A Targeted Computational Screen of the SWEETLEAD Database Reveals FDA-Approved Compounds with Anti-Dengue Viral Activity
ABSTRACT Affordable and effective antiviral therapies are needed worldwide, especially against agents such as dengue virus that are endemic in underserved regions. Many antiviral compounds have been studied in cultured cells but are unsuitable for clinical applications due to pharmacokinetic profile...
Guardado en:
| Autores principales: | , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
American Society for Microbiology
2020
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/9d33b3a657f445fa99ed33577dd68fd2 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:9d33b3a657f445fa99ed33577dd68fd2 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:9d33b3a657f445fa99ed33577dd68fd22021-11-15T15:55:43ZA Targeted Computational Screen of the SWEETLEAD Database Reveals FDA-Approved Compounds with Anti-Dengue Viral Activity10.1128/mBio.02839-202150-7511https://doaj.org/article/9d33b3a657f445fa99ed33577dd68fd22020-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02839-20https://doaj.org/toc/2150-7511ABSTRACT Affordable and effective antiviral therapies are needed worldwide, especially against agents such as dengue virus that are endemic in underserved regions. Many antiviral compounds have been studied in cultured cells but are unsuitable for clinical applications due to pharmacokinetic profiles, side effects, or inconsistent efficacy across dengue serotypes. Such tool compounds can, however, aid in identifying clinically useful treatments. Here, computational screening (Rapid Overlay of Chemical Structures) was used to identify entries in an in silico database of safe-in-human compounds (SWEETLEAD) that display high chemical similarities to known inhibitors of dengue virus. Inhibitors of the dengue proteinase NS2B/3, the dengue capsid, and the host autophagy pathway were used as query compounds. Three FDA-approved compounds that resemble the tool molecules structurally, cause little toxicity, and display strong antiviral activity in cultured cells were selected for further analysis. Pyrimethamine (50% inhibitory concentration [IC50] = 1.2 μM), like the dengue proteinase inhibitor ARDP0006 to which it shows structural similarity, inhibited intramolecular NS2B/3 cleavage. Lack of toxicity early in infection allowed testing in mice, in which pyrimethamine also reduced viral loads. Niclosamide (IC50 = 0.28 μM), like dengue core inhibitor ST-148, affected structural components of the virion and inhibited early processes during infection. Vandetanib (IC50 = 1.6 μM), like cellular autophagy inhibitor spautin-1, blocked viral exit from cells and could be shown to extend survival in vivo. Thus, three FDA-approved compounds with promising utility for repurposing to treat dengue virus infections and their potential mechanisms were identified using computational tools and minimal phenotypic screening. IMPORTANCE No antiviral therapeutics are currently available for dengue virus infections. By computationally overlaying the three-dimensional (3D) chemical structures of compounds known to inhibit dengue virus over those of compounds known to be safe in humans, we identified three FDA-approved compounds that are attractive candidates for repurposing as antivirals. We identified targets for two previously identified antiviral compounds and revealed a previously unknown potential anti-dengue compound, vandetanib. This computational approach to analyze a highly curated library of structures has the benefits of speed and cost efficiency. It also leverages mechanistic work with query compounds used in biomedical research to provide strong hypotheses for the antiviral mechanisms of the safer hit compounds. This workflow to identify compounds with known safety profiles can be expanded to any biological activity for which a small-molecule query compound has been identified, potentially expediting the translation of basic research to clinical interventions.Jasmine MoshiriDavid A. ConstantBowen LiuRoberto MateoSteven KearnesPaul NovickRitika PrasadClaude NagamineVijay PandeKarla KirkegaardAmerican Society for Microbiologyarticleantiviral pharmacologycapsidcomputational biologydengue virusproteasesrepurposingMicrobiologyQR1-502ENmBio, Vol 11, Iss 6 (2020) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
antiviral pharmacology capsid computational biology dengue virus proteases repurposing Microbiology QR1-502 |
| spellingShingle |
antiviral pharmacology capsid computational biology dengue virus proteases repurposing Microbiology QR1-502 Jasmine Moshiri David A. Constant Bowen Liu Roberto Mateo Steven Kearnes Paul Novick Ritika Prasad Claude Nagamine Vijay Pande Karla Kirkegaard A Targeted Computational Screen of the SWEETLEAD Database Reveals FDA-Approved Compounds with Anti-Dengue Viral Activity |
| description |
ABSTRACT Affordable and effective antiviral therapies are needed worldwide, especially against agents such as dengue virus that are endemic in underserved regions. Many antiviral compounds have been studied in cultured cells but are unsuitable for clinical applications due to pharmacokinetic profiles, side effects, or inconsistent efficacy across dengue serotypes. Such tool compounds can, however, aid in identifying clinically useful treatments. Here, computational screening (Rapid Overlay of Chemical Structures) was used to identify entries in an in silico database of safe-in-human compounds (SWEETLEAD) that display high chemical similarities to known inhibitors of dengue virus. Inhibitors of the dengue proteinase NS2B/3, the dengue capsid, and the host autophagy pathway were used as query compounds. Three FDA-approved compounds that resemble the tool molecules structurally, cause little toxicity, and display strong antiviral activity in cultured cells were selected for further analysis. Pyrimethamine (50% inhibitory concentration [IC50] = 1.2 μM), like the dengue proteinase inhibitor ARDP0006 to which it shows structural similarity, inhibited intramolecular NS2B/3 cleavage. Lack of toxicity early in infection allowed testing in mice, in which pyrimethamine also reduced viral loads. Niclosamide (IC50 = 0.28 μM), like dengue core inhibitor ST-148, affected structural components of the virion and inhibited early processes during infection. Vandetanib (IC50 = 1.6 μM), like cellular autophagy inhibitor spautin-1, blocked viral exit from cells and could be shown to extend survival in vivo. Thus, three FDA-approved compounds with promising utility for repurposing to treat dengue virus infections and their potential mechanisms were identified using computational tools and minimal phenotypic screening. IMPORTANCE No antiviral therapeutics are currently available for dengue virus infections. By computationally overlaying the three-dimensional (3D) chemical structures of compounds known to inhibit dengue virus over those of compounds known to be safe in humans, we identified three FDA-approved compounds that are attractive candidates for repurposing as antivirals. We identified targets for two previously identified antiviral compounds and revealed a previously unknown potential anti-dengue compound, vandetanib. This computational approach to analyze a highly curated library of structures has the benefits of speed and cost efficiency. It also leverages mechanistic work with query compounds used in biomedical research to provide strong hypotheses for the antiviral mechanisms of the safer hit compounds. This workflow to identify compounds with known safety profiles can be expanded to any biological activity for which a small-molecule query compound has been identified, potentially expediting the translation of basic research to clinical interventions. |
| format |
article |
| author |
Jasmine Moshiri David A. Constant Bowen Liu Roberto Mateo Steven Kearnes Paul Novick Ritika Prasad Claude Nagamine Vijay Pande Karla Kirkegaard |
| author_facet |
Jasmine Moshiri David A. Constant Bowen Liu Roberto Mateo Steven Kearnes Paul Novick Ritika Prasad Claude Nagamine Vijay Pande Karla Kirkegaard |
| author_sort |
Jasmine Moshiri |
| title |
A Targeted Computational Screen of the SWEETLEAD Database Reveals FDA-Approved Compounds with Anti-Dengue Viral Activity |
| title_short |
A Targeted Computational Screen of the SWEETLEAD Database Reveals FDA-Approved Compounds with Anti-Dengue Viral Activity |
| title_full |
A Targeted Computational Screen of the SWEETLEAD Database Reveals FDA-Approved Compounds with Anti-Dengue Viral Activity |
| title_fullStr |
A Targeted Computational Screen of the SWEETLEAD Database Reveals FDA-Approved Compounds with Anti-Dengue Viral Activity |
| title_full_unstemmed |
A Targeted Computational Screen of the SWEETLEAD Database Reveals FDA-Approved Compounds with Anti-Dengue Viral Activity |
| title_sort |
targeted computational screen of the sweetlead database reveals fda-approved compounds with anti-dengue viral activity |
| publisher |
American Society for Microbiology |
| publishDate |
2020 |
| url |
https://doaj.org/article/9d33b3a657f445fa99ed33577dd68fd2 |
| work_keys_str_mv |
AT jasminemoshiri atargetedcomputationalscreenofthesweetleaddatabaserevealsfdaapprovedcompoundswithantidengueviralactivity AT davidaconstant atargetedcomputationalscreenofthesweetleaddatabaserevealsfdaapprovedcompoundswithantidengueviralactivity AT bowenliu atargetedcomputationalscreenofthesweetleaddatabaserevealsfdaapprovedcompoundswithantidengueviralactivity AT robertomateo atargetedcomputationalscreenofthesweetleaddatabaserevealsfdaapprovedcompoundswithantidengueviralactivity AT stevenkearnes atargetedcomputationalscreenofthesweetleaddatabaserevealsfdaapprovedcompoundswithantidengueviralactivity AT paulnovick atargetedcomputationalscreenofthesweetleaddatabaserevealsfdaapprovedcompoundswithantidengueviralactivity AT ritikaprasad atargetedcomputationalscreenofthesweetleaddatabaserevealsfdaapprovedcompoundswithantidengueviralactivity AT claudenagamine atargetedcomputationalscreenofthesweetleaddatabaserevealsfdaapprovedcompoundswithantidengueviralactivity AT vijaypande atargetedcomputationalscreenofthesweetleaddatabaserevealsfdaapprovedcompoundswithantidengueviralactivity AT karlakirkegaard atargetedcomputationalscreenofthesweetleaddatabaserevealsfdaapprovedcompoundswithantidengueviralactivity AT jasminemoshiri targetedcomputationalscreenofthesweetleaddatabaserevealsfdaapprovedcompoundswithantidengueviralactivity AT davidaconstant targetedcomputationalscreenofthesweetleaddatabaserevealsfdaapprovedcompoundswithantidengueviralactivity AT bowenliu targetedcomputationalscreenofthesweetleaddatabaserevealsfdaapprovedcompoundswithantidengueviralactivity AT robertomateo targetedcomputationalscreenofthesweetleaddatabaserevealsfdaapprovedcompoundswithantidengueviralactivity AT stevenkearnes targetedcomputationalscreenofthesweetleaddatabaserevealsfdaapprovedcompoundswithantidengueviralactivity AT paulnovick targetedcomputationalscreenofthesweetleaddatabaserevealsfdaapprovedcompoundswithantidengueviralactivity AT ritikaprasad targetedcomputationalscreenofthesweetleaddatabaserevealsfdaapprovedcompoundswithantidengueviralactivity AT claudenagamine targetedcomputationalscreenofthesweetleaddatabaserevealsfdaapprovedcompoundswithantidengueviralactivity AT vijaypande targetedcomputationalscreenofthesweetleaddatabaserevealsfdaapprovedcompoundswithantidengueviralactivity AT karlakirkegaard targetedcomputationalscreenofthesweetleaddatabaserevealsfdaapprovedcompoundswithantidengueviralactivity |
| _version_ |
1718427163867217920 |