Challenges and opportunities in developing respiratory syncytial virus therapeutics (original) (raw)
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Pharmacologic Advances in the Treatment and Prevention of Respiratory Syncytial Virus
Clinical Infectious Diseases, 2010
Currently, only 2 drugs have been approved for the treatment of respiratory syncytial virus (RSV). Palivizumab is a monoclonal antibody for the prevention of RSV in high-risk children. Ribavirin is approved for treatment of severe RSV disease; however, its effectiveness in improving outcomes is questionable. During the past 40 years, many obstacles have delayed the development of safe and effective vaccines and treatment regimens. This article reviews these obstacles and presents the novel development strategies used to overcome many of them. Also discussed are promising new antiviral treatment candidates and their associated mechanism of action, the significant advances made in vaccine development, and exciting, new studies directed at improving outcomes through pharmacologic manipulation of the host response to RSV disease. Respiratory syncytial virus (RSV) is the leading cause of pediatric viral respiratory tract infections. The World Health Organization estimates an annual mortality rate of ∼160,000 deaths worldwide [1]; more inclusive all-cause mortality rates related to RSV approach 600,000 deaths [2]. RSV is also the second leading cause of viral death in elderly individuals [3]. By 18 months of age, 87% of children have developed RSVspecific antibodies [4]; by 3 years of age, virtually all children have been infected. In the United States alone, RSV infection results in 1120,000 childhood hospitalizations and up to 500 deaths [5]. Compared with influenza, RSV accounts for 19 times more deaths in children younger than 1 year [6-11]. Only 2 US Food and Drug Administration (FDA)-approved drugs are currently available for RSV disease. Palivizumab is indicated for RSV prevention in high-risk infants, including those with chronic lung disease, those with congenital heart disease, and those born prematurely [12]. This indication is based on hospitalization rates that are ∼5 times greater in highrisk versus non-high-risk infants. However, among all infants hospitalized with severe RSV disease, ∼70% are term infants
Antimicrobial Agents and Chemotherapy
Effective treatments for respiratory syncytial virus (RSV) infection are lacking. We report a human proof-of-concept study for RV521, a small-molecule antiviral inhibitor of the RSV-F protein. In this randomized, double-blind, placebo-controlled trial (NCT03258502), healthy adults were challenged with RSV-A Memphis-37b. After infection was confirmed (or 5 days after challenge virus inoculation), subjects received RV521 (350 mg or 200 mg) or placebo, orally every 12 hours for 5 days. Primary endpoint was area under the curve (AUC) for viral load, as assessed by reverse transcriptase quantitative PCR (RT-qPCR), in nasal wash samples. Primary efficacy analysis set included subjects successfully infected with RSV who received ≥1 dose of study drug. Sixty-six subjects were enrolled (n=22 per group); 53 were included in the primary analysis set (RV521 350 mg: n=16; 200 mg: n=18; placebo: n=19). Mean AUC of RT-qPCR-assessed RSV viral load (log10 PFUe/mL x hours) was significantly lower wit...
Respiratory syncytial virus: current and emerging treatment options
ClinicoEconomics and Outcomes Research, 2014
Respiratory syncytial virus (RSV) is an important respiratory pathogen in infants and children worldwide. Although RSV typically causes mild upper respiratory infections, it frequently causes severe morbidity and mortality, especially in premature infants and children with other chronic diseases. Treatment of RSV is limited by a lack of effective antiviral treatments; however, ribavirin has been used in complicated cases, along with the addition of intravenous immune globulin in specific patients. Vaccination strategies for RSV prevention are heavily studied, but only palivizumab (Synagis ®) has been approved for use in the United States in very select patient populations. Research is ongoing in developing additional vaccines, along with alternative therapies that may help prevent or decrease the severity of RSV infections in infants and children. To date, we have not seen a decrement in RSV morbidity and mortality with our current options; therefore, there is a clear need for novel RSV preventative and therapeutic strategies. In this review, we discuss the current and evolving trends in RSV treatment for infants and children.
Proceedings of the National Academy of Sciences, 2011
The search for novel therapeutic interventions for viral disease is a challenging pursuit, hallmarked by the paucity of antiviral agents currently prescribed. Targeting of viral proteins has the inextricable challenge of rise of resistance. Safe and effective vaccines are not possible for many viral pathogens. New approaches are required to address the unmet medical need in this area. We undertook a cell-based high-throughput screen to identify leads for development of drugs to treat respiratory syncytial virus (RSV), a serious pediatric pathogen. We identified compounds that are potent (nanomolar) inhibitors of RSV in vitro in HEp-2 cells and in primary human bronchial epithelial cells and were shown to act postentry. Interestingly, two scaffolds exhibited broad-spectrum activity among multiple RNA viruses. Using the chemical matter as a probe, we identified the targets and identified a common cellular pathway: the de novo pyrimidine biosynthesis pathway. Both targets were validate...
Pharmacological targets and emerging treatments for respiratory syncytial virus bronchiolitis
Pharmacology & Therapeutics, 2021
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Expert Opinion on Pharmacotherapy, 2003
Respiratory syncytial virus (RSV) infection causes a huge burden to the health service, as it results in a large number of in-patient days each year and increases the risk of asthma in childhood. In the acute phase, therapy is supportive as bronchodilators and corticosteroids have resulted, at best, only in short-term benefits; promising treatments for ventilated patients, such as exogenous surfactant, require further testing. Passive immunoprophylaxis reduces hospital admission in high risk groups. In the prevention of chronic respiratory morbidity following RSV infection, however, studies are needed to determine whether immunoprophylaxis will have a useful role and to identify which drug treatment will be most cost-effective.
Revisiting respiratory syncytial virus’s interaction with host immunity, towards novel therapeutics
Cellular and Molecular Life Sciences, 2020
Every year there are > 33 million cases of Respiratory Syncytial Virus (RSV)-related respiratory infection in children under the age of five, making RSV the leading cause of lower respiratory tract infection (LRTI) in infants. RSV is a global infection, but 99% of related mortality is in low/middle-income countries. Unbelievably, 62 years after its identification, there remains no effective treatment nor vaccine for this deadly virus, leaving infants, elderly and immunocompromised patients at high risk. The success of all pathogens depends on their ability to evade and modulate the host immune response. RSV has a complex and intricate relationship with our immune systems, but a clearer understanding of these interactions is essential in the development of effective medicines. Therefore, in a bid to update and focus our research community's understanding of RSV's interaction with immune defences, this review aims to discuss how our current knowledgebase could be used to combat this global viral threat.
Respiratory syncytial virus prophylaxis—the story so far
Respiratory Medicine, 2002
Respiratory syncytialvirus (RSV) is a common and highlycontagious pathogenthatinfects nearly all children by the age of 2 years.It is responsible for significant morbidity and mortality worldwide among certain high-risk paediatric populations.Therapyis sub-optimal for RSV, thus treatmentfocuses on ameliorating symptoms.Since discoveryofthe virus in the1950s, efforts have been ongoing to develop a safe and effective vaccine.These efforts have met with serious obstacles. Passive immunoprophylaxis presents a viable alternative to active immunization. In 1998, the genetically engineered humanized monoclonal antibody (palivizumab) was granted FDA (Food and Drug Administration) approval for prophylaxis of high-riskchildren in the United States;EMEA (European Agency for the Evaluation of Medicinal Products) approval followed in 1999 for Europe. It is now approved in over 45 countries worldwide. Palivizumab was shown to significantly reduce RSV-related hospitalizations in North America and Europe with few adverse effects.Clinical trial and outcomes data documenting experience with palivizumab to date continue to extend the initial safety and efficacy observations.
Journal of medicinal chemistry, 2015
GS-5806 is a novel, orally bioavailable RSV fusion inhibitor discovered following a lead optimization campaign on a screening hit. The oral absorption properties were optimized by converting to the pyrazolo[1,5-a]-pyrimidine heterocycle, while potency, metabolic, and physicochemical properties were optimized by introducing the para-chloro and aminopyrrolidine groups. A mean EC50 = 0.43 nM was found toward a panel of 75 RSV A and B clinical isolates and dose-dependent antiviral efficacy in the cotton rat model of RSV infection. Oral bioavailability in preclinical species ranged from 46 to 100%, with evidence of efficient penetration into lung tissue. In healthy human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a mean 4.2 log10 reduction in peak viral load and a significant reduction in disease severity compared to placebo. In conclusion, a potent, once daily, oral RSV fusion inhibitor with the potential to treat RSV infection in infants an...