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3. Three SARS-CoV-2 spike protein variants delivered intranasally by measles and mumps vaccines are broadly protective

Author

Zhang, Yuexiu, Chamblee, Michelle, Xu, Jiayu, Qu, Panke, Shamseldin, Mohamed M., Yoo, Sung J., Misny, Jack, Thongpan, Ilada, KC, Mahesh, Hall, Jesse M., Gupta, Yash A., Evans, John P., Lu, Mijia, Ye, Chengjin, Hsu, Cheng Chih, Liang, Xueya, Martinez-Sobrido, Luis, Yount, Jacob S., Boyaka, Prosper N., Liu, Shan-Lu, Dubey, Purnima, Peeples, Mark E., and Li, Jianrong

Published
2024
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4. Anti-rheumatic colchicine phytochemical exhibits potent antiviral activities against avian and seasonal Influenza A viruses (IAVs) via targeting different stages of IAV replication cycle

Author

Hegazy, Akram, Soltane, Raya, Alasiri, Ahlam, Mostafa, Islam, Metwaly, Ahmed M., Eissa, Ibrahim H., Mahmoud, Sara H., Allayeh, Abdou Kamal, Shama, Noura M. Abo, Khalil, Ahmed A., Barre, Ramya S., El-Shazly, Assem Mohamed, Ali, Mohamed A., Martinez-Sobrido, Luis, and Mostafa, Ahmed

Published
2024
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6. Author Correction: Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing

Author

Riva, Laura, Yuan, Shuofeng, Yin, Xin, Martin-Sancho, Laura, Matsunaga, Naoko, Pache, Lars, Burgstaller-Muehlbacher, Sebastian, De Jesus, Paul D., Teriete, Peter, Hull, Mitchell V., Chang, Max W., Chan, Jasper Fuk-Woo, Cao, Jianli, Poon, Vincent Kwok-Man, Herbert, Kristina M., Cheng, Kuoyuan, Nguyen, Tu-Trinh H., Rubanov, Andrey, Pu, Yuan, Nguyen, Courtney, Choi, Angela, Rathnasinghe, Raveen, Schotsaert, Michael, Miorin, Lisa, Dejosez, Marion, Zwaka, Thomas P., Sit, Ko-Yung, Martinez-Sobrido, Luis, Liu, Wen-Chun, White, Kris M., Chapman, Mackenzie E., Lendy, Emma K., Glynne, Richard J., Albrecht, Randy, Ruppin, Eytan, Mesecar, Andrew D., Johnson, Jeffrey R., Benner, Christopher, Sun, Ren, Schultz, Peter G., Su, Andrew I., García-Sastre, Adolfo, Chatterjee, Arnab K., Yuen, Kwok-Yung, and Chanda, Sumit K.

Published
2024
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7. SARS-CoV-2 prefusion spike protein stabilized by six rather than two prolines is more potent for inducing antibodies that neutralize viral variants of concern

Author

Lu, Mijia, Chamblee, Michelle, Zhang, Yuexiu, Ye, Chengjin, Dravid, Piyush, Park, Jun-Gyu, Mahesh, KC, Trivedi, Sheetal, Murthy, Satyapramod, Sharma, Himanshu, Cassady, Cole, Chaiwatpongsakorn, Supranee, Liang, Xueya, Yount, Jacob S., Boyaka, Prosper N., Peeples, Mark E., Martinez-Sobrido, Luis, Kapoor, Amit, and Li, Jianrong

Published
2022

8. A highly efficacious live attenuated mumps virus—based SARS-CoV-2 vaccine candidate expressing a six-proline stabilized prefusion spike

Author

Zhang, Yuexiu, Lu, Mijia, Mahesh, K C, Kim, Eunsoo, Shamseldin, Mohamed M., Ye, Chengjin, Dravid, Piyush, Chamblee, Michelle, Park, Jun-Gyu, Hall, Jesse M., Trivedi, Sheetal, Chaiwatpongsakorn, Supranee, Kenny, Adam D., Murthy, Satyapramod Srinivasa, Sharma, Himanshu, Liang, Xueya, Yount, Jacob S., Kapoor, Amit, Martinez-Sobrido, Luis, Dubey, Purnima, Boyaka, Prosper N., Peeples, Mark E., and Li, Jianrong

Published
2022

9. SARS-CoV-2 variants evolve convergent strategies to remodel the host response

Author

Bouhaddou, Mehdi, Reuschl, Ann-Kathrin, Polacco, Benjamin J., Thorne, Lucy G., Ummadi, Manisha R., Ye, Chengjin, Rosales, Romel, Pelin, Adrian, Batra, Jyoti, Jang, Gwendolyn M., Xu, Jiewei, Moen, Jack M., Richards, Alicia L., Zhou, Yuan, Harjai, Bhavya, Stevenson, Erica, Rojc, Ajda, Ragazzini, Roberta, Whelan, Matthew V.X., Furnon, Wilhelm, De Lorenzo, Giuditta, Cowton, Vanessa, Syed, Abdullah M., Ciling, Alison, Deutsch, Noa, Pirak, Daniel, Dowgier, Giulia, Mesner, Dejan, Turner, Jane L., McGovern, Briana L., Rodriguez, M. Luis, Leiva-Rebollo, Rocio, Dunham, Alistair S., Zhong, Xiaofang, Eckhardt, Manon, Fossati, Andrea, Liotta, Nicholas F., Kehrer, Thomas, Cupic, Anastasija, Rutkowska, Magdalena, Mena, Ignacio, Aslam, Sadaf, Hoffert, Alyssa, Foussard, Helene, Olwal, Charles Ochieng’, Huang, Weiqing, Zwaka, Thomas, Pham, John, Lyons, Molly, Donohue, Laura, Griffin, Aliesha, Nugent, Rebecca, Holden, Kevin, Deans, Robert, Aviles, Pablo, Lopez-Martin, Jose A., Jimeno, Jose M., Obernier, Kirsten, Fabius, Jacqueline M., Soucheray, Margaret, Hüttenhain, Ruth, Jungreis, Irwin, Kellis, Manolis, Echeverria, Ignacia, Verba, Kliment, Bonfanti, Paola, Beltrao, Pedro, Sharan, Roded, Doudna, Jennifer A., Martinez-Sobrido, Luis, Patel, Arvind H., Palmarini, Massimo, Miorin, Lisa, White, Kris, Swaney, Danielle L., Garcia-Sastre, Adolfo, Jolly, Clare, Zuliani-Alvarez, Lorena, Towers, Greg J., and Krogan, Nevan J.

Published
2023
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10. Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis

Author

Kehrer, Thomas, Cupic, Anastasija, Ye, Chengjin, Yildiz, Soner, Bouhaddou, Mehdi, Crossland, Nicholas A., Barrall, Erika A., Cohen, Phillip, Tseng, Anna, Çağatay, Tolga, Rathnasinghe, Raveen, Flores, Daniel, Jangra, Sonia, Alam, Fahmida, Mena, Ignacio, Aslam, Sadaf, Saqi, Anjali, Rutkowska, Magdalena, Ummadi, Manisha R., Pisanelli, Giuseppe, Richardson, R. Blake, Veit, Ethan C., Fabius, Jacqueline M., Soucheray, Margaret, Polacco, Benjamin J., Ak, Baran, Marin, Arturo, Evans, Matthew J., Swaney, Danielle L., Gonzalez-Reiche, Ana S., Sordillo, Emilia M., van Bakel, Harm, Simon, Viviana, Zuliani-Alvarez, Lorena, Fontoura, Beatriz M.A., Rosenberg, Brad R., Krogan, Nevan J., Martinez-Sobrido, Luis, García-Sastre, Adolfo, and Miorin, Lisa

Published
2023
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11. Aerosol delivery of SARS-CoV-2 human monoclonal antibodies in macaques limits viral replication and lung pathology

Author

Streblow, Daniel N., Hirsch, Alec J., Stanton, Jeffrey J., Lewis, Anne D., Colgin, Lois, Hessell, Ann J., Kreklywich, Craig N., Smith, Jessica L., Sutton, William F., Chauvin, David, Woo, Jennifer, Bimber, Benjamin N., LeBlanc, Cierra N., Acharya, Sonia N., O’Roak, Brian J., Sardar, Harjinder, Sajadi, Mohammad M., Tehrani, Zahra R., Walter, Mark R., Martinez-Sobrido, Luis, Kobie, James J., Reader, Rachel J., Olstad, Katherine J., Hobbs, Theodore R., Saphire, Erica Ollmann, Schendel, Sharon L., Carnahan, Robert H., Knoch, Jonas, Branco, Luis M., Crowe, Jr., James E., Van Rompay, Koen K. A., Lovalenti, Phillip, Vu Truong, Forthal, Donald N., and Haigwood, Nancy L.

Published
2023
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14. SARS-CoV-2 replication in airway epithelia requires motile cilia and microvillar reprogramming

Author

Wu, Chien-Ting, Lidsky, Peter V., Xiao, Yinghong, Cheng, Ran, Lee, Ivan T., Nakayama, Tsuguhisa, Jiang, Sizun, He, Wei, Demeter, Janos, Knight, Miguel G., Turn, Rachel E., Rojas-Hernandez, Laura S., Ye, Chengjin, Chiem, Kevin, Shon, Judy, Martinez-Sobrido, Luis, Bertozzi, Carolyn R., Nolan, Garry P., Nayak, Jayakar V., Milla, Carlos, Andino, Raul, and Jackson, Peter K.

Published
2023
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18. Repurposing Drugs for Synergistic Combination Therapies to Counteract Monkeypox Virus Tecovirimat Resistance.

Author

Witwit, Haydar, Cubitt, Beatrice, Khafaji, Roaa, Castro, Esteban M., Goicoechea, Miguel, Lorenzo, Maria M., Blasco, Rafael, Martinez-Sobrido, Luis, and de la Torre, Juan C.

Subjects
MONKEYPOX, COMBINATION drug therapy, DRUG repositioning, MEDICAL practice, MEDICAL care
Abstract

The ongoing monkeypox (mpox) disease outbreak has spread to multiple countries in Central Africa and evidence indicates it is driven by a more virulent clade I monkeypox virus (MPXV) strain than the clade II strain associated with the 2022 global mpox outbreak, which led the WHO to declare this mpox outbreak a public health emergency of international concern. The FDA-approved small molecule antiviral tecovirimat (TPOXX) is recommended to treat mpox cases with severe symptoms, but the limited efficacy of TPOXX and the emergence of TPOXX resistant MPXV variants has challenged this medical practice of care and highlighted the urgent need for alternative therapeutic strategies. In this study we have used vaccinia virus (VACV) as a surrogate of MPXV to assess the antiviral efficacy of combination therapy of TPOXX together with mycophenolate mofetil (MMF), an FDA-approved immunosuppressive agent that we have shown to inhibit VACV and MPXV, or the N-myristoyltransferase (NMT) inhibitor IMP-1088. Both MMF and IMP-1088 drugs exhibited strong dose-dependent antiviral activity against VACV and mpox, and potent synergistic effects in conjunction with TPOXX. Our findings support combination therapy of direct-acting (TPOXX) and host-targeted (MMF and IMP-1088) antivirals as a promising approach to treat mpox and prevent the emergence and spread of TPOXX-resistant MPXV variants. [ABSTRACT FROM AUTHOR]

Published
2025
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19. Anticancer pan-ErbB inhibitors reduce inflammation and tissue injury and exert broad-spectrum antiviral effects

Author

Saul, Sirle, Karim, Marwah, Ghita, Luca, Huang, Pei-Tzu, Chiu, Winston, Duran, Veronica, Lo, Chieh-Wen, Kumar, Sathish, Bhalla, Nishank, Leyssen, Pieter, Alem, Farhang, Boghdeh, Niloufar A., Tran, Do H.N., Cohen, Courtney A., Brown, Jacquelyn A., Huie, Kathleen E., Tindle, Courtney, Sibai, Mamdouh, Ye, Chengjin, Khalil, Ahmed Magdy, Chiem, Kevin, Martinez-Sobrido, Luis, Dye, John M., Pinsky, Benjamin A., Ghosh, Pradipta, Das, Soumita, Solow-Cordero, David E., Jin, Jing, Wikswo, John P., Jochmans, Dirk, Neyts, Johan, De Jonghe, Steven, Narayanan, Aarthi, and Einav, Shirit

Subjects
Drug therapy, Research, Health aspects, Lapatinib -- Research, Pharmaceutical research, Antiviral agents -- Research, Inflammation -- Drug therapy, Epidermal growth factor receptors -- Health aspects, COVID-19 -- Drug therapy, Drug discovery
Abstract

Introduction Acute emerging viral infections can cause epidemics and pandemics and thus pose major threats to human health. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread Authorship note: SS [...], Targeting host factors exploited by multiple viruses could offer broad-spectrum solutions for pandemic preparedness. Seventeen candidates targeting diverse functions emerged in a screen of 4,413 compounds for SARS-CoV-2 inhibitors. We demonstrated that lapatinib and other approved inhibitors of the ErbB family of receptor tyrosine kinases suppress replication of SARS-CoV-2, Venezuelan equine encephalitis virus (VEEV), and other emerging viruses with a high barrier to resistance. Lapatinib suppressed SARS-CoV-2 entry and later stages of the viral life cycle and showed synergistic effect with the directacting antiviral nirmatrelvir. We discovered that ErbB1, ErbB2, and ErbB4 bind SARS-CoV-2 S1 protein and regulate viral and ACE2 internalization, and they are required for VEEV infection. In human lung organoids, lapatinib protected from SARSCoV-2-induced activation of ErbB-regulated pathways implicated in non-infectious lung injury, proinflammatory cytokine production, and epithelial barrier injury. Lapatinib suppressed VEEV replication, cytokine production, and disruption of bloodbrain barrier integrity in microfluidics-based human neurovascular units, and reduced mortality in a lethal infection murine model. We validated lapatinib-mediated inhibition of ErbB activity as an important mechanism of antiviral action. These findings reveal regulation of viral replication, inflammation, and tissue injury via ErbBs and establish a proof of principle for a repurposed, ErbB-targeted approach to combat emerging viruses.

Published
2023
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20. SARS-CoV-2 infection enhances mitochondrial PTP complex activity to perturb cardiac energetics

Author

Ramachandran, Karthik, Maity, Soumya, Muthukumar, Alagar R., Kandala, Soundarya, Tomar, Dhanendra, Abd El-Aziz, Tarek Mohamed, Allen, Cristel, Sun, Yuyang, Venkatesan, Manigandan, Madaris, Travis R., Chiem, Kevin, Truitt, Rachel, Vishnu, Neelanjan, Aune, Gregory, Anderson, Allen, Martinez-Sobrido, Luis, Yang, Wenli, Stockand, James D., Singh, Brij B., Srikantan, Subramanya, Reeves, W. Brian, and Madesh, Muniswamy

Published
2022
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21. A safe and highly efficacious measles virus-based vaccine expressing SARS-CoV-2 stabilized prefusion spike

Author

Lu, Mijia, Dravid, Piyush, Zhang, Yuexiu, Trivedi, Sheetal, Li, Anzhong, Harder, Olivia, KC, Mahesh, Chaiwatpongsakorn, Supranee, Zani, Ashley, Kenney, Adam, Zeng, Cong, Cai, Chuanxi, Ye, Chengjin, Liang, Xueya, Shimamura, Masako, Liu, Shan-Lu, Mejias, Asuncion, Ramilo, Octavio, Boyaka, Prosper N., Qiu, Jianming, Martinez-Sobrido, Luis, Yount, Jacob S., Peeples, Mark E., Kapoor, Amit, Niewiesk, Stefan, and Li, Jianrong

Published
2021

22. Characterization of SARS-CoV-2 Spike mutations important for infection of mice and escape from human immune sera

Author

Rathnasinghe, Raveen, Jangra, Sonia, Ye, Chengjin, Cupic, Anastasija, Singh, Gagandeep, Martínez-Romero, Carles, Mulder, Lubbertus C. F., Kehrer, Thomas, Yildiz, Soner, Choi, Angela, Yeung, Stephen T., Mena, Ignacio, Gillespie, Virginia, De Vrieze, Jana, Aslam, Sadaf, Stadlbauer, Daniel, Meekins, David A., McDowell, Chester D., Balaraman, Velmurugan, Corley, Michael J., Richt, Juergen A., De Geest, Bruno G., Miorin, Lisa, Krammer, Florian, Martinez-Sobrido, Luis, Simon, Viviana, García-Sastre, Adolfo, and Schotsaert, Michael

Published
2022
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23. Modeling SARS-CoV-2 and influenza infections and antiviral treatments in human lung epithelial tissue equivalents

Author

Zarkoob, Hoda, Allué-Guardia, Anna, Chen, Yu-Chi, Garcia-Vilanova, Andreu, Jung, Olive, Coon, Steven, Song, Min Jae, Park, Jun-Gyu, Oladunni, Fatai, Miller, Jesse, Tung, Yen-Ting, Kosik, Ivan, Schultz, David, Iben, James, Li, Tianwei, Fu, Jiaqi, Porter, Forbes D., Yewdell, Jonathan, Martinez-Sobrido, Luis, Cherry, Sara, Torrelles, Jordi B., Ferrer, Marc, and Lee, Emily M.

Published
2022
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24. Immunogenicity and protective efficacy of an intranasal live-attenuated vaccine against SARS-CoV-2

Author

Park, Jun-Gyu, Oladunni, Fatai S., Rohaim, Mohammed A., Whittingham-Dowd, Jayde, Tollitt, James, Hodges, Matthew D.J., Fathallah, Nadin, Assas, Muhsref Bakri, Alhazmi, Wafaa, Almilaibary, Abdullah, Iqbal, Munir, Chang, Pengxiang, Escalona, Renee, Shivanna, Vinay, Torrelles, Jordi B., Worthington, John J., Jackson-Jones, Lucy H., Martinez-Sobrido, Luis, and Munir, Muhammad

Published
2021
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27. Therapeutic activity of an inhaled potent SARS-CoV-2 neutralizing human monoclonal antibody in hamsters

Author

Piepenbrink, Michael S., Park, Jun-Gyu, Oladunni, Fatai S., Deshpande, Ashlesha, Basu, Madhubanti, Sarkar, Sanghita, Loos, Andreas, Woo, Jennifer, Lovalenti, Phillip, Sloan, Derek, Ye, Chengjin, Chiem, Kevin, Bates, Christopher W., Burch, Reuben E., Erdmann, Nathaniel B., Goepfert, Paul A., Truong, Vu L., Walter, Mark R., Martinez-Sobrido, Luis, and Kobie, James J.

Published
2021
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29. Recombinant Influenza A Viruses Expressing Reporter Genes from the Viral NS Segment.

Author

Martinez-Sobrido, Luis and Nogales, Aitor

Subjects
*REPORTER genes, *REVERSE genetics, *INFLUENZA A virus, *INFLUENZA viruses, *VIRUS diseases
Abstract

Studying influenza A viruses (IAVs) requires secondary experimental procedures to detect the presence of the virus in infected cells or animals. The ability to generate recombinant (r)IAV using reverse genetics techniques has allowed investigators to generate viruses expressing foreign genes, including fluorescent and luciferase proteins. These rIAVs expressing reporter genes have allowed for easily tracking viral infections in cultured cells and animal models of infection without the need for secondary approaches, representing an excellent option to study different aspects in the biology of IAV where expression of reporter genes can be used as a readout of viral replication and spread. Likewise, these reporter-expressing rIAVs provide an excellent opportunity for the rapid identification and characterization of prophylactic and/or therapeutic approaches. To date, rIAV expressing reporter genes from different viral segments have been described in the literature. Among those, rIAV expressing reporter genes from the viral NS segment have been shown to represent an excellent option to track IAV infection in vitro and in vivo, eliminating the need for secondary approaches to identify the presence of the virus. Here, we summarize the status on rIAV expressing traceable reporter genes from the viral NS segment and their applications for in vitro and in vivo influenza research. [ABSTRACT FROM AUTHOR]

Published
2024
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33. A safe and efficacious Lassa virus live-attenuated vaccine candidate based on rearrangement of the intergenic region and codon-deoptimization of the glycoprotein gene

Author

Carey, Dr Brian, Yu, Shuiqing, Geiger, Jillian, Ye, Chengjin, Huzella, Louis, Reeder, Rebecca, Mehta, Monika, Hirsch, Shawn, Bernbaum, Rebecca, Cubitt, Beatrice, Pahar, Bapi, Anthony, Scott, Marketon, Anthony, Bernbaum, John, Tran, Julie, Crozier, Ian, Martinez-Sobrido, Luis, Worwa, Gabriella, de la Torre, Juan Carlos, and Kuhn, Jens

Published
2025
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36. Responses to acute infection with SARS-CoV-2 in the lungs of rhesus macaques, baboons and marmosets

Author

Singh, Dhiraj Kumar, Singh, Bindu, Ganatra, Shashank R., Gazi, Michal, Cole, Journey, Thippeshappa, Rajesh, Alfson, Kendra J., Clemmons, Elizabeth, Gonzalez, Olga, Escobedo, Ruby, Lee, Tae-Hyung, Chatterjee, Ayan, Goez-Gazi, Yenny, Sharan, Riti, Gough, Maya, Alvarez, Cynthia, Blakley, Alyssa, Ferdin, Justin, Bartley, Carmen, Staples, Hilary, Parodi, Laura, Callery, Jessica, Mannino, Amanda, Klaffke, Benjamin, Escareno, Priscilla, Platt, II, Roy N., Hodara, Vida, Scordo, Julia, Gautam, Shalini, Vilanova, Andreu G., Olmo-Fontanez, Angelica, Schami, Alyssa, Oyejide, Adelekan, Ajithdoss, Dharani K., Copin, Richard, Baum, Alina, Kyratsous, Christos, Alvarez, Xavier, Ahmed, Mushtaq, Rosa, Bruce, Goodroe, Anna, Dutton, John, Hall-Ursone, Shannan, Frost, Patrice A., Voges, Andra K., Ross, Corinna N., Sayers, Ken, Chen, Christopher, Hallam, Cory, Khader, Shabaana A., Mitreva, Makedonka, Anderson, Timothy J. C., Martinez-Sobrido, Luis, Patterson, Jean L., Turner, Joanne, Torrelles, Jordi B., Dick, Jr, Edward J., Brasky, Kathleen, Schlesinger, Larry S., Giavedoni, Luis D., Carrion, Jr, Ricardo, and Kaushal, Deepak

Published
2021
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37. Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing

Author

Riva, Laura, Yuan, Shuofeng, Yin, Xin, Martin-Sancho, Laura, Matsunaga, Naoko, Pache, Lars, Burgstaller-Muehlbacher, Sebastian, De Jesus, Paul D., Teriete, Peter, Hull, Mitchell V., Chang, Max W., Chan, Jasper Fuk-Woo, Cao, Jianli, Poon, Vincent Kwok-Man, Herbert, Kristina M., Cheng, Kuoyuan, Nguyen, Tu-Trinh H., Rubanov, Andrey, Pu, Yuan, Nguyen, Courtney, Choi, Angela, Rathnasinghe, Raveen, Schotsaert, Michael, Miorin, Lisa, Dejosez, Marion, Zwaka, Thomas P., Sit, Ko-Yung, Martinez-Sobrido, Luis, Liu, Wen-Chun, White, Kris M., Chapman, Mackenzie E., Lendy, Emma K., Glynne, Richard J., Albrecht, Randy, Ruppin, Eytan, Mesecar, Andrew D., Johnson, Jeffrey R., Benner, Christopher, Sun, Ren, Schultz, Peter G., Su, Andrew I., García-Sastre, Adolfo, Chatterjee, Arnab K., Yuen, Kwok-Yung, and Chanda, Sumit K.

Published
2020
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40. Cellular N-Myristoyl Transferases Are Required for Mammarenavirus Multiplication.

Author

Witwit, Haydar, Betancourt, Carlos Alberto, Cubitt, Beatrice, Khafaji, Roaa, Kowalski, Heinrich, Jackson, Nathaniel, Ye, Chengjin, Martinez-Sobrido, Luis, and de la Torre, Juan C.

Subjects
LYMPHOCYTIC choriomeningitis virus, EXTRACELLULAR matrix proteins, PEPTIDES, MYRISTOYLATION, PROTEOLYSIS
Abstract

The mammarenavirus matrix Z protein plays critical roles in virus assembly and cell egress. Meanwhile, heterotrimer complexes of a stable signal peptide (SSP) together with glycoprotein subunits GP1 and GP2, generated via co-and post-translational processing of the surface glycoprotein precursor GPC, form the spikes that decorate the virion surface and mediate virus cell entry via receptor-mediated endocytosis. The Z protein and the SSP undergo N-terminal myristoylation by host cell N-myristoyltransferases (NMT1 and NMT2), and G2A mutations that prevent myristoylation of Z or SSP have been shown to affect the Z-mediated virus budding and GP2-mediated fusion activity that is required to complete the virus cell entry process. In the present work, we present evidence that the validated on-target specific pan-NMT inhibitor DDD85646 exerts a potent antiviral activity against the prototypic mammarenavirus lymphocytic choriomeningitis virus (LCMV) that correlates with reduced Z budding activity and GP2-mediated fusion activity as well as with proteasome-mediated degradation of the Z protein. The potent anti-mammarenaviral activity of DDD85646 was also observed with the hemorrhagic-fever-causing Junin (JUNV) and Lassa (LASV) mammarenaviruses. Our results support the exploration of NMT inhibition as a broad-spectrum antiviral against human pathogenic mammarenaviruses. [ABSTRACT FROM AUTHOR]

Published
2024
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41. Valproic acid use is associated with diminished risk of contracting COVID-19, and diminished disease severity: Epidemiologic and in vitro analysis reveal mechanistic insights.

Author

Watson, Amanda, Shah, Pankil, Lee, Doug, Liang, Sitai, Joshi, Geeta, Metitiri, Ediri, Chowdhury, Wasim H., Bacich, Dean, Dube, Peter, Xiang, Yan, Hanley, Daniel, Martinez-Sobrido, Luis, and Rodriguez, Ronald

Abstract

The SARS-CoV-2 pandemic has caused unprecedented worldwide infections from persistent mutant variants with various degrees of infectivity and virulence. The elusiveness of a highly penetrant, worldwide vaccination strategy suggests that the complete eradication of SARS-CoV-2 is unlikely. Even with the advent of new antiviral agents, the disease burden worldwide continues to exceed current preventative and therapeutic strategies. Greater interest has been placed towards the development of affordable,broadly effective antiviral therapeutics. Here, we report that the small branched-chain fatty acid Valproic acid (VPA), approved for maintenance of seizure and bipolar disorder, has a novel anti- coronavirus activity that can be augmented with the addition of a long-chain, polyunsaturated omega-3 fatty acid, Docosahexaenoic acid (DHA). An EMR-based epidemiological study of patients tested for COVID-19 demonstrated a correlation exists between a reduced infection rate in patients treated withVPA of up to 25%, as well as a decreased risk of emergency room visits, hospitalization, ICU admission,and use of mechanical ventilation. In vitro studies have demonstrated that VPA modifies gene expression in MRC5 cells. Interestingly, VPA correlates with the inhibition of several SARS-CoV2 interacting genes and the greater inhibition of alpha-coronavirus HCoV-229E (a "common cold" virus) and SARS-CoV2. The VPA-DHA combination activates pre-existing intracellular antiviral mechanisms normally repressed by coronaviruses. Gene expression profiles demonstrate subtle differences in overall gene expression between VPA-treated and VPA-DHA-treated cells. HCoV-229E infection caused an intensely different response with a marked induction of multiple intracellular inflammatory genes. Changes in gene expression took at least 24 hours to manifest and most likely why prior drug screens failed to identify any antiviral VPA activity despite in silico predictions. This report demonstrates an interaction between HDAC inhibition and the potent activation of cellular antiviral responses. A foundation now exists for a low-cost, highly effective antiviral strategy when supplemented with DHA. [ABSTRACT FROM AUTHOR]

Published
2024
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42. New Advances on Zika Virus Research.

Author

Martinez-Sobrido, Luis and Almazan Toral, Fernando

Subjects
Aedes aegypti, African-lineage, Asian lineage, Asian-lineage, Bacterial artificial chromosome, Bayesian analyses, ELISA, EQA, FSS13025, Full-length cDNA infectious clones, IgA, IgG avidity tests, MR766, NHP, NS1 protein, NS2A protein, NS5, Non-human primates, QCMD, RNA-seq, TLR7/8, Tet-inducible, ZIKV, ZIKV-associated neurologic disorders, ZIKV-host interactions, Zika, Zika virus, Zika virus (ZIKV), Ziks virus, anti-viral immunity, antiviral, antiviral compounds, antiviral responses, antivirals, apoptosis, arbovirus, assay standardization, astrocytomas, bacterial artificial chromosome, blood-retinal barrier, boolean logic-processing nucleic acid probes, cell surface receptors, chimeric viruses, clinical trials, congenital Zika syndrome, cross-reactions, cryptic promoter silencing, cytopathic effects, dengue virus, dengue viruses, detoxification and immune system responses, diagnosis, dsRNA, eIF4A, emerging arbovirus, external quality assessment, eye, fetal infection, flavivirus, flaviviruses, full-length molecular clone, gene expression, genetic variability, heme-oxygenase 1, hepatocytes, host genetic variation, host-directed antivirals, human brain glial cells, immune response, indirect immunofluorescence, infection, infectious RNA, infectious cDNA, infectious clone, innate response, insecticide resistance, isothermal nucleic acid amplification, laboratory preparedness, microRNAs, microcephaly, microglia cells, microsphere immunoassay, molecular diagnostics, monoclonal antibodies, mosquito, mosquito surveillance, mosquito-borne flavivirus, multiplex nucleic acid detection, mutagenesis, natural history, neural cells, neural progenitor cells, neuroinflammation, neurons, neuropathogenesis, nucleic acid computation, nucleic acid strand exchange, ocular, optimised, outbreak control, placenta cells, plaque reduction neutralization test, plasmid toxicity, point-of-care diagnostics, polymerase chain reaction, prM-E proteins, pregnancy, prostate, replication, replicon, reporter virus, research models and tools, reverse genetics, rhesus macaques, secondary infections, serology, sexual transmission, siRNA, silvestrol, subgenomic replicon, testes, testicular cells, testis, therapeutics, therapy, type I IFN antagonist, vaccines, validated, viral counteraction, viral evolution, viral fitness, viral genetic variation, viral pathogenesis, viral pathogenicity, viral permissiveness, viral persistence, viral replication, viral survival, virus attachment, virus like particles, zika virus
Abstract

Summary: Zika virus (ZIKV) is a mosquito-borne member of the Flaviviridae family that historically has been associated with mild febrile illness. However, the recent outbreaks in Brazil in 2015 and its rapid spread throughout South and Central America and the Caribbean, together with its association with severe neurological disorders-including fetal microcephaly and Guillain-Barré syndrome in adults-have changed the historic perspective of ZIKV. Currently, ZIKV is considered an important public health concern that has the potential to affect millions of people worldwide. The significance of ZIKV in human health and the lack of approved vaccines and/or antiviral drugs to combat ZIKV infection have triggered a global effort to develop effective countermeasures to prevent and/or treat ZIKV infection. In this Special Issue of Viruses, we have assembled a collection of 32 research and review articles that cover the more recent advances on ZIKV molecular biology, replication and transmission, virus-host interactions, pathogenesis, epidemiology, vaccine development, antivirals, and viral diagnosis.

44. The immunological potency and therapeutic potential of a prototype dual vaccine against influenza and Alzheimer's disease

Author

Davtyan, Hayk, Ghochikyan, Anahit, Cadagan, Richard, Zamarin, Dmitriy, Petrushina, Irina, Movsesyan, Nina, Martinez-Sobrido, Luis, Albrecht, Randy A, García-Sastre, Adolfo, and Agadjanyan, Michael G

Abstract

Abstract Background Numerous pre-clinical studies and clinical trials demonstrated that induction of antibodies to the β-amyloid peptide of 42 residues (Aβ42) elicits therapeutic effects in Alzheimer's disease (AD). However, an active vaccination strategy based on full length Aβ42 is currently hampered by elicitation of T cell pathological autoreactivity. We attempt to improve vaccine efficacy by creating a novel chimeric flu vaccine expressing the small immunodominant B cell epitope of Aβ42. We hypothesized that in elderly people with pre-existing memory Th cells specific to influenza this dual vaccine will simultaneously boost anti-influenza immunity and induce production of therapeutically active anti-Aβ antibodies. Methods Plasmid-based reverse genetics system was used for the rescue of recombinant influenza virus containing immunodominant B cell epitopes of Aβ42 (Aβ1-7/10). Results Two chimeric flu viruses expressing either 7 or 10 aa of Aβ42 (flu-Aβ1-7 or flu-Aβ1-10) were generated and tested in mice as conventional inactivated vaccines. We demonstrated that this dual vaccine induced therapeutically potent anti-Aβ antibodies and anti-influenza antibodies in mice. Conclusion We suggest that this strategy might be beneficial for treatment of AD patients as well as for prevention of development of AD pathology in pre-symptomatic individuals while concurrently boosting immunity against influenza.

Published
2011

46. Lethality of SARS-CoV-2 infection in K18 human angiotensin-converting enzyme 2 transgenic mice

Author

Oladunni, Fatai S., Park, Jun-Gyu, Pino, Paula A., Gonzalez, Olga, Akhter, Anwari, Allué-Guardia, Anna, Olmo-Fontánez, Angélica, Gautam, Shalini, Garcia-Vilanova, Andreu, Ye, Chengjin, Chiem, Kevin, Headley, Colwyn, Dwivedi, Varun, Parodi, Laura M., Alfson, Kendra J., Staples, Hilary M., Schami, Alyssa, Garcia, Juan I., Whigham, Alison, Platt, II, Roy Neal, Gazi, Michal, Martinez, Jesse, Chuba, Colin, Earley, Stephanie, Rodriguez, Oscar H., Mdaki, Stephanie Davis, Kavelish, Katrina N., Escalona, Renee, Hallam, Cory R. A., Christie, Corbett, Patterson, Jean L., Anderson, Tim J. C., Carrion, Jr, Ricardo, Dick, Jr, Edward J., Hall-Ursone, Shannan, Schlesinger, Larry S., Alvarez, Xavier, Kaushal, Deepak, Giavedoni, Luis D., Turner, Joanne, Martinez-Sobrido, Luis, and Torrelles, Jordi B.

Published
2020
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48. New Advances on Zika Virus Research

Author

Martinez-Sobrido, Luis and Almazan Toral, Fernando

Abstract

Zika virus (ZIKV) is a mosquito-borne member of the Flaviviridae family that historically has been associated with mild febrile illness. However, the recent outbreaks in Brazil in 2015 and its rapid spread throughout South and Central America and the Caribbean, together with its association with severe neurological disorders—including fetal microcephaly and Guillain-Barré syndrome in adults—have changed the historic perspective of ZIKV. Currently, ZIKV is considered an important public health concern that has the potential to affect millions of people worldwide. The significance of ZIKV in human health and the lack of approved vaccines and/or antiviral drugs to combat ZIKV infection have triggered a global effort to develop effective countermeasures to prevent and/or treat ZIKV infection. In this Special Issue of Viruses, we have assembled a collection of 32 research and review articles that cover the more recent advances on ZIKV molecular biology, replication and transmission, virus–host interactions, pathogenesis, epidemiology, vaccine development, antivirals, and viral diagnosis.

Published
2019

49. Inhibition of mRNA nuclear export promotes SARS-CoV-2 pathogenesis.

Author

Mei, Menghan, Cupic, Anastasija, Miorin, Lisa, Chengjin Ye, Cagatay, Tolga, Ke Zhang, Patel, Komal, Wilson, Natalie, McDonald, W. Hayes, Crossland, Nicholas A., Ming Lo, Rutkowska, Magdalena, Aslam, Sadaf, Mena, Ignacio, Martinez-Sobrido, Luis, Yi Ren, García-Sastre, Adolfo, and Fontoura, Beatriz M. A.

Subjects
SARS-CoV-2, MESSENGER RNA
Abstract

The nonstructural protein 1 (Nsp1) of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is a virulence factor that targets multiple cellular pathways to inhibit host gene expression and antiviral response. However, the underlying mechanisms of the various Nsp1-mediated functions and their contributions to SARS-CoV-2 virulence remain unclear. Among the targets of Nsp1 is the mRNA (messenger ribonucleic acid) export receptor NXF1-NXT1, which mediates nuclear export of mRNAs from the nucleus to the cytoplasm. Based on Nsp1 crystal structure, we generated mutants on Nsp1 surfaces and identified an acidic N-terminal patch that is critical for interaction with NXF1-NXT1. Photoactivatable Nsp1 probe reveals the RNA Recognition Motif (RRM) domain of NXF1 as an Nsp1 N-terminal binding site. By mutating the Nsp1 N-terminal acidic patch, we identified a separation-of-function mutant of Nsp1 that retains its translation inhibitory function but substantially loses its interaction with NXF1 and reverts Nsp1-mediated mRNA export inhibition. We then generated a recombinant (r)SARS-CoV-2 mutant on the Nsp1 N-terminal acidic patch and found that this surface is key to promote NXF1 binding and inhibition of host mRNA nuclear export, viral replication, and pathogenicity in vivo. Thus, these findings provide a mechanistic understanding of Nsp1-mediated mRNA export inhibition and establish the importance of this pathway in the virulence of SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Published
2024
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50. SARS-CoV-2 nsp15 endoribonuclease antagonizes dsRNA-induced antiviral signaling.

Author

Otter, Clayton J., Bracci, Nicole, Parenti, Nicholas A., Chengjin Ye, Asthana, Abhishek, Blomqvist, Ebba K., Li Hui Tan, Pfannenstiel, Jessica J., Jackson, Nathaniel, Fehr, Anthony R., Silverman, Robert H., Burke, James M., Cohen, Noam A., Martinez-Sobrido, Luis, and Weiss, Susan R.

Subjects
MERS coronavirus, SARS-CoV-2, OLIGOADENYLATE synthetase, ENDORIBONUCLEASES
Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has caused millions of deaths since its emergence in 2019. Innate immune antagonism by lethal CoVs such as SARS-CoV-2 is crucial for optimal replication and pathogenesis. The conserved nonstructural protein 15 (nsp15) endoribonuclease (EndoU) limits activation of double-stranded (ds)RNA-induced pathways, including interferon (IFN) signaling, protein kinase R (PKR), and oligoadenylate synthetase/ribonuclease L (OAS/RNase L) during diverse CoV infections including murine coronavirus and Middle East respiratory syndrome (MERS)-CoV. To determine how nsp15 functions during SARS-CoV-2 infection, we constructed a recombinant SARS-CoV-2 (nsp15mut) expressing catalytically inactivated nsp15, which we show promoted increased dsRNA accumulation. Infection with SARS-CoV-2 nsp15mut led to increased activation of the IFN signaling and PKR pathways in lung-derived epithelial cell lines and primary nasal epithelial air-liquid interface (ALI) cultures as well as significant attenuation of replication in ALI cultures compared to wild-type virus. This replication defect was rescued when IFN signaling was inhibited with the Janus activated kinase (JAK) inhibitor ruxolitinib. Finally, to assess nsp15 function in the context of minimal (MERS-CoV) or moderate (SARS-CoV-2) innate immune induction, we compared infections with SARS-CoV-2 nsp15mut and previously described MERS-CoV nsp15 mutants. Inactivation of nsp15 had a more dramatic impact on MERS-CoV replication than SARS-CoV-2 in both Calu3 cells and nasal ALI cultures suggesting that SARS-CoV-2 can better tolerate innate immune responses. Taken together, SARS-CoV-2 nsp15 is a potent inhibitor of dsRNA-induced innate immune response and its antagonism of IFN signaling is necessary for optimal viral replication in primary nasal ALI cultures. [ABSTRACT FROM AUTHOR]

Published
2024
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