Amilorides inhibit SARS-CoV-2 replication in vitro by targeting RNA structures

Martina Zafferani; Christina Haddad; Le Luo; Jesse Davila-Calderon; Liang Yuan Chiu; Christian Shema Mugisha; Adeline G. Monaghan; Andrew A. Kennedy; Joseph D. Yesselman; Robert J. Gifford; Andrew W. Tai; Sebla B. Kutluay; Mei Ling Li; Gary Brewer; Blanton S. Tolbert; Amanda E. Hargrove

doi:10.1126/sciadv.abl6096

Amilorides inhibit SARS-CoV-2 replication in vitro by targeting RNA structures

Martina Zafferani, Christina Haddad, Le Luo, Jesse Davila-Calderon, Liang Yuan Chiu, Christian Shema Mugisha, Adeline G. Monaghan, Andrew A. Kennedy, Joseph D. Yesselman, Robert J. Gifford, Andrew W. Tai, Sebla B. Kutluay, Mei Ling Li, Gary Brewer, Blanton S. Tolbert, Amanda E. Hargrove

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

Abstract

The SARS-CoV-2 pandemic, and the likelihood of future coronavirus pandemics, emphasized the urgent need for development of novel antivirals. Small-molecule chemical probes offer both to reveal aspects of virus replication and to serve as leads for antiviral therapeutic development. Here, we report on the identification of amiloride-based small molecules that potently inhibit OC43 and SARS-CoV-2 replication through targeting of conserved structured elements within the viral 5′-end. Nuclear magnetic resonance–based structural studies revealed specific amiloride interactions with stem loops containing bulge like structures and were predicted to be strongly bound by the lead amilorides in retrospective docking studies. Amilorides represent the first antiviral small molecules that target RNA structures within the 5′ untranslated regions and proximal region of the CoV genomes. These molecules will serve as chemical probes to further understand CoV RNA biology and can pave the way for the development of specific CoV RNA–targeted antivirals.

Original language	English
Article number	eabl6096
Journal	Science Advances
Volume	7
Issue number	48
DOIs	https://doi.org/10.1126/sciadv.abl6096
State	Published - Nov 2021

Access to Document

10.1126/sciadv.abl6096

Cite this

Zafferani, M., Haddad, C., Luo, L., Davila-Calderon, J., Chiu, L. Y., Mugisha, C. S., Monaghan, A. G., Kennedy, A. A., Yesselman, J. D., Gifford, R. J., Tai, A. W., Kutluay, S. B., Li, M. L., Brewer, G., Tolbert, B. S., & Hargrove, A. E. (2021). Amilorides inhibit SARS-CoV-2 replication in vitro by targeting RNA structures. Science Advances, 7(48), Article eabl6096. https://doi.org/10.1126/sciadv.abl6096

@article{3498cd31e6594951801f7d57acc607c8,

title = "Amilorides inhibit SARS-CoV-2 replication in vitro by targeting RNA structures",

abstract = "The SARS-CoV-2 pandemic, and the likelihood of future coronavirus pandemics, emphasized the urgent need for development of novel antivirals. Small-molecule chemical probes offer both to reveal aspects of virus replication and to serve as leads for antiviral therapeutic development. Here, we report on the identification of amiloride-based small molecules that potently inhibit OC43 and SARS-CoV-2 replication through targeting of conserved structured elements within the viral 5′-end. Nuclear magnetic resonance–based structural studies revealed specific amiloride interactions with stem loops containing bulge like structures and were predicted to be strongly bound by the lead amilorides in retrospective docking studies. Amilorides represent the first antiviral small molecules that target RNA structures within the 5′ untranslated regions and proximal region of the CoV genomes. These molecules will serve as chemical probes to further understand CoV RNA biology and can pave the way for the development of specific CoV RNA–targeted antivirals.",

author = "Martina Zafferani and Christina Haddad and Le Luo and Jesse Davila-Calderon and Chiu, {Liang Yuan} and Mugisha, {Christian Shema} and Monaghan, {Adeline G.} and Kennedy, {Andrew A.} and Yesselman, {Joseph D.} and Gifford, {Robert J.} and Tai, {Andrew W.} and Kutluay, {Sebla B.} and Li, {Mei Ling} and Gary Brewer and Tolbert, {Blanton S.} and Hargrove, {Amanda E.}",

note = "Funding Information: Research Council of the United Kingdom (MC_UU_12014/12) to R.J.G. Publisher Copyright: Copyright {\textcopyright} 2021 The Authors, some rights reserved.",

year = "2021",

month = nov,

doi = "10.1126/sciadv.abl6096",

language = "English",

volume = "7",

journal = "Science Advances",

issn = "2375-2548",

number = "48",

}

TY - JOUR

T1 - Amilorides inhibit SARS-CoV-2 replication in vitro by targeting RNA structures

AU - Zafferani, Martina

AU - Haddad, Christina

AU - Luo, Le

AU - Davila-Calderon, Jesse

AU - Chiu, Liang Yuan

AU - Mugisha, Christian Shema

AU - Monaghan, Adeline G.

AU - Kennedy, Andrew A.

AU - Yesselman, Joseph D.

AU - Gifford, Robert J.

AU - Tai, Andrew W.

AU - Kutluay, Sebla B.

AU - Li, Mei Ling

AU - Brewer, Gary

AU - Tolbert, Blanton S.

AU - Hargrove, Amanda E.

PY - 2021/11

Y1 - 2021/11

N2 - The SARS-CoV-2 pandemic, and the likelihood of future coronavirus pandemics, emphasized the urgent need for development of novel antivirals. Small-molecule chemical probes offer both to reveal aspects of virus replication and to serve as leads for antiviral therapeutic development. Here, we report on the identification of amiloride-based small molecules that potently inhibit OC43 and SARS-CoV-2 replication through targeting of conserved structured elements within the viral 5′-end. Nuclear magnetic resonance–based structural studies revealed specific amiloride interactions with stem loops containing bulge like structures and were predicted to be strongly bound by the lead amilorides in retrospective docking studies. Amilorides represent the first antiviral small molecules that target RNA structures within the 5′ untranslated regions and proximal region of the CoV genomes. These molecules will serve as chemical probes to further understand CoV RNA biology and can pave the way for the development of specific CoV RNA–targeted antivirals.

AB - The SARS-CoV-2 pandemic, and the likelihood of future coronavirus pandemics, emphasized the urgent need for development of novel antivirals. Small-molecule chemical probes offer both to reveal aspects of virus replication and to serve as leads for antiviral therapeutic development. Here, we report on the identification of amiloride-based small molecules that potently inhibit OC43 and SARS-CoV-2 replication through targeting of conserved structured elements within the viral 5′-end. Nuclear magnetic resonance–based structural studies revealed specific amiloride interactions with stem loops containing bulge like structures and were predicted to be strongly bound by the lead amilorides in retrospective docking studies. Amilorides represent the first antiviral small molecules that target RNA structures within the 5′ untranslated regions and proximal region of the CoV genomes. These molecules will serve as chemical probes to further understand CoV RNA biology and can pave the way for the development of specific CoV RNA–targeted antivirals.

UR - http://www.scopus.com/inward/record.url?scp=85120384509&partnerID=8YFLogxK

U2 - 10.1126/sciadv.abl6096

DO - 10.1126/sciadv.abl6096

M3 - Article

C2 - 34826236

AN - SCOPUS:85120384509

SN - 2375-2548

VL - 7

JO - Science Advances

JF - Science Advances

IS - 48

M1 - eabl6096

ER -

Amilorides inhibit SARS-CoV-2 replication in vitro by targeting RNA structures

Abstract

Access to Document

Other files and links

Fingerprint

Cite this