafianos' team uses their virological expertise, crystallography and nuclear magnetic resonance spectroscopy to help them piece together the exact structure and to correlate this with activity.

Girls on film

EFdA has a "sugar-like" ring system and the ongoing structure-activity analysis has revealed which characteristics of this sub-structure not only make it most resemble a natural nucleoside but also make it the effective viral dead end it is proving to be. Moreover, the analyses has revealed novel, but closely related structures that are as effective in being activated by the virally hijacked genetic machinery of the host cells of HIV, the CD4+ T lymphocyte white blood cells.

"The structure of this compound is very important because it's a lock and key kind of mechanism that can be recognized by the target," Sarafianos says. "We're looking at small changes and the ideal scenario is a compound bound very efficiently by the target and activating enzyme but not efficiently by the degrading enzymes." Tests in severely ill laboratory monkeys infected with simian immunodeficiency virus (SIV) showed significant remission.

With this efficacy data in hand, however, the team has now turned to the idea of HIV prevention. They have recruited drug formulation expert Lisa Rohan of the University of Pittsburgh to develop a vaginal film containing EFdA that could be used to kill HIV at the point of transmission, during sexual intercourse, in other words. "The only way we are going to make a difference with HIV is prevention," Parniak explains. "If we can prevent transmission, this approach could make a huge difference in minimizing the continued spread of the disease when combined with existing therapies for people already infected."

"Women in Africa [where HIV is rife] would benefit from a formulation like this as a means to protect themselves," Sarafianos adds. "We hope that EFdA will enter clinical trials for the treatment of HIV infection," Sarafianos told SpectroscopyNOW. "At the same time, our collaborative efforts focus on establishing that EFdA can be used for the prevention of HIV infection. Finally, we will continue to use structural tools to understand the molecular basis of the efficient activation of EFdA by deoxycytidine kinase and poor degradation by adenosine deaminase."

Related Links

Antimicrob Agents Chemother, 2013, 57, 6254-6264: "Effects of Substitutions at the 4' and 2 Positions on the Bioactivity of 4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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