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Reaching beyond HIV/HCV: nelfinavir as a potential starting point for broad-spectrum protease inhibitors against dengue and chikungunya virus

Bhakat, Soumendranath LU ; Delang, Leen; Kaptein, Suzanne; Neyts, Johan; Leyssen, Pieter and Jayaprakash, Venkatesan (2015) In RSC Advances 5(104). p.85938-85949
Abstract
Drug repurposing or re-profiling has become an effective strategy to identify novel indications for already-approved drugs. In this study, peptidomimetic FDA-approved HIV/HCV inhibitors were explored for their potential to be repurposed for the inhibition of the replication of dengue (DENV) and chikungunya virus (CHIKV) by targeting the NS2B-NS3 and NSP2 protease, respectively. MM/GBSA-based binding free energy results put nelfinavir forward as a potential inhibitor of both dengue and chikungunya virus, which subsequently was further explored in a virus-cell-based assay for both viruses. Nelfinavir showed modest antiviral activity against CHIKV (EC50 = 14 +/- 1 mu M and a selectivity index of 1.6) and was slightly more active against... (More)
Drug repurposing or re-profiling has become an effective strategy to identify novel indications for already-approved drugs. In this study, peptidomimetic FDA-approved HIV/HCV inhibitors were explored for their potential to be repurposed for the inhibition of the replication of dengue (DENV) and chikungunya virus (CHIKV) by targeting the NS2B-NS3 and NSP2 protease, respectively. MM/GBSA-based binding free energy results put nelfinavir forward as a potential inhibitor of both dengue and chikungunya virus, which subsequently was further explored in a virus-cell-based assay for both viruses. Nelfinavir showed modest antiviral activity against CHIKV (EC50 = 14 +/- 1 mu M and a selectivity index of 1.6) and was slightly more active against DENV-2 (EC50 = 3.5 +/- 0.4 mu M and a selectivity index of 4.6). Even though the antiviral potency was limited, the fact that some activity was observed in these assays made it worthwhile exploring the potential and properties of nelfinavir as a stepping-stone compound: a more detailed computational analysis was performed to understand the binding mode, interaction, hydrogen bond distance, occupancy and minimum pharmacophoric features. The comprehensive data set that resulted from these analyses may prove to be useful for the development of novel DENV and CHIKV protease inhibitors. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
RSC Advances
volume
5
issue
104
pages
85938 - 85949
publisher
Royal Society of Chemistry
external identifiers
  • wos:000363179900094
  • scopus:84944754654
ISSN
2046-2069
DOI
10.1039/c5ra14469h
language
English
LU publication?
yes
id
bd41c8d5-bb77-4a19-9f0f-3be551931c25 (old id 8201741)
date added to LUP
2015-11-26 13:10:10
date last changed
2017-08-13 04:07:55
@article{bd41c8d5-bb77-4a19-9f0f-3be551931c25,
  abstract     = {Drug repurposing or re-profiling has become an effective strategy to identify novel indications for already-approved drugs. In this study, peptidomimetic FDA-approved HIV/HCV inhibitors were explored for their potential to be repurposed for the inhibition of the replication of dengue (DENV) and chikungunya virus (CHIKV) by targeting the NS2B-NS3 and NSP2 protease, respectively. MM/GBSA-based binding free energy results put nelfinavir forward as a potential inhibitor of both dengue and chikungunya virus, which subsequently was further explored in a virus-cell-based assay for both viruses. Nelfinavir showed modest antiviral activity against CHIKV (EC50 = 14 +/- 1 mu M and a selectivity index of 1.6) and was slightly more active against DENV-2 (EC50 = 3.5 +/- 0.4 mu M and a selectivity index of 4.6). Even though the antiviral potency was limited, the fact that some activity was observed in these assays made it worthwhile exploring the potential and properties of nelfinavir as a stepping-stone compound: a more detailed computational analysis was performed to understand the binding mode, interaction, hydrogen bond distance, occupancy and minimum pharmacophoric features. The comprehensive data set that resulted from these analyses may prove to be useful for the development of novel DENV and CHIKV protease inhibitors.},
  author       = {Bhakat, Soumendranath and Delang, Leen and Kaptein, Suzanne and Neyts, Johan and Leyssen, Pieter and Jayaprakash, Venkatesan},
  issn         = {2046-2069},
  language     = {eng},
  number       = {104},
  pages        = {85938--85949},
  publisher    = {Royal Society of Chemistry},
  series       = {RSC Advances},
  title        = {Reaching beyond HIV/HCV: nelfinavir as a potential starting point for broad-spectrum protease inhibitors against dengue and chikungunya virus},
  url          = {http://dx.doi.org/10.1039/c5ra14469h},
  volume       = {5},
  year         = {2015},
}