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Structure-Guided Development of Bivalent Aptamers Blocking SARS-CoV-2 Infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused devastation to human society through its high virulence, infectivity, and genomic mutations, which reduced the efficacy of vaccines. Here, we report the development of aptamers that effectively interfere with SARS-CoV-2 infectio...

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Autores principales: Rahman, Md Shafiqur, Han, Min Jung, Kim, Sang Won, Kang, Seong Mu, Kim, Bo Ri, Kim, Heesun, Lee, Chang Jun, Noh, Jung Eun, Kim, Hanseong, Lee, Jie-Oh, Jang, Sung Key
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10303109/
https://www.ncbi.nlm.nih.gov/pubmed/37375202
http://dx.doi.org/10.3390/molecules28124645
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author Rahman, Md Shafiqur
Han, Min Jung
Kim, Sang Won
Kang, Seong Mu
Kim, Bo Ri
Kim, Heesun
Lee, Chang Jun
Noh, Jung Eun
Kim, Hanseong
Lee, Jie-Oh
Jang, Sung Key
author_facet Rahman, Md Shafiqur
Han, Min Jung
Kim, Sang Won
Kang, Seong Mu
Kim, Bo Ri
Kim, Heesun
Lee, Chang Jun
Noh, Jung Eun
Kim, Hanseong
Lee, Jie-Oh
Jang, Sung Key
author_sort Rahman, Md Shafiqur
collection PubMed
description Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused devastation to human society through its high virulence, infectivity, and genomic mutations, which reduced the efficacy of vaccines. Here, we report the development of aptamers that effectively interfere with SARS-CoV-2 infection by targeting its spike protein, which plays a pivotal role in host cell entry of the virus through interaction with the viral receptor angiotensin-converting enzyme 2 (ACE2). To develop highly effective aptamers and to understand their mechanism in inhibiting viral infection, we determined the three-dimensional (3D) structures of aptamer/receptor-binding domain (RBD) complexes using cryogenic electron microscopy (cryo-EM). Moreover, we developed bivalent aptamers targeting two distinct regions of the RBD in the spike protein that directly interact with ACE2. One aptamer interferes with the binding of ACE2 by blocking the ACE2-binding site in RBD, and the other aptamer allosterically inhibits ACE2 by binding to a distinct face of RBD. Using the 3D structures of aptamer–RBD complexes, we minimized and optimized these aptamers. By combining the optimized aptamers, we developed a bivalent aptamer that showed a stronger inhibitory effect on virus infection than the component aptamers. This study confirms that the structure-based aptamer-design approach has a high potential in developing antiviral drugs against SARS-CoV-2 and other viruses.
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spelling pubmed-103031092023-06-29 Structure-Guided Development of Bivalent Aptamers Blocking SARS-CoV-2 Infection Rahman, Md Shafiqur Han, Min Jung Kim, Sang Won Kang, Seong Mu Kim, Bo Ri Kim, Heesun Lee, Chang Jun Noh, Jung Eun Kim, Hanseong Lee, Jie-Oh Jang, Sung Key Molecules Article Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused devastation to human society through its high virulence, infectivity, and genomic mutations, which reduced the efficacy of vaccines. Here, we report the development of aptamers that effectively interfere with SARS-CoV-2 infection by targeting its spike protein, which plays a pivotal role in host cell entry of the virus through interaction with the viral receptor angiotensin-converting enzyme 2 (ACE2). To develop highly effective aptamers and to understand their mechanism in inhibiting viral infection, we determined the three-dimensional (3D) structures of aptamer/receptor-binding domain (RBD) complexes using cryogenic electron microscopy (cryo-EM). Moreover, we developed bivalent aptamers targeting two distinct regions of the RBD in the spike protein that directly interact with ACE2. One aptamer interferes with the binding of ACE2 by blocking the ACE2-binding site in RBD, and the other aptamer allosterically inhibits ACE2 by binding to a distinct face of RBD. Using the 3D structures of aptamer–RBD complexes, we minimized and optimized these aptamers. By combining the optimized aptamers, we developed a bivalent aptamer that showed a stronger inhibitory effect on virus infection than the component aptamers. This study confirms that the structure-based aptamer-design approach has a high potential in developing antiviral drugs against SARS-CoV-2 and other viruses. MDPI 2023-06-08 /pmc/articles/PMC10303109/ /pubmed/37375202 http://dx.doi.org/10.3390/molecules28124645 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Rahman, Md Shafiqur
Han, Min Jung
Kim, Sang Won
Kang, Seong Mu
Kim, Bo Ri
Kim, Heesun
Lee, Chang Jun
Noh, Jung Eun
Kim, Hanseong
Lee, Jie-Oh
Jang, Sung Key
Structure-Guided Development of Bivalent Aptamers Blocking SARS-CoV-2 Infection
title Structure-Guided Development of Bivalent Aptamers Blocking SARS-CoV-2 Infection
title_full Structure-Guided Development of Bivalent Aptamers Blocking SARS-CoV-2 Infection
title_fullStr Structure-Guided Development of Bivalent Aptamers Blocking SARS-CoV-2 Infection
title_full_unstemmed Structure-Guided Development of Bivalent Aptamers Blocking SARS-CoV-2 Infection
title_short Structure-Guided Development of Bivalent Aptamers Blocking SARS-CoV-2 Infection
title_sort structure-guided development of bivalent aptamers blocking sars-cov-2 infection
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10303109/
https://www.ncbi.nlm.nih.gov/pubmed/37375202
http://dx.doi.org/10.3390/molecules28124645
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