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...
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doaj-5e5ed15cf26846bfa2b70b2f2ca759ae2020-11-25T02:47:47ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2020-04-011110.3389/fmicb.2020.00603515036Discovery of Retro-1 Analogs Exhibiting Enhanced Anti-vaccinia Virus ActivityLalita Priyamvada0Philip Alabi1Andres Leon2Amrita Kumar3Suryaprakash Sambhara4Victoria A. Olson5Jason K. Sello6Panayampalli S. Satheshkumar7Poxvirus and Rabies Branch, Centers for Disease Control and Prevention, Atlanta, GA, United StatesDepartment of Chemistry, Brown University, Providence, RI, United StatesDepartment of Chemistry, Brown University, Providence, RI, United StatesImmunology and Pathogenesis Branch, Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA, United StatesImmunology and Pathogenesis Branch, Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA, United StatesPoxvirus and Rabies Branch, Centers for Disease Control and Prevention, Atlanta, GA, United StatesDepartment of Chemistry, Brown University, Providence, RI, United StatesPoxvirus and Rabies Branch, Centers for Disease Control and Prevention, Atlanta, GA, United StatesOrthopoxviruses (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.https://www.frontiersin.org/article/10.3389/fmicb.2020.00603/fullviral inhibitorpoxvirusantiviral agentretrograde transportvaccinia virusRetro-1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lalita Priyamvada Philip Alabi Andres Leon Amrita Kumar Suryaprakash Sambhara Victoria A. Olson Jason K. Sello Panayampalli S. Satheshkumar |
spellingShingle |
Lalita Priyamvada Philip Alabi Andres Leon Amrita Kumar Suryaprakash Sambhara Victoria A. Olson Jason K. Sello Panayampalli S. Satheshkumar Discovery of Retro-1 Analogs Exhibiting Enhanced Anti-vaccinia Virus Activity Frontiers in Microbiology viral inhibitor poxvirus antiviral agent retrograde transport vaccinia virus Retro-1 |
author_facet |
Lalita Priyamvada Philip Alabi Andres Leon Amrita Kumar Suryaprakash Sambhara Victoria A. Olson Jason K. Sello Panayampalli S. Satheshkumar |
author_sort |
Lalita Priyamvada |
title |
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_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_sort |
discovery of retro-1 analogs exhibiting enhanced anti-vaccinia virus activity |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Microbiology |
issn |
1664-302X |
publishDate |
2020-04-01 |
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. |
topic |
viral inhibitor poxvirus antiviral agent retrograde transport vaccinia virus Retro-1 |
url |
https://www.frontiersin.org/article/10.3389/fmicb.2020.00603/full |
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