An oral antiviral drug that targets a key part of the respiratory syncytial virus (RSV) polymerase and inhibits the synthesis of viral genetic material has been identified, a finding that could provide an effective treatment against RSV disease, according to researchers in the Center for Translational Antiviral Research at Georgia State University.
The findings, published in the journal Science Advances, identify AVG-388 as the lead drug candidate, which effectively blocks the activity of the viral RNA polymerase, an enzyme responsible for replication of the viral genome. RSV is a leading cause of lower respiratory infections in infants and immunocompromised individuals, but no efficient therapeutic exists.
The virus caused an estimated 33.1 million cases worldwide in 2015 that required 3.2 million hospitalizations and resulted in 59,800 deaths.
Finding effective drugs to fight RSV has been challenging. Through mutations, RSV has escaped advanced candidate classes that prevent the virus from entering a cell. To overcome this issue, recent drug development efforts have focused on the viral RNA-dependent RNA polymerase complex of RSV because of the possible broader window of opportunity to fight the virus during viral genome replication and transcription.
“We have identified the AVG class of inhibitors of RSV RNA synthesis,” said Dr. Richard K. Plemper, senior author of the study, Distinguished University Professor and director of the Center for Translational Antiviral Research in the Institute for Biomedical Sciences at Georgia State. “Through chemical optimization, we have developed the clinical candidate AVG-388, which is orally efficacious against RSV in animal models of infection.”
“In this study, we have mapped an exciting druggable target in the RSV RNA-dependent RNA-polymerase and established the clinical potential of the AVG inhibitor class against RSV disease,” said Dr. Julien Sourimant, first author of the study and a postdoctoral fellow in the Center for Translational Antiviral Research in the Institute for Biomedical Sciences at Georgia State.
The research team investigated the effect of treatment on viral replication at different oral doses intended to prevent or cure disease. They demonstrated that treatment reduced virus load by several orders of magnitude in the different disease models.
“Our results lay the foundation for formal development of the AVG class and the structure-guided identification of companion drugs with overlapping target sites but distinct resistance profiles,” Plemper said.
Co-authors of the study include Julien Sourimant (first author), Carolin M. Lieber, Jeong-Joong Yoon, Mart Toots and Richard K. Plemper of the Center for Translational Antiviral Research in the Institute for Biomedical Sciences at Georgia State; Mugunthan Govindarajan, Venkata Udumula and Michael G. Natchus of Emory Institute for Drug Development at Emory University; Kaori Sakamoto of the College of Veterinary Medicine at the University of Georgia; Joseph Patti of Aviragen Therapeutics Inc. (now at JP Biotech Advisors Inc.); and John Vernachio of Aviragen Therapeutics Inc.
RSV is a widespread pathogen of humans, due in part to the lack of long-term immunity after infection, making reinfection frequent. It infects 90% of children within the first 2 years of life and frequently reinfects older children and adults. The majority of patients with RSV will have an upper respiratory illness, but a significant minority will develop lower respiratory tract illness, predominantly in the form of bronchiolitis.
Children under the age of one year are especially likely to develop lower respiratory involvement, with up to 40% of primary infections resulting in bronchiolitis. Worldwide, it is estimated that RSV is responsible for approximately 33 million lower respiratory tract illnesses, three million hospitalizations, and up to 199,000 childhood deaths; the majority of deaths are in resource-limited countries.
There is seasonal variation in RSV incidence, but seasonal effects vary with worldwide geography; temperate climates have a marked winter-spring predominance, and tropical and equatorial climates may have less pronounced spikes with the more interseasonal disease. Morbidity and mortality are significantly higher in a subset of patients, including premature infants, patients with preexisting cardiac, pulmonary, neurologic, and immunosuppressive disorders, and the elderly.
Treatment / Management
Treatment for RSV falls into three categories: supportive care, immune prophylaxis, and antiviral medication. The majority of RSV and bronchiolitis cases require no specific medical intervention, and many attempted treatments throughout history are ineffective. Vaccines for RSV and therapeutic interventions in RSV remain a target of intense scientific interest.
The mainstay of treatment for patients with RSV is supportive care. The spectrum of supportive care includes nasal suction and lubrication to provide relief from nasal congestion, antipyretics for fever, assisted hydration in the event of dehydration (assistance may be by mouth, by nasogastric tube, or intravenously), and oxygen for patients experiencing hypoxia. Patients with severe presentation and respiratory compromise/failure may require ventilatory support in the form of a high-flow nasal cannula, CPAP, or intubation, and mechanical ventilation. Hospitalization is recommended for patients who are experiencing or are at risk for moderate to severe disease, patients requiring supplemental fluids, and patients requiring respiratory support.
Effective passive immune prophylaxis for RSV exists in the form of palivizumab, a humanized murine monoclonal antibody with activity against the RSV membrane fusion protein required for fusion with host cell membranes. Palivizumab must be administered monthly for the duration of the RSV season. Palivizumab is relatively expensive and is the subject of some debate regarding cost-effectiveness. The American Academy of Pediatrics publishes guidelines regarding which patients are candidates for palivizumab and its discontinuation in breakthrough infection, and we refer readers to those guidelines for specific recommendations regarding palivizumab eligibility. Broadly, these recommendations include prophylaxis for children in the first year of life with: prematurity less than or equal to 29 weeks gestational age, chronic lung disease of prematurity, congenital heart disease, or neuromuscular disorders.
There is a single antiviral medication approved for use against RSV in the United States, ribavirin. It is a nucleoside analog with application in several RNA viruses, and it shows in vitro activity against RSV and may be administered in aerosolized form. However, its use in RSV remains controversial due to expense, questions of danger to exposed health care providers, and questions of efficacy, specifically regarding mortality, length of mechanical ventilation, and length of hospital stay. Ribavirin’s routine use is discouraged, but it may be considered on a case-by-case basis.
Many other treatment modalities for bronchiolitis have been tried in the past, and all others have failed to show broad, reproducible efficacy on clinically significant outcomes in RSV and bronchiolitis. These include albuterol, racemic epinephrine, steroids, hypertonic saline, antibiotics, and chest physical therapy, and routine use of these interventions is not recommended.
reference link :https://www.ncbi.nlm.nih.gov/books/NBK459215/
More information: Julien Sourimant et al, Orally efficacious lead of the AVG inhibitor series targeting a dynamic interface in the respiratory syncytial virus polymerase, Science Advances (2022). DOI: 10.1126/sciadv.abo2236. www.science.org/doi/10.1126/sciadv.abo2236