Structural optimization and de novo design of dengue virus entry inhibitory peptides.
Viral fusogenic envelope proteins are important targets for the development of inhibitors of viral entry. We report an approach for the computational design of peptide inhibitors of the dengue 2 virus (DENV-2) envelope (E) protein using high-resolution structural data from a pre-entry dimeric form o...
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Online Access: | https://doi.org/10.1371/journal.pntd.0000721 https://doaj.org/article/f2a1eca4a9a5439db0bff740f5d6cbf3 |
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ftdoajarticles:oai:doaj.org/article:f2a1eca4a9a5439db0bff740f5d6cbf3 2023-05-15T15:06:18+02:00 Structural optimization and de novo design of dengue virus entry inhibitory peptides. Joshua M Costin Ekachai Jenwitheesuk Shee-Mei Lok Elizabeth Hunsperger Kelly A Conrads Krystal A Fontaine Craig R Rees Michael G Rossmann Sharon Isern Ram Samudrala Scott F Michael 2010-06-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0000721 https://doaj.org/article/f2a1eca4a9a5439db0bff740f5d6cbf3 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC2889824?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0000721 https://doaj.org/article/f2a1eca4a9a5439db0bff740f5d6cbf3 PLoS Neglected Tropical Diseases, Vol 4, Iss 6, p e721 (2010) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2010 ftdoajarticles https://doi.org/10.1371/journal.pntd.0000721 2022-12-31T09:49:45Z Viral fusogenic envelope proteins are important targets for the development of inhibitors of viral entry. We report an approach for the computational design of peptide inhibitors of the dengue 2 virus (DENV-2) envelope (E) protein using high-resolution structural data from a pre-entry dimeric form of the protein. By using predictive strategies together with computational optimization of binding "pseudoenergies", we were able to design multiple peptide sequences that showed low micromolar viral entry inhibitory activity. The two most active peptides, DN57opt and 1OAN1, were designed to displace regions in the domain II hinge, and the first domain I/domain II beta sheet connection, respectively, and show fifty percent inhibitory concentrations of 8 and 7 microM respectively in a focus forming unit assay. The antiviral peptides were shown to interfere with virus:cell binding, interact directly with the E proteins and also cause changes to the viral surface using biolayer interferometry and cryo-electron microscopy, respectively. These peptides may be useful for characterization of intermediate states in the membrane fusion process, investigation of DENV receptor molecules, and as lead compounds for drug discovery. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 4 6 e721 |
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Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Joshua M Costin Ekachai Jenwitheesuk Shee-Mei Lok Elizabeth Hunsperger Kelly A Conrads Krystal A Fontaine Craig R Rees Michael G Rossmann Sharon Isern Ram Samudrala Scott F Michael Structural optimization and de novo design of dengue virus entry inhibitory peptides. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Viral fusogenic envelope proteins are important targets for the development of inhibitors of viral entry. We report an approach for the computational design of peptide inhibitors of the dengue 2 virus (DENV-2) envelope (E) protein using high-resolution structural data from a pre-entry dimeric form of the protein. By using predictive strategies together with computational optimization of binding "pseudoenergies", we were able to design multiple peptide sequences that showed low micromolar viral entry inhibitory activity. The two most active peptides, DN57opt and 1OAN1, were designed to displace regions in the domain II hinge, and the first domain I/domain II beta sheet connection, respectively, and show fifty percent inhibitory concentrations of 8 and 7 microM respectively in a focus forming unit assay. The antiviral peptides were shown to interfere with virus:cell binding, interact directly with the E proteins and also cause changes to the viral surface using biolayer interferometry and cryo-electron microscopy, respectively. These peptides may be useful for characterization of intermediate states in the membrane fusion process, investigation of DENV receptor molecules, and as lead compounds for drug discovery. |
format |
Article in Journal/Newspaper |
author |
Joshua M Costin Ekachai Jenwitheesuk Shee-Mei Lok Elizabeth Hunsperger Kelly A Conrads Krystal A Fontaine Craig R Rees Michael G Rossmann Sharon Isern Ram Samudrala Scott F Michael |
author_facet |
Joshua M Costin Ekachai Jenwitheesuk Shee-Mei Lok Elizabeth Hunsperger Kelly A Conrads Krystal A Fontaine Craig R Rees Michael G Rossmann Sharon Isern Ram Samudrala Scott F Michael |
author_sort |
Joshua M Costin |
title |
Structural optimization and de novo design of dengue virus entry inhibitory peptides. |
title_short |
Structural optimization and de novo design of dengue virus entry inhibitory peptides. |
title_full |
Structural optimization and de novo design of dengue virus entry inhibitory peptides. |
title_fullStr |
Structural optimization and de novo design of dengue virus entry inhibitory peptides. |
title_full_unstemmed |
Structural optimization and de novo design of dengue virus entry inhibitory peptides. |
title_sort |
structural optimization and de novo design of dengue virus entry inhibitory peptides. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2010 |
url |
https://doi.org/10.1371/journal.pntd.0000721 https://doaj.org/article/f2a1eca4a9a5439db0bff740f5d6cbf3 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 4, Iss 6, p e721 (2010) |
op_relation |
http://europepmc.org/articles/PMC2889824?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0000721 https://doaj.org/article/f2a1eca4a9a5439db0bff740f5d6cbf3 |
op_doi |
https://doi.org/10.1371/journal.pntd.0000721 |
container_title |
PLoS Neglected Tropical Diseases |
container_volume |
4 |
container_issue |
6 |
container_start_page |
e721 |
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1766337934812774400 |