Antiviral Efficacy of a Respiratory Syncytial Virus (RSV) Fusion Inhibitor in a Bovine Model of RSV Infection

Jordan, Robert; Shao, Matt X. G.; Mackman, Richard L.; Perron, Michel; Cihlář, Tomáš; Lewis, Sandy; Eisenberg, Eugene; Carey, Anne; Strickley, Robert G.; Chien, Jason W.; Anderson, Margaret Lavinia; McEligot, Heather; Behrens, Nicole E.; Gershwin, Laurel J.

doi:10.1128/aac.00487-15

Cited by 31 publications

(37 citation statements)

References 40 publications

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“…Small-molecule viral entry inhibitors have proven efficacious against different viral targets in clinical and preclinical settings (50)(51)(52). In the past few decades, a number of influenza virus fusion blockers were described that originated from structure- aided drug discovery or screening campaigns (53)(54)(55)(56)(57)(58).…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Influenza Virus Entry Inhibitors through Dual Myxovirus High-Throughput Screening

Weisshaar

Cox

Morehouse

et al. 2016

J Virol

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Influenza A virus (IAV) infections cause major morbidity and mortality, generating an urgent need for novel antiviral therapeutics. We recently established a dual myxovirus high-throughput screening protocol that combines a fully replication-competent IAV-WSN strain and a respiratory syncytial virus reporter strain for the simultaneous identification of IAV-specific, paramyxovirus-specific, and broad-spectrum inhibitors. In the present study, this protocol was applied to a screening campaign to assess a diverse chemical library with over 142,000 entries. Focusing on IAV-specific hits, we obtained a hit rate of 0.03% after cytotoxicity testing and counterscreening. Three chemically distinct hit classes with nanomolar potency and favorable cytotoxicity profiles were selected. Time-of-addition, minigenome, and viral entry studies demonstrated that these classes block hemagglutinin (HA)-mediated membrane fusion. Antiviral activity extends to an isolate from the 2009 pandemic and, in one case, another group 1 subtype. Target identification through biolayer interferometry confirmed binding of all hit compounds to HA. Resistance profiling revealed two distinct escape mechanisms: primary resistance, associated with reduced compound binding, and secondary resistance, associated with unaltered binding. Secondary resistance was mediated, unusually, through two different pairs of cooperative mutations, each combining a mutation eliminating the membrane-proximal stalk N-glycan with a membrane-distal change in HA1 or HA2. Chemical synthesis of an analog library combined with in silico docking extracted a docking pose for the hit classes. Chemical interrogation spotlights IAV HA as a major druggable target for small-molecule inhibition. Our study identifies novel chemical scaffolds with high developmental potential, outlines diverse routes of IAV escape from entry inhibition, and establishes a path toward structure-aided lead development. IMPORTANCEThis study is one of the first to apply a fully replication-competent third-generation IAV reporter strain to a large-scale highthroughput screen (HTS) drug discovery campaign, allowing multicycle infection and screening in physiologically relevant human respiratory cells. A large number of potential druggable targets was thus chemically interrogated, but mechanistic characterization, positive target identification, and resistance profiling demonstrated that three chemically promising and structurally distinct hit classes selected for further analysis all block HA-mediated membrane fusion. Viral escape from inhibition could be achieved through primary and secondary resistance mechanisms. In silico docking predicted compound binding to a microdomain located at the membrane-distal site of the prefusion HA stalk that was also previously suggested as a target site for chemically unrelated HA inhibitors. This study identifies an unexpected chemodominance of the HA stalk microdomain for smallmolecule inhibitors in IAV inhibitor screening campaigns and highlights a novel mechanism ...

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Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Influenza Virus Entry Inhibitors through Dual Myxovirus High-Throughput Screening

Weisshaar

Cox

Morehouse

et al. 2016

J Virol

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“…There are a limited number of safe and effective prophylactic therapeutic options for RSV infections in at‐risk populations, including infants and young children and immunocompromised and elderly patients . Presatovir is an orally administered RSV fusion inhibitor that has potent in vitro antiviral activity and has demonstrated a favorable safety profile in studies to date . In vitro drug‐interaction studies determined that the clinical dose of presatovir is unlikely to affect the PK of other drugs; thus, this study focused on evaluating the potential impact of other drugs on presatovir PK.…”

Section: Discussionmentioning

confidence: 99%

“…Presatovir (previously GS‐5806) is a novel, orally administered RSV fusion inhibitor that interferes with the viral fusion process, thereby inhibiting entry into the host cell . The antiviral efficacy of presatovir has been demonstrated in both preclinical and clinical studies . Presatovir exhibited potent in vitro activity against a broad range of RSV A and B clinical isolates; reduced viral load, respiration rates, and lung pathology in a bovine RSV model; and lowered viral loads and symptom scores in healthy RSV‐infected volunteers .…”

mentioning

confidence: 99%

“…19,20 The antiviral efficacy of presatovir has been demonstrated in both preclinical and clinical studies. [20][21][22] Presatovir exhibited potent in vitro activity against a broad range of RSV A and B clinical isolates; reduced viral load, respiration rates, and lung pathology in a bovine RSV model; and lowered viral loads and symptom scores in healthy RSV-infected volunteers. [19][20][21][22] Furthermore, presatovir exhibited a favorable safety profile in both nonclinical and clinical studies.…”

mentioning

confidence: 99%

“…[20][21][22] Presatovir exhibited potent in vitro activity against a broad range of RSV A and B clinical isolates; reduced viral load, respiration rates, and lung pathology in a bovine RSV model; and lowered viral loads and symptom scores in healthy RSV-infected volunteers. [19][20][21][22] Furthermore, presatovir exhibited a favorable safety profile in both nonclinical and clinical studies. 19,21 Presatovir exhibited approximately dose-proportional pharmacokinetics (PK), with a long terminal half-life of approximately 35 hours.…”

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confidence: 99%

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The Drug–Drug Interaction Profile of Presatovir

Yan

Weng

Murray

et al. 2018

The Journal of Clinical Pharma

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Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in young children. Presatovir (previously GS-5806) is a novel, orally administered RSV fusion inhibitor with a favorable safety profile and proven antiviral efficacy in preclinical and clinical studies. In vitro, presatovir is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and hepatic uptake transporters organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 and is slowly metabolized by cytochrome P450 (CYP) 3A4 and CYP3A5. This study enrolled 64 healthy subjects to evaluate the effect of cyclosporine, a P-gp, BCRP, and OATP1B1/1B3 inhibitor; rifampin, a strong CYP3A4 and P-gp inducer; efavirenz, a moderate CYP3A4 inducer; and cobicistat, a potent CYP3A inhibitor, on presatovir pharmacokinetics. Presatovir plasma exposures (maximum observed plasma concentration [C ] and area under the plasma concentration-time curve from time 0 extrapolated to infinity [AUC ]) were not affected by coadministration of cyclosporine, suggesting presatovir is not a sensitive substrate of P-gp, BCRP, or OATP1B1/1B3. As expected, based on the role of CYP3A in presatovir metabolism, presatovir exposure was increased by cobicistat (122% in AUC ), and decreased by rifampin (40.3% in C and 82.5% in AUC ) and efavirenz (55.7% in AUC ). These data support coadministration of presatovir with inhibitors of P-gp, BCRP, OATP1B1/1B3, or CYP3A, but not with moderate or strong CYP3A4 inducers. Presatovir was well-tolerated with the most common drug-related adverse events of dizziness (n = 12) and somnolence (n = 4) reported during efavirenz treatment.

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The contribution of bovines to human health against viral infections

Saied

Metwally

Mohamed

et al. 2021

Environ Sci Pollut Res

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In the last 40 years, novel viruses have evolved at a much faster pace than other pathogens. Viral diseases pose a significant threat to public health around the world. Bovines have a longstanding history of significant contributions to human nutrition, agricultural, industrial purposes, medical research, drug and vaccine development, and livelihood. The life cycle, genomic structures, viral proteins, and pathophysiology of bovine viruses studied in vitro paved the way for understanding the human counterparts. Calf model has been used for testing vaccines against RSV, papillomavirus vaccines and anti-HCV agents were principally developed after using the BPV and BVDV model, respectively. Some bovine viruses-based vaccines (BPIV-3 and bovine rotaviruses) were successfully developed, clinically tried, and commercially produced. Cows, immunized with HIV envelope glycoprotein, produced effective broadly neutralizing antibodies in their serum and colostrum against HIV. Here, we have summarized a few examples of human viral infections for which the use of bovines has contributed to the acquisition of new knowledge to improve human health against viral infections covering the convergence between some human and bovine viruses and using bovines as disease models. Additionally, the production of vaccines and drugs, bovine-based products were covered, and the precautions in dealing with bovines and bovine-based materials.

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Antiviral Efficacy of a Respiratory Syncytial Virus (RSV) Fusion Inhibitor in a Bovine Model of RSV Infection

Cited by 31 publications

References 40 publications

Identification and Characterization of Influenza Virus Entry Inhibitors through Dual Myxovirus High-Throughput Screening

Identification and Characterization of Influenza Virus Entry Inhibitors through Dual Myxovirus High-Throughput Screening

The Drug–Drug Interaction Profile of Presatovir

The contribution of bovines to human health against viral infections

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