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17 results on '"Moreira, Fernando R."'

1. 1‑O‑Octadecyl-2‑O‑benzyl-sn-glyceryl-3-phospho-GS-441524 (V2043). Evaluation of Oral V2043 in a Mouse Model of SARS-CoV‑2 Infection and Synthesis and Antiviral Evaluation of Additional Phospholipid Esters with Enhanced Anti-SARS-CoV‑2 Activity

Author

Carlin, Aaron F, Beadle, James R, Clark, Alex E, Gully, Kendra L, Moreira, Fernando R, Baric, Ralph S, Graham, Rachel L, Valiaeva, Nadejda, Leibel, Sandra L, Bray, William, McMillan, Rachel E, Freshman, Jonathan E, Garretson, Aaron F, McVicar, Rachael N, Rana, Tariq, Zhang, Xing-Quan, Murphy, Joyce A, Schooley, Robert T, and Hostetler, Karl Y

Subjects
Lung, Prevention, Emerging Infectious Diseases, Infectious Diseases, Infection, Animals, Mice, Antiviral Agents, SARS-CoV-2, COVID-19, Phospholipids, Medicinal and Biomolecular Chemistry, Organic Chemistry, Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry
Abstract

Early antiviral treatments, including intravenous remdesivir (RDV), reduce hospitalization and severe disease caused by COVID-19. An orally bioavailable RDV analog may facilitate earlier treatment of non-hospitalized COVID-19 patients. Here we describe the synthesis and evaluation of alkyl glyceryl ether phosphodiesters of GS-441524 (RVn), lysophospholipid analogs which allow for oral bioavailability and stability in plasma. Oral treatment of SARS-CoV-2-infected BALB/c mice with 1-O-octadecyl-2-O-benzyl-sn-glyceryl-3-phospho-RVn (60 mg/kg orally, once daily for 5 days starting 12h after infection) reduced lung viral load by 1.5 log10 units versus vehicle at day 2 and to below the limit of detection at day 5. Structure/activity evaluation of additional analogs that have hydrophobic ethers at the sn-2 of glycerol revealed improved in vitro antiviral activity by introduction of a 3-fluoro-4-methoxy-substituted benzyl or a 3- or 4-cyano-substituted benzyl. Collectively, our data support the development of RVn phospholipid prodrugs as oral antiviral agents for prevention and treatment of SARS-CoV-2 infections.

Published
2023

2. Programmable antivirals targeting critical conserved viral RNA secondary structures from influenza A virus and SARS-CoV-2

Author

Hagey, Rachel J., Elazar, Menashe, Pham, Edward A., Tian, Siqi, Ben-Avi, Lily, Bernardin-Souibgui, Claire, Yee, Matthew F., Moreira, Fernando R., Rabinovitch, Meirav Vilan, Meganck, Rita M., Fram, Benjamin, Beck, Aimee, Gibson, Scott A., Lam, Grace, Devera, Josephine, Kladwang, Wipapat, Nguyen, Khanh, Xiong, Anming, Schaffert, Steven, Avisar, Talia, Liu, Ping, Rustagi, Arjun, Fichtenbaum, Carl J., Pang, Phillip S., Khatri, Purvesh, Tseng, Chien-Te, Taubenberger, Jeffery K., Blish, Catherine A., Hurst, Brett L., Sheahan, Timothy P., Das, Rhiju, and Glenn, Jeffrey S.

Published
2022
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3. The oral nucleoside prodrug GS-5245 is efficacious against SARS-CoV-2 and other endemic, epidemic, and enzootic coronaviruses

Author

Martinez, David R., primary, Moreira, Fernando R., additional, Catanzaro, Nicholas J., additional, Diefenbacher, Meghan V., additional, Zweigart, Mark R., additional, Gully, Kendra L., additional, De la Cruz, Gabriela, additional, Brown, Ariane J., additional, Adams, Lily E., additional, Yount, Boyd, additional, Baric, Thomas J., additional, Mallory, Michael L., additional, Conrad, Helen, additional, May, Samantha R., additional, Dong, Stephanie, additional, Scobey, D. Trevor, additional, Nguyen, Cameron, additional, Montgomery, Stephanie A., additional, Perry, Jason K., additional, Babusis, Darius, additional, Barrett, Kimberly T., additional, Nguyen, Anh-Hoa, additional, Nguyen, Anh-Quan, additional, Kalla, Rao, additional, Bannister, Roy, additional, Feng, Joy Y., additional, Cihlar, Tomas, additional, Baric, Ralph S., additional, Mackman, Richard L., additional, Bilello, John P., additional, Schäfer, Alexandra, additional, and Sheahan, Timothy P., additional

Published
2024
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4. Host genetic variation guides hepacivirus clearance, chronicity, and liver fibrosis in mice

Author

Brown, Ariane J., Won, John J., Wolfisberg, Raphael, Fahnøe, Ulrik, Catanzaro, Nicholas, West, Ande, Moreira, Fernando R., Nogueira Batista, Mariana, Ferris, Martin T., Linnertz, Colton L., Leist, Sarah R., Nguyen, Cameron, De La Cruz, Gabriela, Midkiff, Bentley R., Xia, Yongjuan, Evangelista, Mia D., Montgomery, Stephanie A., Billerbeck, Eva, Bukh, Jens, Scheel, Troels K.H., Rice, Charles M., Sheahan, Timothy P., Brown, Ariane J., Won, John J., Wolfisberg, Raphael, Fahnøe, Ulrik, Catanzaro, Nicholas, West, Ande, Moreira, Fernando R., Nogueira Batista, Mariana, Ferris, Martin T., Linnertz, Colton L., Leist, Sarah R., Nguyen, Cameron, De La Cruz, Gabriela, Midkiff, Bentley R., Xia, Yongjuan, Evangelista, Mia D., Montgomery, Stephanie A., Billerbeck, Eva, Bukh, Jens, Scheel, Troels K.H., Rice, Charles M., and Sheahan, Timothy P.

Abstract

Background & Aims: Human genetic variation is thought to guide the outcome of HCV infection, but model systems within which to dissect these host genetic mechanisms are limited. Norway rat hepacivirus, closely related to HCV, causes chronic liver infection in rats but causes acute self-limiting hepatitis in typical strains of laboratory mice, which resolves in 2 weeks. The Collaborative Cross (CC) is a robust mouse genetics resource comprised of a panel of recombinant inbred strains, which model the complexity of the human genome and provide a system within which to understand diseases driven by complex allelic variation. Approach & Results: We infected a panel of CC strains with Norway rat hepacivirus and identified several that failed to clear the virus after 4 weeks. Strains displayed an array of virologic phenotypes ranging from delayed clearance (CC046) to chronicity (CC071, CC080) with viremia for at least 10 months. Body weight loss, hepatocyte infection frequency, viral evolution, T-cell recruitment to the liver, liver inflammation, and the capacity to develop liver fibrosis varied among infected CC strains. Conclusions: These models recapitulate many aspects of HCV infection in humans and demonstrate that host genetic variation affects a multitude of viruses and host phenotypes. These models can be used to better understand the molecular mechanisms that drive hepacivirus clearance and chronicity, the virus and host interactions that promote chronic disease manifestations like liver fibrosis, therapeutic and vaccine performance, and how these factors are affected by host genetic variation.

Published
2024

5. Host genetic variation guides hepacivirus clearance, chronicity, and liver fibrosis in mice

Author

Brown, Ariane J., primary, Won, John J., additional, Wolfisberg, Raphael, additional, Fahnøe, Ulrik, additional, Catanzaro, Nicholas, additional, West, Ande, additional, Moreira, Fernando R., additional, Nogueira Batista, Mariana, additional, Ferris, Martin T., additional, Linnertz, Colton L., additional, Leist, Sarah R., additional, Nguyen, Cameron, additional, De la Cruz, Gabriela, additional, Midkiff, Bentley R., additional, Xia, Yongjuan, additional, Evangelista, Mia D., additional, Montgomery, Stephanie A., additional, Billerbeck, Eva, additional, Bukh, Jens, additional, Scheel, Troels K.H., additional, Rice, Charles M., additional, and Sheahan, Timothy P., additional

Published
2023
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6. Efficacy of the oral nucleoside prodrug GS-5245 (Obeldesivir) against SARS-CoV-2 and coronaviruses with pandemic potential

Author

Martinez, David R., primary, Moreira, Fernando R., additional, Zweigart, Mark R., additional, Gully, Kendra L., additional, Cruz, Gabriela De la, additional, Brown, Ariane J., additional, Adams, Lily E., additional, Catanzaro, Nicholas, additional, Yount, Boyd, additional, Baric, Thomas J., additional, Mallory, Michael L., additional, Conrad, Helen, additional, May, Samantha R., additional, Dong, Stephanie, additional, Scobey, D. Trevor, additional, Montgomery, Stephanie A., additional, Perry, Jason, additional, Babusis, Darius, additional, Barrett, Kimberly T., additional, Nguyen, Anh-Hoa, additional, Nguyen, Anh-Quan, additional, Kalla, Rao, additional, Bannister, Roy, additional, Bilello, John P., additional, Feng, Joy Y., additional, Cihlar, Tomas, additional, Baric, Ralph S., additional, Mackman, Richard L., additional, Schäfer, Alexandra, additional, and Sheahan, Timothy P., additional

Published
2023
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7. Therapeutic treatment with an oral prodrug of the remdesivir parental nucleoside is protective against SARS-CoV-2 pathogenesis in mice

Author

Schäfer, Alexandra, primary, Martinez, David R., additional, Won, John J., additional, Meganck, Rita M., additional, Moreira, Fernando R., additional, Brown, Ariane J., additional, Gully, Kendra L., additional, Zweigart, Mark R., additional, Conrad, William S., additional, May, Samantha R., additional, Dong, Stephanie, additional, Kalla, Rao, additional, Chun, Kwon, additional, Du Pont, Venice, additional, Babusis, Darius, additional, Tang, Jennifer, additional, Murakami, Eisuke, additional, Subramanian, Raju, additional, Barrett, Kimberly T., additional, Bleier, Blake J., additional, Bannister, Roy, additional, Feng, Joy Y., additional, Bilello, John P., additional, Cihlar, Tomas, additional, Mackman, Richard L., additional, Montgomery, Stephanie A., additional, Baric, Ralph S., additional, and Sheahan, Timothy P., additional

Published
2022
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8. Facile discovery of surrogate cytokine agonists

Author

Yen, Michelle, primary, Ren, Junming, additional, Liu, Qingxiang, additional, Glassman, Caleb R., additional, Sheahan, Timothy P., additional, Picton, Lora K., additional, Moreira, Fernando R., additional, Rustagi, Arjun, additional, Jude, Kevin M., additional, Zhao, Xiang, additional, Blish, Catherine A., additional, Baric, Ralph S., additional, Su, Leon L., additional, and Garcia, K. Christopher, additional

Published
2022
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10. Therapeutic efficacy of an oral nucleoside analog of remdesivir against SARS-CoV-2 pathogenesis in mice

Author

Schäfer, Alexandra, primary, Martinez, David R., additional, Won, John J., additional, Moreira, Fernando R., additional, Brown, Ariane J., additional, Gully, Kendra L., additional, Kalla, Rao, additional, Chun, Kwon, additional, Du Pont, Venice, additional, Babusis, Darius, additional, Tang, Jennifer, additional, Murakami, Eisuke, additional, Subramanian, Raju, additional, Barrett, Kimberly T, additional, Bleier, Blake J., additional, Bannister, Roy, additional, Feng, Joy Y., additional, Bilello, John P., additional, Cihlar, Tomas, additional, Mackman, Richard L., additional, Montgomery, Stephanie A., additional, Baric, Ralph S., additional, and Sheahan, Timothy P., additional

Published
2021
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11. An oral non-covalent non-peptidic inhibitor of SARS-CoV-2 Mpro ameliorates viral replication and pathogenesis in vivo

Author

Zhou, Nian E., Tang, Su, Bian, Xuelin, Parai, Maloy K., Krieger, Inna V., Flores, Armando, Jaiswal, Pradeep K., Bam, Radha, Wood, Jeremy L., Shi, Zhe, Stevens, Laura J., Scobey, Trevor, Diefenbacher, Meghan V., Moreira, Fernando R., Baric, Thomas J., Acharya, Arjun, Shin, Joonyoung, Rathi, Manish M., Wolff, Karen C., Riva, Laura, Bakowski, Malina A., McNamara, Case W., Catanzaro, Nicholas J., Graham, Rachel L., Schultz, David C., Cherry, Sara, Kawaoka, Yoshihiro, Halfmann, Peter J., Baric, Ralph S., Denison, Mark R., Sheahan, Timothy P., and Sacchettini, James C.

Abstract

Safe, effective, and low-cost oral antiviral therapies are needed to treat those at high risk for developing severe COVID-19. To that end, we performed a high-throughput screen to identify non-peptidic, non-covalent inhibitors of the SARS-CoV-2 main protease (Mpro), an essential enzyme in viral replication. NZ-804 was developed from a screening hit through iterative rounds of structure-guided medicinal chemistry. NZ-804 potently inhibits SARS-CoV-2 Mpro (0.009 μM IC50) as well as SARS-CoV-2 replication in human lung cell lines (0.008 μM EC50) and primary human airway epithelial cell cultures. Antiviral activity is maintained against distantly related sarbecoviruses and endemic human CoV OC43. In SARS-CoV-2 mouse and hamster disease models, NZ-804 therapy given once or twice daily significantly diminished SARS-CoV-2 replication and pathogenesis. NZ-804 synthesis is low cost and uncomplicated, simplifying global production and access. These data support the exploration of NZ-804 as a therapy for COVID-19 and future emerging sarbecovirus infections.

Published
2024
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15. Host genetic variation guides hepacivirus clearance, chronicity, and liver fibrosis in mice.

Author

Brown AJ, Won JJ, Wolfisberg R, Fahnøe U, Catanzaro N, West A, Moreira FR, Nogueira Batista M, Ferris MT, Linnertz CL, Leist SR, Nguyen C, De la Cruz G, Midkiff BR, Xia Y, Evangelista MD, Montgomery SA, Billerbeck E, Bukh J, Scheel TKH, Rice CM, and Sheahan TP

Subjects
Mice, Humans, Rats, Animals, Liver Cirrhosis genetics, Acute Disease, Genetic Variation, Hepacivirus genetics, Hepatitis C
Abstract

Background Aims: Human genetic variation is thought to guide the outcome of HCV infection, but model systems within which to dissect these host genetic mechanisms are limited. Norway rat hepacivirus, closely related to HCV, causes chronic liver infection in rats but causes acute self-limiting hepatitis in typical strains of laboratory mice, which resolves in 2 weeks. The Collaborative Cross (CC) is a robust mouse genetics resource comprised of a panel of recombinant inbred strains, which model the complexity of the human genome and provide a system within which to understand diseases driven by complex allelic variation., Approach Results: We infected a panel of CC strains with Norway rat hepacivirus and identified several that failed to clear the virus after 4 weeks. Strains displayed an array of virologic phenotypes ranging from delayed clearance (CC046) to chronicity (CC071, CC080) with viremia for at least 10 months. Body weight loss, hepatocyte infection frequency, viral evolution, T-cell recruitment to the liver, liver inflammation, and the capacity to develop liver fibrosis varied among infected CC strains., Conclusions: These models recapitulate many aspects of HCV infection in humans and demonstrate that host genetic variation affects a multitude of viruses and host phenotypes. These models can be used to better understand the molecular mechanisms that drive hepacivirus clearance and chronicity, the virus and host interactions that promote chronic disease manifestations like liver fibrosis, therapeutic and vaccine performance, and how these factors are affected by host genetic variation., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Published
2024
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16. Efficacy of the oral nucleoside prodrug GS-5245 (Obeldesivir) against SARS-CoV-2 and coronaviruses with pandemic potential.

Author

Martinez DR, Moreira FR, Zweigart MR, Gully KL, De la Cruz G, Brown AJ, Adams LE, Catanzaro N, Yount B, Baric TJ, Mallory ML, Conrad H, May SR, Dong S, Scobey DT, Montgomery SA, Perry J, Babusis D, Barrett KT, Nguyen AH, Nguyen AQ, Kalla R, Bannister R, Bilello JP, Feng JY, Cihlar T, Baric RS, Mackman RL, Schäfer A, and Sheahan TP

Abstract

Despite the wide availability of several safe and effective vaccines that can prevent severe COVID-19 disease, the emergence of SARS-CoV-2 variants of concern (VOC) that can partially evade vaccine immunity remains a global health concern. In addition, the emergence of highly mutated and neutralization-resistant SARS-CoV-2 VOCs such as BA.1 and BA.5 that can partially or fully evade (1) many therapeutic monoclonal antibodies in clinical use underlines the need for additional effective treatment strategies. Here, we characterize the antiviral activity of GS-5245, Obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved RNA-dependent viral RNA polymerase (RdRp). Importantly, we show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-related Bat-CoV RsSHC014, Middle East Respiratory Syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant in vitro and highly effective as antiviral therapy in mouse models of SARS-CoV, SARS-CoV-2 (WA/1), MERS-CoV and Bat-CoV RsSHC014 pathogenesis. In all these models of divergent coronaviruses, we observed protection and/or significant reduction of disease metrics such as weight loss, lung viral replication, acute lung injury, and degradation in pulmonary function in GS-5245-treated mice compared to vehicle controls. Finally, we demonstrate that GS-5245 in combination with the main protease (M pro ) inhibitor nirmatrelvir had increased efficacy in vivo against SARS-CoV-2 compared to each single agent. Altogether, our data supports the continuing clinical evaluation of GS-5245 in humans infected with COVID-19, including as part of a combination antiviral therapy, especially in populations with the most urgent need for more efficacious and durable interventions., Competing Interests: DECLARATION OF INTERESTS These authors are employees of Gilead Sciences and hold stock in Gilead Sciences: D.B., A.N., K.T.B., R.B, J.P.B., J.Y.F., T.C., R.L.M.

Published
2023
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17. Therapeutic efficacy of an oral nucleoside analog of remdesivir against SARS-CoV-2 pathogenesis in mice.

Author

Schäfer A, Martinez DR, Won JJ, Moreira FR, Brown AJ, Gully KL, Kalla R, Chun K, Du Pont V, Babusis D, Tang J, Murakami E, Subramanian R, Barrett KT, Bleier BJ, Bannister R, Feng JY, Bilello JP, Cihlar T, Mackman RL, Montgomery SA, Baric RS, and Sheahan TP

Abstract

The COVID-19 pandemic remains uncontrolled despite the rapid rollout of safe and effective SARS-CoV-2 vaccines, underscoring the need to develop highly effective antivirals. In the setting of waning immunity from infection and vaccination, breakthrough infections are becoming increasingly common and treatment options remain limited. Additionally, the emergence of SARS-CoV-2 variants of concern with their potential to escape therapeutic monoclonal antibodies emphasizes the need to develop second-generation oral antivirals targeting highly conserved viral proteins that can be rapidly deployed to outpatients. Here, we demonstrate the in vitro antiviral activity and in vivo therapeutic efficacy of GS-621763, an orally bioavailable prodrug of GS-441524, the parental nucleoside of remdesivir, which targets the highly conserved RNA-dependent RNA polymerase. GS-621763 exhibited significant antiviral activity in lung cell lines and two different human primary lung cell culture systems. The dose-proportional pharmacokinetic profile observed after oral administration of GS-621763 translated to dose-dependent antiviral activity in mice infected with SARS-CoV-2. Therapeutic GS-621763 significantly reduced viral load, lung pathology, and improved pulmonary function in COVID-19 mouse model. A direct comparison of GS-621763 with molnupiravir, an oral nucleoside analog antiviral currently in human clinical trial, proved both drugs to be similarly efficacious. These data demonstrate that therapy with oral prodrugs of remdesivir can significantly improve outcomes in SARS-CoV-2 infected mice. Thus, GS-621763 supports the exploration of GS-441524 oral prodrugs for the treatment of COVID-19 in humans.

Published
2021
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