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2. A nanobody recognizes a unique conserved epitope and potently neutralizes SARS-CoV-2 omicron variants

Author

Modhiran, Naphak, Lauer, Simon Malte, Amarilla, Alberto A., Hewins, Peter, Lopes van den Broek, Sara Irene, Low, Yu Shang, Thakur, Nazia, Liang, Benjamin, Nieto, Guillermo Valenzuela, Jung, James, Paramitha, Devina, Isaacs, Ariel, Sng, Julian D.J., Song, David, Jørgensen, Jesper Tranekjær, Cheuquemilla, Yorka, Bürger, Jörg, Andersen, Ida Vang, Himelreichs, Johanna, Jara, Ronald, MacLoughlin, Ronan, Miranda-Chacon, Zaray, Chana-Cuevas, Pedro, Kramer, Vasko, Spahn, Christian, Mielke, Thorsten, Khromykh, Alexander A., Munro, Trent, Jones, Martina L., Young, Paul R., Chappell, Keith, Bailey, Dalan, Kjaer, Andreas, Herth, Matthias Manfred, Jurado, Kellie Ann, Schwefel, David, Rojas-Fernandez, Alejandro, and Watterson, Daniel

Published
2023
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4. Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology

Author

Aguado, Julio, primary, Amarilla, Alberto A., additional, Taherian Fard, Atefeh, additional, Albornoz, Eduardo A., additional, Tyshkovskiy, Alexander, additional, Schwabenland, Marius, additional, Chaggar, Harman K., additional, Modhiran, Naphak, additional, Gómez-Inclán, Cecilia, additional, Javed, Ibrahim, additional, Baradar, Alireza A., additional, Liang, Benjamin, additional, Dharmaratne, Malindrie, additional, Pietrogrande, Giovanni, additional, Padmanabhan, Pranesh, additional, Freney, Morgan E., additional, Parry, Rhys, additional, Sng, Julian D.J., additional, Isaacs, Ariel, additional, Khromykh, Alexander A., additional, Rojas-Fernandez, Alejandro, additional, Davis, Thomas P., additional, Prinz, Marco, additional, Bengsch, Bertram, additional, Gladyshev, Vadim N., additional, Woodruff, Trent M., additional, Mar, Jessica C., additional, Watterson, Daniel, additional, and Wolvetang, Ernst J., additional

Published
2023
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5. Monoclonal Antibodies Specific for SARS-CoV-2 Spike Protein Suitable for Multiple Applications for Current Variants of Concern

Author

Morgan, Mahali S., primary, Yan, Kexin, additional, Le, Thuy T., additional, Johnston, Ryan A., additional, Amarilla, Alberto A., additional, Muller, David A., additional, McMillan, Christopher L. D., additional, Modhiran, Naphak, additional, Watterson, Daniel, additional, Potter, James R., additional, Sng, Julian D.J., additional, Lor, Mary, additional, Paramitha, Devina, additional, Isaacs, Ariel, additional, Khromykh, Alexander A., additional, Hall, Roy A., additional, Suhrbier, Andreas, additional, Rawle, Daniel J., additional, and Hobson-Peters, Jody, additional

Published
2022
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6. Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction

Author

Guimond, Scott E., Mycroft-West, Courtney J., Gandhi, Neha S., Tree, Julia A., Le, Thuy T., Spalluto, C. Mirella, Humbert, Maria V., Buttigieg, Karen R., Coombes, Naomi, Elmore, Michael J., Wand, Matthew, Nyström, Kristina, Said, Joanna, Setoh, Yin Xiang, Amarilla, Alberto A., Modhiran, Naphak, Sng, Julian D.J., Chhabra, Mohit, Young, Paul R., Rawle, Daniel J., Lima, Marcelo A., Yates, Edwin A., Karlsson, Richard, Miller, Rebecca L., Chen, Yen Hsi, Bagdonaite, Ieva, Yang, Zhang, Stewart, James, Nguyen, Dung, Laidlaw, Stephen, Hammond, Edward, Dredge, Keith, Wilkinson, Tom M.A., Watterson, Daniel, Khromykh, Alexander A., Suhrbier, Andreas, Carroll, Miles W., Trybala, Edward, Bergström, Tomas, Ferro, Vito, Skidmore, Mark A., Turnbull, Jeremy E., Guimond, Scott E., Mycroft-West, Courtney J., Gandhi, Neha S., Tree, Julia A., Le, Thuy T., Spalluto, C. Mirella, Humbert, Maria V., Buttigieg, Karen R., Coombes, Naomi, Elmore, Michael J., Wand, Matthew, Nyström, Kristina, Said, Joanna, Setoh, Yin Xiang, Amarilla, Alberto A., Modhiran, Naphak, Sng, Julian D.J., Chhabra, Mohit, Young, Paul R., Rawle, Daniel J., Lima, Marcelo A., Yates, Edwin A., Karlsson, Richard, Miller, Rebecca L., Chen, Yen Hsi, Bagdonaite, Ieva, Yang, Zhang, Stewart, James, Nguyen, Dung, Laidlaw, Stephen, Hammond, Edward, Dredge, Keith, Wilkinson, Tom M.A., Watterson, Daniel, Khromykh, Alexander A., Suhrbier, Andreas, Carroll, Miles W., Trybala, Edward, Bergström, Tomas, Ferro, Vito, Skidmore, Mark A., and Turnbull, Jeremy E.

Abstract

Heparan sulfate (HS) is a cell surface polysaccharide recently identified as a coreceptor with the ACE2 protein for the S1 spike protein on SARS-CoV-2 virus, providing a tractable new therapeutic target. Clinically used heparins demonstrate an inhibitory activity but have an anticoagulant activity and are supply-limited, necessitating alternative solutions. Here, we show that synthetic HS mimetic pixatimod (PG545), a cancer drug candidate, binds and destabilizes the SARS-CoV-2 spike protein receptor binding domain and directly inhibits its binding to ACE2, consistent with molecular modeling identification of multiple molecular contacts and overlapping pixatimod and ACE2 binding sites. Assays with multiple clinical isolates of SARS-CoV-2 virus show that pixatimod potently inhibits the infection of monkey Vero E6 cells and physiologically relevant human bronchial epithelial cells at safe therapeutic concentrations. Pixatimod also retained broad potency against variants of concern (VOC) including B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Furthermore, in a K18-hACE2 mouse model, pixatimod significantly reduced SARS-CoV-2 viral titers in the upper respiratory tract and virus-induced weight loss. This demonstration of potent anti-SARS-CoV-2 activity tolerant to emerging mutations establishes proof-of-concept for targeting the HS-Spike protein-ACE2 axis with synthetic HS mimetics and provides a strong rationale for clinical investigation of pixatimod as a potential multimodal therapeutic for COVID-19.

Published
2022

7. SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike-ACE2 receptor interaction

Author

Albornoz, Eduardo A, primary, Amarilla, Alberto A, additional, Modhiran, Naphak, additional, Parker, Sandra, additional, Li, Xaria X, additional, Wijesundara, Danushka K, additional, Pliego Zamora, Adriana, additional, McMillan, Christopher LD, additional, Liang, Benjamin, additional, Peng, Nias Y.G, additional, Sng, Julian D.J, additional, Tuj Saima, Fatema, additional, Paramitha, Devina, additional, Parry, Rhys, additional, Avumegah, Michael S, additional, Isaacs, Ariel, additional, Lo, Martin, additional, Miranda-Chacon, Zaray, additional, Bradshaw, Daniella, additional, Salinas-Rebolledo, Constanza, additional, Rajapakse, Niwanthi W, additional, Munro, Trent, additional, Rojas-Fernandez, Alejandro, additional, Young, Paul R, additional, Stacey, Katryn J, additional, Khromykh, Alexander A, additional, Chappell, Keith J, additional, Watterson, Daniel, additional, and Woodruff, Trent M, additional

Published
2022
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8. Monoclonal Antibodies Specific for SARS-CoV-2 Spike Protein Suitable for Multiple Applications for Current Variants of Concern.

Author

Morgan, Mahali S., Yan, Kexin, Le, Thuy T., Johnston, Ryan A., Amarilla, Alberto A., Muller, David A., McMillan, Christopher L. D., Modhiran, Naphak, Watterson, Daniel, Potter, James R., Sng, Julian D.J., Lor, Mary, Paramitha, Devina, Isaacs, Ariel, Khromykh, Alexander A., Hall, Roy A., Suhrbier, Andreas, Rawle, Daniel J., and Hobson-Peters, Jody

Subjects
MONOCLONAL antibodies, SARS-CoV-2, SARS-CoV-2 Omicron variant, COVID-19, COVID-19 pandemic
Abstract

The global coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spawned an ongoing demand for new research reagents and interventions. Herein we describe a panel of monoclonal antibodies raised against SARS-CoV-2. One antibody showed excellent utility for immunohistochemistry, clearly staining infected cells in formalin-fixed and paraffin embedded lungs and brains of mice infected with the original and the omicron variants of SARS-CoV-2. We demonstrate the reactivity to multiple variants of concern using ELISAs and describe the use of the antibodies in indirect immunofluorescence assays, Western blots, and rapid antigen tests. Finally, we illustrate the ability of two antibodies to reduce significantly viral tissue titers in K18-hACE2 transgenic mice infected with the original and an omicron isolate of SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Published
2023
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9. Structural analysis of 3’UTRs in insect flaviviruses reveals novel determinant of sfRNA biogenesis and provides new insights into flavivirus evolution

Author

Slonchak, Andrii, primary, Parry, Rhys, additional, Pullinger, Brody, additional, Sng, Julian D.J., additional, Wang, Xiaohui, additional, Buck, Teresa F, additional, Torres, Francisco J, additional, Harrison, Jessica J, additional, Colmant, Agathe M G, additional, Hobson-Peters, Jody, additional, Hall, Roy A, additional, Tuplin, Andrew, additional, and Khromykh, Alexander A, additional

Published
2021
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10. Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 By Disrupting The Spike-ACE2 interaction

Author

Guimond, Scott E., primary, Mycroft-West, Courtney J., additional, Gandhi, Neha S., additional, Tree, Julia A., additional, Le, Thuy T, additional, Spalluto, C. Mirella, additional, Humbert, Maria V., additional, Buttigieg, Karen R., additional, Coombes, Naomi, additional, Elmore, Michael J., additional, Nyström, Kristina, additional, Said, Joanna, additional, Setoh, Yin Xiang, additional, Amarilla, Alberto A., additional, Modhiran, Naphak, additional, Sng, Julian D.J., additional, Chhabra, Mohit, additional, Young, Paul R., additional, Lima, Marcelo A., additional, A.Yates, Edwin, additional, Karlsson, Richard, additional, Miller, Rebecca L., additional, Chen, Yen-Hsi, additional, Bagdonaite, Ieva, additional, Yang, Zhang, additional, Stewart, James, additional, Hammond, Edward, additional, Dredge, Keith, additional, Wilkinson, Tom M.A., additional, Watterson, Daniel, additional, Khromykh, Alexander A., additional, Suhrbier, Andreas, additional, Carroll, Miles W., additional, Trybala, Edward, additional, Bergström, Tomas, additional, Ferro, Vito, additional, Skidmore, Mark A., additional, and Turnbull, Jeremy E., additional

Published
2020
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