Novel RU486 (mifepristone) analogues with increased activity against Venezuelan Equine Encephalitis Virus but reduced progesterone receptor antagonistic activity

DeBono, Aaron; Thomas, David R.; Lundberg, Lindsay; Pinkham, Chelsea; Cao, Ying; Graham, J. Dinny; Clarke, Christine L.; Wagstaff, Kylie M.; Shechter, Sharon; Kehn-Hall, Kylene; Jans, David A.

doi:10.1038/s41598-019-38671-y

Cited by 15 publications

(12 citation statements)

References 68 publications

(92 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The 23 furanocoumarins that were considered for the study were obtained from PubChem (https://pubchem.ncbi.nih.gov/). The X-ray crystal structures of the receptors ERα, PR, EGFR and mTOR were retrieved from the Protein Data Bank having PDB IDs 3ERT 22 , 4OAR 23 , 2J6M 24 and 4DRH 25 respectively.…”

Section: Methodsmentioning

confidence: 99%

Structure Based Multitargeted Molecular Docking Analysis of Selected Furanocoumarins against Breast Cancer

Acharya

Chacko

Bose

et al. 2019

Sci Rep

127

View full text Add to dashboard Cite

Breast cancer is one of the biggest global dilemmas and its current therapy is to target the hormone receptors by the use of partial agonists/antagonists. Potent drugs for breast cancer treatment are Tamoxifen, Trastuzumab, Paclitaxel, etc. which show adverse effects and resistance in patients. The aim of the study has been on certain phytochemicals which has potent actions on ERα, PR, EGFR and mTOR inhibition. The current study is performed by the use of molecular docking as protein-ligand interactions play a vital role in drug design. The 3D structures of ERα, PR, EGFR and mTOR were obtained from the protein data bank and docked with 23 3D PubChem structures of furanocoumarin compounds using FlexX. Drug-likeness property was checked by applying the Lipinski’s rule of five on the furanocoumarins to evaluate anti-breast cancer activity. Antagonist and inhibition assay of ERα, EGFR and mTOR respectively has been performed using appropriate in-vitro techniques. The results confirm that Xanthotoxol has the best docking score for breast cancer followed by Bergapten, Angelicin, Psoralen and Isoimperatorin. Further, the in-vitro results also validate the molecular docking analysis. This study suggests that the selected furanocoumarins can be further investigated and evaluated for breast cancer treatment and management strategies.

show abstract

Section: Methodsmentioning

confidence: 99%

Structure Based Multitargeted Molecular Docking Analysis of Selected Furanocoumarins against Breast Cancer

Acharya

Chacko

Bose

et al. 2019

Sci Rep

127

View full text Add to dashboard Cite

show abstract

“… 1 Approved for human use in medical termination of pregnancy, hyperglycaemia treatment in Cushing's syndrome patients; 2 Analogue of mifepristone ((8S,13S,14S,17S)-17-hydroxy-13-methyl-11-phenyl-17-((trimethylsilyl) ethynyl)-1,2,6,7,8,11,12,13, 14,15,16,17-dodecahydro-3H-cyclopenta[a] phenanthren-3-one)) lacking progesterone receptor antagonism [ 52 ]; 3 Approved for asthma, chronic obstructive pulmonary disease, allergic rhinitis and nasal polyps, inflammatory bowel diseases; 4 Approved for the treatment of asthma, allergic rhinitis; 5 Selectivity index > 9.3; 6 Progressed to clinical trials (incl. Phase III) for indications including breast, bladder and paediatric cancers, macular degeneration; other actions include increased phosphorylation of eIF2α, promoting an antiviral state not related to long-chain ceramide biosynthesis, PERK pathway or ATF-4 [ 15 , 55 , 77 ]; 7 ADE model uses subneutralising concentrations of anti-E protein antibody prior to infection; 8 Mechanism of action against influenza to be determined.…”

Section: Viral Proteins Subvert the Host Nuclear Import Machinerymentioning

confidence: 99%

“… 2 Analogue of mifepristone ((8S,13S,14S,17S)-17-hydroxy-13-methyl-11-phenyl-17-((trimethylsilyl) ethynyl)-1,2,6,7,8,11,12,13, 14,15,16,17-dodecahydro-3H-cyclopenta[a] phenanthren-3-one)) lacking progesterone receptor antagonism [ 52 ]; …”

Section: Viral Proteins Subvert the Host Nuclear Import Machinerymentioning

confidence: 99%

Antivirals that target the host IMPα/β1-virus interface

Martin

Jans

2021

Biochemical Society Transactions

Self Cite

View full text Add to dashboard Cite

Although transport into the nucleus mediated by the importin (IMP) α/β1-heterodimer is central to viral infection, small molecule inhibitors of IMPα/β1-dependent nuclear import have only been described and shown to have antiviral activity in the last decade. Their robust antiviral activity is due to the strong reliance of many different viruses, including RNA viruses such as human immunodeficiency virus-1 (HIV-1), dengue (DENV), and Zika (ZIKV), on the IMPα/β1-virus interface. High-throughput compound screens have identified many agents that specifically target this interface. Of these, agents targeting IMPα/β1 directly include the FDA-approved macrocyclic lactone ivermectin, which has documented broad-spectrum activity against a whole range of viruses, including HIV-1, DENV1–4, ZIKV, West Nile virus (WNV), Venezuelan equine encephalitis virus, chikungunya, and most recently, SARS-CoV-2 (COVID-19). Ivermectin has thus far been tested in Phase III human clinical trials for DENV, while there are currently close to 80 trials in progress worldwide for SARS-CoV-2; preliminary results for randomised clinical trials (RCTs) as well as observational/retrospective studies are consistent with ivermectin affording clinical benefit. Agents that target the viral component of the IMPα/β1-virus interface include N-(4-hydroxyphenyl) retinamide (4-HPR), which specifically targets DENV/ZIKV/WNV non-structural protein 5 (NS5). 4-HPR has been shown to be a potent inhibitor of infection by DENV1–4, including in an antibody-dependent enhanced animal challenge model, as well as ZIKV, with Phase II clinical challenge trials planned. The results from rigorous RCTs will help determine the therapeutic potential of the IMPα/β1-virus interface as a target for antiviral development.

show abstract

“…The high infectivity of VEEV and the presence of circulating virus in animal reservoirs creates a constant risk of a new outbreak (Weaver and Barrett, 2004 ; Weaver et al, 2004 ). Treatment options are limited and there is no vaccine approved for the general public (Sharma and Knollmann-Ritschel, 2019 ), making the development of anti-VEEV agents a high priority (Reichert et al, 2009 ; Chung et al, 2014 ; Lundberg et al, 2016 ; Urakova et al, 2018 ; Carey et al, 2019 ; DeBono et al, 2019 ).…”

Section: Venezuelan Equine Encephalitis Virus: a Target For Antiviralmentioning

confidence: 99%

Application of In Silico and HTS Approaches to Identify Nuclear Import Inhibitors for Venezuelan Equine Encephalitis Virus Capsid Protein: A Case Study

2020

Self Cite

View full text Add to dashboard Cite

The development of new drugs is costly and time-consuming, with estimates of over $US1 billion and 15 years for a product to reach the market. As understanding of the molecular basis of disease improves, various approaches have been used to target specific molecular interactions in the search for effective drugs. These include high-throughput screening (HTS) for novel drug identification and computer-aided drug design (CADD) to assess the properties of putative drugs before experimental work begins. We have applied conventional HTS and CADD approaches to the problem of identifying antiviral compounds to limit infection by Venezuelan equine encephalitis virus (VEEV). Nuclear targeting of the VEEV capsid (CP) protein through interaction with the host nuclear import machinery has been shown to be essential for viral pathogenicity, with viruses incapable of this interaction being greatly attenuated. Our previous conventional HTS and in silico structure-based drug design (SBDD) screens were successful in identifying novel inhibitors of CP interaction with the host nuclear import machinery, thus providing a unique opportunity to assess the relative value of the two screening approaches directly. This focused review compares and contrasts the two screening approaches, together with the properties of the inhibitors identified, as a case study for parallel use of the two approaches to identify antivirals. The utility of SBDD screens, especially when used in parallel with traditional HTS, in identifying agents of interest to target the host–pathogen interface is highlighted.

show abstract

Novel RU486 (mifepristone) analogues with increased activity against Venezuelan Equine Encephalitis Virus but reduced progesterone receptor antagonistic activity

Cited by 15 publications

References 68 publications

Structure Based Multitargeted Molecular Docking Analysis of Selected Furanocoumarins against Breast Cancer

Structure Based Multitargeted Molecular Docking Analysis of Selected Furanocoumarins against Breast Cancer

Antivirals that target the host IMPα/β1-virus interface

Application of In Silico and HTS Approaches to Identify Nuclear Import Inhibitors for Venezuelan Equine Encephalitis Virus Capsid Protein: A Case Study

Contact Info

Product

Resources

About