Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV) (original) (raw)
Related papers
High-throughput screening of active compounds against human respiratory syncytial virus
Virology, 2019
Human respiratory syncytial virus (RSV) is one of the predominant pathogens causing lower respiratory tract infection in infants and young children worldwide, whereas there is so far no vaccine or drug against RSV infection for clinical use. In this work, we developed and validated a fluorescence-based high-throughput screening (HTS) assay to identify compounds active against RSV, using RSV-mGFP, a recombinant RSV encoding enhanced green fluorescent protein (EGFP). Thereafter, among 54,800 compounds used for our screen, we obtained 62 compounds active against RSV. Among these hits, azathioprine (AZA) and 6-mercaptopurine (6-MP) were identified as RSV inhibitors with half maximal inhibitory concentration (IC 50) values of 6.69 ± 1.41 and 3.13 ± 0.98 μM, respectively. Further experiments revealed that they functioned by targeting virus transcription or/and genome replication. In conclusion, the established HTS assay is suitable to screen anti-RSV compounds , and the screened two hits of AZA and 6-MP, as potential anti-RSV agents targeting RSV genome re-plication/transcription, are worthy of further investigation on their anti-RSV activity in vivo.
Virology Journal, 2013
Background: Human respiratory syncytial virus (hRSV) is a highly contagious pathogen and is the most common cause of bronchiolitis and pneumonia for infants and children under one year of age. Worldwide, greater than 33 million children under five years of age are affected by hRSV resulting in three million hospitalizations and 200,000 deaths. However, severe lower respiratory tract disease may occur at any age, especially among the elderly or those with compromised cardiac, pulmonary, or immune systems. There is no vaccine commercially available. Existing therapies for the acute infection are ribavirin and the prophylactic humanized monoclonal antibody (Synagis W from MedImmune) that is limited to use in high risk pediatric patients. Thus, the discovery of new inhibitors for hRSV would be clinically beneficial.
Journal of medicinal chemistry, 2015
Respiratory syncytial virus (RSV) is a leading pathogen of childhood and is associated with significant morbidity and mortality. To date, ribavirin is the only approved small molecule drug, which has limited use. The only other RSV drug is palivizumab, a monoclonal antibody, which is used for RSV prophylaxis. Clearly, there is an urgent need for small molecule RSV drugs. This article reports the design, synthesis, anti-RSV activity, metabolism, and pharmacokinetics of a series of…
Evaluation of Small Molecule Combinations against Respiratory Syncytial Virus In Vitro
Molecules, 2021
Respiratory syncytial virus (RSV) is a major pathogen that causes severe lower respiratory tract infection in infants, the elderly and the immunocompromised worldwide. At present no approved specific drugs or vaccines are available to treat this pathogen. Recently, several promising candidates targeting RSV entry and multiplication steps are under investigation. However, it is possible to lead to drug resistance under the long-term treatment. Therapeutic combinations constitute an alternative to prevent resistance and reduce antiviral doses. Therefore, we tested in vitro two-drug combinations of fusion inhibitors (GS5806, Ziresovir and BMS433771) and RNA-dependent RNA polymerase complex (RdRp) inhibitors (ALS8176, RSV604, and Cyclopamine). The statistical program MacSynergy II was employed to determine synergism, additivity or antagonism between drugs. From the result, we found that combinations of ALS8176 and Ziresovir or GS5806 exhibit additive effects against RSV in vitro, with i...
Challenges and opportunities in developing respiratory syncytial virus therapeutics
The Journal of infectious diseases, 2015
Two meetings, one sponsored by the Wellcome Trust in 2012 and the other by the Global Virology Foundation in 2013, assembled academic, public health and pharmaceutical industry experts to assess the challenges and opportunities for developing antivirals for the treatment of respiratory syncytial virus (RSV) infections. The practicalities of clinical trials and establishing reliable outcome measures in different target groups were discussed in the context of the regulatory pathways that could accelerate the translation of promising compounds into licensed agents. RSV drug development is hampered by the perceptions of a relatively small and fragmented market that may discourage major pharmaceutical company investment. Conversely, the public health need is far too large for RSV to be designated an orphan or neglected disease. Recent advances in understanding RSV epidemiology, improved point-of-care diagnostics, and identification of candidate antiviral drugs argue that the major obstac...
Antiviral research, 2016
Respiratory syncytial virus (RSV) infections affect millions of children and adults every year. Despite the significant disease burden, there are currently no safe and effective vaccines or therapeutics. We employed a replicon-based high throughput screen combined with live-virus triaging assays to identify three novel diversity-oriented synthesis-derived scaffolds with activity against RSV. One of these small molecules is shown to target the RSV polymerase (L protein) to inhibit viral replication and transcription; the mechanisms of action of the other small molecules are currently unknown. The compounds described herein may provide attractive inhibitors for lead optimization campaigns.
Identification of Non-Nucleoside Inhibitors of the Respiratory Syncytial Virus Polymerase Complex
Journal of medicinal chemistry, 2017
Respiratory syncytial virus (RSV) represents a threat to infants, the elderly, and the immunocompromised. RSV entry blockers are in clinical trials, but escape mutations challenge their potential. In search of RSV inhibitors, we have integrated a signature resistance mutation into a recombinant RSV virus and applied the strain to high-throughput screening. Counterscreening of candidates returned 14 confirmed hits with activities in the nano- to low-micromolar range. All blocked RSV polymerase activity in minigenome assays. Compound 1a (GRP-74915) was selected for development based on activity (EC50 = 0.21 μM, selectivity index (SI) 40) and scaffold. Resynthesis confirmed the potency of the compound, which suppressed viral RNA synthesis in infected cells. However, metabolic testing revealed a short half-life in the presence of mouse hepatocyte fractions. Metabolite tracking and chemical elaboration combined with 3D-quantitative structure-activity relationship modeling yielded analogu...
Discovery of a Novel Respiratory Syncytial Virus Replication Inhibitor
Antimicrobial Agents and Chemotherapy
A high-throughput screen of a Roche internal chemical library based on inhibition of the respiratory syncytial virus (RSV)-induced cytopathic effect (CPE) on HEp-2 cells was performed to identify RSV inhibitors. Over 2,000 hits were identified and confirmed to be efficacious against RSV infection in vitro .
Design and characterization of human respiratory syncytial virus entry inhibitors
Antiviral …, 2005
Human respiratory syncytial virus (hRSV) is a pathogen of worldwide health concern. The crucial membrane fusion event during viral entry into host cells involves a 'trimerof-hairpins' structure that brings the amino (N)-and carboxy (C)-terminal regions of the viral fusion glycoprotein (F protein) into close proximity. Two heptad repeat regions that are highly conserved in the F protein -HR1 (N-terminal) and HR2 (C-terminal) -have an important role in this process. It has been shown that both HR1and HR2-based peptides can inhibit viral entry. However, these proteins, and the HR1 peptides in particular, are liable to aggregation. We designed three peptides containing multiple copies of alternating HR1 and HR2 sequences denoted 5-Helix, HR121 and HR212, respectively. The 5-Helix, HR121 and HR212 proteins were functionally analogous to single HR1, HR1 and HR2 sequences, respectively. All three proteins were expressed in soluble form and biophysical analysis showed that they exhibited α-helical secondary structures. The three proteins were potent fusion inhibitors in vitro, at the micromolar scale, with the HR1 analogues being approximately two times more effective than the HR2 analogue. Our results suggest that these rationally designed protein inhibitors could serve as a new class of anti-hRSV agents.