Pleconaril is an investigational antiviral drug developed to combat common viral infections. Its clinical development offered insights into antiviral drug design and regulatory approval processes.
How Pleconaril Works
Pleconaril targets the picornavirus family, including rhinoviruses and enteroviruses. The drug binds to a specific hydrophobic pocket within the viral capsid, the protein shell encasing the virus’s genetic material. This binding stabilizes the capsid, making it rigid.
The rigidified capsid prevents the virus from “uncoating,” a process where the virus releases its RNA into the host cell. By inhibiting uncoating, pleconaril stops the virus from replicating and infecting new cells. For enteroviruses, it also interferes with the virus’s ability to attach to host cells, halting the viral infection cycle early.
What Pleconaril Was Designed to Treat
Pleconaril was designed to treat infections caused by picornaviruses. Its main target was rhinoviruses, the most frequent cause of the common cold, which can also lead to asthma exacerbations. The drug was intended to alleviate symptoms and shorten the duration of these respiratory illnesses.
Beyond the common cold, pleconaril showed activity against enteroviruses, which can cause more severe conditions. These include viral meningitis, myocarditis (inflammation of the heart muscle), and neonatal enterovirus sepsis. Enteroviruses are a common cause of central nervous system infections, including viral meningitis, with an estimated 600,000 cases annually in the United States.
The Regulatory Journey and Why it Wasn’t Approved
Pleconaril underwent clinical trials for its effectiveness against picornavirus infections. While some studies showed it could reduce the duration of cold symptoms by about one day and decrease symptom severity, the overall clinical benefit was modest. This limited improvement in efficacy compared to a placebo was a hurdle.
Concerns also arose regarding the drug’s side effects and potential for drug interactions. Pleconaril was found to induce the activity of the CYP3A enzyme, which metabolizes many other drugs, including hormonal contraceptives. This interaction led to an increased risk of serious drug interactions and was linked to side effects such as irregular menstrual bleeding and unplanned pregnancies in trial participants. The potential for viral resistance to develop with widespread use also posed a concern. Because of these factors, including modest clinical benefit and safety concerns, an advisory committee to the U.S. Food and Drug Administration (FDA) voted against its approval in 2002.
Current Status and Research
Despite not receiving FDA approval for widespread use, pleconaril has been explored for limited applications. It was available on a compassionate-use basis for patients with severe, life-threatening enterovirus infections, such as chronic enterovirus meningoencephalitis or neonatal enterovirus sepsis. These compassionate use cases provided indication of its activity against these serious conditions.
Pleconaril’s legacy continues to influence antiviral drug development. Researchers have studied its structure and mechanism to develop new compounds that might overcome its limitations, such as reduced interaction with CYP3A4 and improved activity against resistant viral strains. Although pleconaril itself is not widely available, its research contributed to understanding picornavirus biology and the challenges of developing effective and safe antiviral therapies.