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Discovery of Retro-1 Analogs Exhibiting Enhanced Anti-vaccinia Virus Activity
Orthopoxviruses (OPXVs) are an increasing threat to human health due to the growing population of OPXV-naive individuals after the discontinuation of routine smallpox vaccination. Antiviral drugs that are effective as postexposure treatments against variola virus (the causative agent of smallpox) or...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190985/ https://www.ncbi.nlm.nih.gov/pubmed/32390964 http://dx.doi.org/10.3389/fmicb.2020.00603 |
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author | Priyamvada, Lalita Alabi, Philip Leon, Andres Kumar, Amrita Sambhara, Suryaprakash Olson, Victoria A. Sello, Jason K. Satheshkumar, Panayampalli S. |
author_facet | Priyamvada, Lalita Alabi, Philip Leon, Andres Kumar, Amrita Sambhara, Suryaprakash Olson, Victoria A. Sello, Jason K. Satheshkumar, Panayampalli S. |
author_sort | Priyamvada, Lalita |
collection | PubMed |
description | Orthopoxviruses (OPXVs) are an increasing threat to human health due to the growing population of OPXV-naive individuals after the discontinuation of routine smallpox vaccination. Antiviral drugs that are effective as postexposure treatments against variola virus (the causative agent of smallpox) or other OPXVs are critical in the event of an OPXV outbreak or exposure. The only US Food and Drug Administration-approved drug to treat smallpox, Tecovirimat (ST-246), exerts its antiviral effect by inhibiting extracellular virus (EV) formation, thereby preventing cell–cell and long-distance spread. We and others have previously demonstrated that host Golgi-associated retrograde proteins play an important role in monkeypox virus (MPXV) and vaccinia virus (VACV) EV formation. Inhibition of the retrograde pathway by small molecules such as Retro-2 has been shown to decrease VACV infection in vitro and to a lesser extent in vivo. To identify more potent inhibitors of the retrograde pathway, we screened a large panel of compounds containing a benzodiazepine scaffold like that of Retro-1, against VACV infection. We found that a subset of these compounds displayed better anti-VACV activity, causing a reduction in EV particle formation and viral spread compared to Retro-1. PA104 emerged as the most potent analog, inhibiting 90% viral spread at 1.3 μM with a high selectivity index. In addition, PA104 strongly inhibited two distinct ST-246-resistant viruses, demonstrating its potential benefit for use in combination therapy with ST-246. These data and further characterizations of the specific protein targets and in vivo efficacy of PA104 may have important implications for the design of effective antivirals against OPXV. |
format | Online Article Text |
id | pubmed-7190985 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-71909852020-05-08 Discovery of Retro-1 Analogs Exhibiting Enhanced Anti-vaccinia Virus Activity Priyamvada, Lalita Alabi, Philip Leon, Andres Kumar, Amrita Sambhara, Suryaprakash Olson, Victoria A. Sello, Jason K. Satheshkumar, Panayampalli S. Front Microbiol Microbiology Orthopoxviruses (OPXVs) are an increasing threat to human health due to the growing population of OPXV-naive individuals after the discontinuation of routine smallpox vaccination. Antiviral drugs that are effective as postexposure treatments against variola virus (the causative agent of smallpox) or other OPXVs are critical in the event of an OPXV outbreak or exposure. The only US Food and Drug Administration-approved drug to treat smallpox, Tecovirimat (ST-246), exerts its antiviral effect by inhibiting extracellular virus (EV) formation, thereby preventing cell–cell and long-distance spread. We and others have previously demonstrated that host Golgi-associated retrograde proteins play an important role in monkeypox virus (MPXV) and vaccinia virus (VACV) EV formation. Inhibition of the retrograde pathway by small molecules such as Retro-2 has been shown to decrease VACV infection in vitro and to a lesser extent in vivo. To identify more potent inhibitors of the retrograde pathway, we screened a large panel of compounds containing a benzodiazepine scaffold like that of Retro-1, against VACV infection. We found that a subset of these compounds displayed better anti-VACV activity, causing a reduction in EV particle formation and viral spread compared to Retro-1. PA104 emerged as the most potent analog, inhibiting 90% viral spread at 1.3 μM with a high selectivity index. In addition, PA104 strongly inhibited two distinct ST-246-resistant viruses, demonstrating its potential benefit for use in combination therapy with ST-246. These data and further characterizations of the specific protein targets and in vivo efficacy of PA104 may have important implications for the design of effective antivirals against OPXV. Frontiers Media S.A. 2020-04-23 /pmc/articles/PMC7190985/ /pubmed/32390964 http://dx.doi.org/10.3389/fmicb.2020.00603 Text en Copyright © 2020 Priyamvada, Alabi, Leon, Kumar, Sambhara, Olson, Sello and Satheshkumar. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Microbiology Priyamvada, Lalita Alabi, Philip Leon, Andres Kumar, Amrita Sambhara, Suryaprakash Olson, Victoria A. Sello, Jason K. Satheshkumar, Panayampalli S. Discovery of Retro-1 Analogs Exhibiting Enhanced Anti-vaccinia Virus Activity |
title | Discovery of Retro-1 Analogs Exhibiting Enhanced Anti-vaccinia Virus Activity |
title_full | Discovery of Retro-1 Analogs Exhibiting Enhanced Anti-vaccinia Virus Activity |
title_fullStr | Discovery of Retro-1 Analogs Exhibiting Enhanced Anti-vaccinia Virus Activity |
title_full_unstemmed | Discovery of Retro-1 Analogs Exhibiting Enhanced Anti-vaccinia Virus Activity |
title_short | Discovery of Retro-1 Analogs Exhibiting Enhanced Anti-vaccinia Virus Activity |
title_sort | discovery of retro-1 analogs exhibiting enhanced anti-vaccinia virus activity |
topic | Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190985/ https://www.ncbi.nlm.nih.gov/pubmed/32390964 http://dx.doi.org/10.3389/fmicb.2020.00603 |
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