Discovery of a small molecule inhibitor targeting dengue virus NS5 RNA-dependent RNA polymerase.
Dengue is a mosquito-borne viral infection that has spread globally in recent years. Around half of the world's population, especially in the tropics and subtropics, is at risk of infection. Every year, 50-100 million clinical cases are reported, and more than 500,000 patients develop the sympt...
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ftdoajarticles:oai:doaj.org/article:43f267c34fa24a76ac3ed80987f0f2ce 2023-05-15T15:10:02+02:00 Discovery of a small molecule inhibitor targeting dengue virus NS5 RNA-dependent RNA polymerase. Hideaki Shimizu Akatsuki Saito Junko Mikuni Emi E Nakayama Hiroo Koyama Teruki Honma Mikako Shirouzu Shun-Ichi Sekine Tatsuo Shioda 2019-11-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0007894 https://doaj.org/article/43f267c34fa24a76ac3ed80987f0f2ce EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0007894 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0007894 https://doaj.org/article/43f267c34fa24a76ac3ed80987f0f2ce PLoS Neglected Tropical Diseases, Vol 13, Iss 11, p e0007894 (2019) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2019 ftdoajarticles https://doi.org/10.1371/journal.pntd.0007894 2022-12-31T13:53:26Z Dengue is a mosquito-borne viral infection that has spread globally in recent years. Around half of the world's population, especially in the tropics and subtropics, is at risk of infection. Every year, 50-100 million clinical cases are reported, and more than 500,000 patients develop the symptoms of severe dengue infection: dengue haemorrhagic fever and dengue shock syndrome, which threaten life in Asia and Latin America. No antiviral drug for dengue is available. The dengue virus (DENV) non-structural protein 5 (NS5), which possesses the RNA-dependent RNA polymerase (RdRp) activity and is responsible for viral replication and transcription, is an attractive target for anti-dengue drug development. In the present study, 16,240 small-molecule compounds in a fragment library were screened for their capabilities to inhibit the DENV type 2 (DENV2) RdRp activities in vitro. Based on in cellulo antiviral and cytotoxity assays, we selected the compound RK-0404678 with the EC50 value of 6.0 μM for DENV2. Crystallographic analyses revealed two unique binding sites for RK-0404678 within the RdRp, which are conserved in flavivirus NS5 proteins. No resistant viruses emerged after nine rounds of serial passage of DENV2 in the presence of RK-0404678, suggesting the high genetic barrier of this compound to the emergence of a resistant virus. Collectively, RK-0404678 and its binding sites provide a new framework for antiviral drug development. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 13 11 e0007894 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Hideaki Shimizu Akatsuki Saito Junko Mikuni Emi E Nakayama Hiroo Koyama Teruki Honma Mikako Shirouzu Shun-Ichi Sekine Tatsuo Shioda Discovery of a small molecule inhibitor targeting dengue virus NS5 RNA-dependent RNA polymerase. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Dengue is a mosquito-borne viral infection that has spread globally in recent years. Around half of the world's population, especially in the tropics and subtropics, is at risk of infection. Every year, 50-100 million clinical cases are reported, and more than 500,000 patients develop the symptoms of severe dengue infection: dengue haemorrhagic fever and dengue shock syndrome, which threaten life in Asia and Latin America. No antiviral drug for dengue is available. The dengue virus (DENV) non-structural protein 5 (NS5), which possesses the RNA-dependent RNA polymerase (RdRp) activity and is responsible for viral replication and transcription, is an attractive target for anti-dengue drug development. In the present study, 16,240 small-molecule compounds in a fragment library were screened for their capabilities to inhibit the DENV type 2 (DENV2) RdRp activities in vitro. Based on in cellulo antiviral and cytotoxity assays, we selected the compound RK-0404678 with the EC50 value of 6.0 μM for DENV2. Crystallographic analyses revealed two unique binding sites for RK-0404678 within the RdRp, which are conserved in flavivirus NS5 proteins. No resistant viruses emerged after nine rounds of serial passage of DENV2 in the presence of RK-0404678, suggesting the high genetic barrier of this compound to the emergence of a resistant virus. Collectively, RK-0404678 and its binding sites provide a new framework for antiviral drug development. |
format |
Article in Journal/Newspaper |
author |
Hideaki Shimizu Akatsuki Saito Junko Mikuni Emi E Nakayama Hiroo Koyama Teruki Honma Mikako Shirouzu Shun-Ichi Sekine Tatsuo Shioda |
author_facet |
Hideaki Shimizu Akatsuki Saito Junko Mikuni Emi E Nakayama Hiroo Koyama Teruki Honma Mikako Shirouzu Shun-Ichi Sekine Tatsuo Shioda |
author_sort |
Hideaki Shimizu |
title |
Discovery of a small molecule inhibitor targeting dengue virus NS5 RNA-dependent RNA polymerase. |
title_short |
Discovery of a small molecule inhibitor targeting dengue virus NS5 RNA-dependent RNA polymerase. |
title_full |
Discovery of a small molecule inhibitor targeting dengue virus NS5 RNA-dependent RNA polymerase. |
title_fullStr |
Discovery of a small molecule inhibitor targeting dengue virus NS5 RNA-dependent RNA polymerase. |
title_full_unstemmed |
Discovery of a small molecule inhibitor targeting dengue virus NS5 RNA-dependent RNA polymerase. |
title_sort |
discovery of a small molecule inhibitor targeting dengue virus ns5 rna-dependent rna polymerase. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2019 |
url |
https://doi.org/10.1371/journal.pntd.0007894 https://doaj.org/article/43f267c34fa24a76ac3ed80987f0f2ce |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 13, Iss 11, p e0007894 (2019) |
op_relation |
https://doi.org/10.1371/journal.pntd.0007894 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0007894 https://doaj.org/article/43f267c34fa24a76ac3ed80987f0f2ce |
op_doi |
https://doi.org/10.1371/journal.pntd.0007894 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
13 |
container_issue |
11 |
container_start_page |
e0007894 |
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