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Identification of 6′-β-fluoro-homoaristeromycin as a potent inhibitor of chikungunya virus replication

We have reported on aristeromycin (1) and 6′-fluorinated-aristeromycin analogues (2), which are active against RNA viruses such as Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), Zika virus (ZIKV), and Chikungunya virus (CHIKV). Howe...

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Autores principales: Shin, Young Sup, Jarhad, Dnyandev B., Jang, Min Hwan, Kovacikova, Kristina, Kim, Gyudong, Yoon, Ji-seong, Kim, Hong-Rae, Hyun, Young Eum, Tipnis, Amol S., Chang, Tong-Shin, van Hemert, Martijn J., Jeong, Lak Shin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Masson SAS. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115507/
https://www.ncbi.nlm.nih.gov/pubmed/31841728
http://dx.doi.org/10.1016/j.ejmech.2019.111956
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author Shin, Young Sup
Jarhad, Dnyandev B.
Jang, Min Hwan
Kovacikova, Kristina
Kim, Gyudong
Yoon, Ji-seong
Kim, Hong-Rae
Hyun, Young Eum
Tipnis, Amol S.
Chang, Tong-Shin
van Hemert, Martijn J.
Jeong, Lak Shin
author_facet Shin, Young Sup
Jarhad, Dnyandev B.
Jang, Min Hwan
Kovacikova, Kristina
Kim, Gyudong
Yoon, Ji-seong
Kim, Hong-Rae
Hyun, Young Eum
Tipnis, Amol S.
Chang, Tong-Shin
van Hemert, Martijn J.
Jeong, Lak Shin
author_sort Shin, Young Sup
collection PubMed
description We have reported on aristeromycin (1) and 6′-fluorinated-aristeromycin analogues (2), which are active against RNA viruses such as Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), Zika virus (ZIKV), and Chikungunya virus (CHIKV). However, these exhibit substantial cytotoxicity. As this cytotoxicity may be attributed to 5′-phosphorylation, we designed and synthesized one-carbon homologated 6′-fluorinated-aristeromycin analogues. This modification prevents 5′-phosphorlyation by cellular kinases, whereas the inhibitory activity towards S-adenosyl-l-homocysteine (SAH) hydrolase will be retained. The enantiomerically pure 6′-fluorinated-5′-homoaristeromycin analogues 3a-e were synthesized via the electrophilic fluorination of the silyl enol ether with Selectfluor, using a base-build up approach as the key steps. All synthesized compounds exhibited potent inhibitory activity towards SAH hydrolase, among which 6′-β-fluoroadenosine analogue 3a was the most potent (IC(50) = 0.36 μM). Among the compounds tested, 6′-β-fluoro-homoaristeromycin 3a showed potent antiviral activity (EC(50) = 0.12 μM) against the CHIKV, without noticeable cytotoxicity up to 250 μM. Only 3a displayed anti-CHIKV activity, whereas both3a and 3b inhibited SAH hydrolase with similar IC(50) values (0.36 and 0.37 μM, respectively), which suggested that 3a’s antiviral activity did not merely depend on the inhibition of SAH hydrolase. This is further supported by the fact that the antiviral effect was specific for CHIKV and some other alphaviruses and none of the homologated analogues inhibited other RNA viruses, such as SARS-CoV, MERS-CoV, and ZIKV. The potent inhibition and high selectivity index make 6′-β-fluoro-homoaristeromycin (3a) a promising new template for the development of antivirals against CHIKV, a serious re-emerging pathogen that has infected millions of people over the past 15 years.
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spelling pubmed-71155072020-04-02 Identification of 6′-β-fluoro-homoaristeromycin as a potent inhibitor of chikungunya virus replication Shin, Young Sup Jarhad, Dnyandev B. Jang, Min Hwan Kovacikova, Kristina Kim, Gyudong Yoon, Ji-seong Kim, Hong-Rae Hyun, Young Eum Tipnis, Amol S. Chang, Tong-Shin van Hemert, Martijn J. Jeong, Lak Shin Eur J Med Chem Research Paper We have reported on aristeromycin (1) and 6′-fluorinated-aristeromycin analogues (2), which are active against RNA viruses such as Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), Zika virus (ZIKV), and Chikungunya virus (CHIKV). However, these exhibit substantial cytotoxicity. As this cytotoxicity may be attributed to 5′-phosphorylation, we designed and synthesized one-carbon homologated 6′-fluorinated-aristeromycin analogues. This modification prevents 5′-phosphorlyation by cellular kinases, whereas the inhibitory activity towards S-adenosyl-l-homocysteine (SAH) hydrolase will be retained. The enantiomerically pure 6′-fluorinated-5′-homoaristeromycin analogues 3a-e were synthesized via the electrophilic fluorination of the silyl enol ether with Selectfluor, using a base-build up approach as the key steps. All synthesized compounds exhibited potent inhibitory activity towards SAH hydrolase, among which 6′-β-fluoroadenosine analogue 3a was the most potent (IC(50) = 0.36 μM). Among the compounds tested, 6′-β-fluoro-homoaristeromycin 3a showed potent antiviral activity (EC(50) = 0.12 μM) against the CHIKV, without noticeable cytotoxicity up to 250 μM. Only 3a displayed anti-CHIKV activity, whereas both3a and 3b inhibited SAH hydrolase with similar IC(50) values (0.36 and 0.37 μM, respectively), which suggested that 3a’s antiviral activity did not merely depend on the inhibition of SAH hydrolase. This is further supported by the fact that the antiviral effect was specific for CHIKV and some other alphaviruses and none of the homologated analogues inhibited other RNA viruses, such as SARS-CoV, MERS-CoV, and ZIKV. The potent inhibition and high selectivity index make 6′-β-fluoro-homoaristeromycin (3a) a promising new template for the development of antivirals against CHIKV, a serious re-emerging pathogen that has infected millions of people over the past 15 years. Elsevier Masson SAS. 2020-02-01 2019-12-09 /pmc/articles/PMC7115507/ /pubmed/31841728 http://dx.doi.org/10.1016/j.ejmech.2019.111956 Text en © 2019 Elsevier Masson SAS. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Research Paper
Shin, Young Sup
Jarhad, Dnyandev B.
Jang, Min Hwan
Kovacikova, Kristina
Kim, Gyudong
Yoon, Ji-seong
Kim, Hong-Rae
Hyun, Young Eum
Tipnis, Amol S.
Chang, Tong-Shin
van Hemert, Martijn J.
Jeong, Lak Shin
Identification of 6′-β-fluoro-homoaristeromycin as a potent inhibitor of chikungunya virus replication
title Identification of 6′-β-fluoro-homoaristeromycin as a potent inhibitor of chikungunya virus replication
title_full Identification of 6′-β-fluoro-homoaristeromycin as a potent inhibitor of chikungunya virus replication
title_fullStr Identification of 6′-β-fluoro-homoaristeromycin as a potent inhibitor of chikungunya virus replication
title_full_unstemmed Identification of 6′-β-fluoro-homoaristeromycin as a potent inhibitor of chikungunya virus replication
title_short Identification of 6′-β-fluoro-homoaristeromycin as a potent inhibitor of chikungunya virus replication
title_sort identification of 6′-β-fluoro-homoaristeromycin as a potent inhibitor of chikungunya virus replication
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115507/
https://www.ncbi.nlm.nih.gov/pubmed/31841728
http://dx.doi.org/10.1016/j.ejmech.2019.111956
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