It is hoped that this proof of concept research may lead to promising new drug candidates to combat hPIV-3, which is the principal cause of acute respiratory illness in infants.
The results of a study recently published in Scientific Reports offer evidence for the effectiveness of a combination of agents in the fight against human parainfluenza type-3 virus (hPIV-3). It is hoped that this proof of concept research may lead to promising new drug candidates to combat hPIV-3, which is the principal cause of acute respiratory illness in infants. Additionally, it is a significant health concern among the elderly and the immunocompromised. Despite the negative clinical impact of this viral infection, there are no approved treatments for its treatment or prevention infection.
The study was presented by Benjamin Bailly, a joint PhD student working in the Institute for Glycomics on the Gold Coast Campus of Griffith University in Australia and the unit of anti-infective research at the Institut Pasteur of Shanghai in the Chinese Academy of Sciences in China. In the study, Bailly et al conducted a battery of molecular and cellular experiments to investigate the ability and potency of two agents approved for uses other than the treatment of hPIV-3 to inhibit hPIV-3 infection.
Bailly and colleagues were interested in targeting haemagglutinin-neuraminidase (HN), which is an important hPIV-3 surface envelope glycoprotein that plays multiple roles in the virus's life cycle. In describing the study's rationale, the investigators explained that the majority of anti-hPIV-3 investigational agents have been N-acylneuraminic acid derivatives that act as competitive inhibitors of HN. In describing their study rationale, Bailly et al stated, "In the present study we look into another strategy to block HN-mediated hPIV-3 infection, by investigating approved drugs, not related to N-acylneuraminic acids, that may inhibit hPIV-3 HN haemagglutination and neuraminidase functions. Such drugs could provide an alternative approach for hPIV-3 infection blockade and have an advantage for potential repositioning."
To find drugs approved for other indications that could act as hPIV-3 HN haemagglutination and neuraminidase inhibitors, Bailly et al used an enzyme-based semi-high throughput screening of hPIV-3 neuraminidase activity inhibitors. In total, a library of 1280 approved drugs were screened, three of which were inhibitors of hPIV-3 neuraminidase activity, as confirmed in a secondary screening. Only one of the compounds, suramin, indicated for the treatment of trypanosomiasis and onchocerciasis, was found to be suitable for further study.
In subsequent experiments focused on elucidating the potential mechanisms underlying the ability of suramin to block HN-mediated hPIV-3 infection, Bailly and colleagues found that suramin inhibited hPIV-3 HN haemagglutinin and neuraminidase activities in a dose-dependent manner, and inhibited hPIV-3 HN neuraminidase activity via a non-competitive mechanism. It was also determined that suramin binds to a site distinct from the hPIV-3 HN primary binding site. Such a finding suggests that the suramin binding site and the hPIV-3 HN primary binding site could be targeted by suramin and N-acylneuraminic acid derivatives simultaneously.
In previous studies, both suramin and the N-acetylneuraminic acid-based drug zanamivir were shown to have low potency in vitro activity against hPIV-3; however, suramin was found to have in vitro antiviral activity in the Bailly et al study and could act in a synergistic manner with the competitive HN inhibitor to block in vitro infection. These results strongly implicate suramin as a non-competitive inhibitor for the HN enzyme. Regarding the significance of these findings, Bailly et al stated, "As a result, we showed that the dose of both drugs can be significantly reduced to reach high levels of inhibition, as compared to the individual dose that would otherwise be needed to reach a similar effect."
According to Bailly and colleagues, the suite of results generated in this study serve as an in vitro proof of concept for the repurposing of drugs approved for other indications, particularly when used in combinations, and present an exciting new avenue for research on new therapeutic interventions for a common cause of potentially dangerous acute respiratory infections.
William Perlman, PhD, CMPP is a former research scientist currently working as a medical/scientific content development specialist. He earned his BA in Psychology from Johns Hopkins University, his PhD in Neuroscience at UCLA, and completed three years of postdoctoral fellowship in the Neuropathology Section of the Clinical Brain Disorders Branch of the National Institute of Mental Health.