Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pntd.0000721
Title: Structural optimization and de novo design of dengue virus entry inhibitory peptides
Authors: Costin J.M.
Jenwitheesuk E.
Lok S.-M. 
Hunsperger E.
Conrads K.A.
Fontaine K.A.
Rees C.R.
Rossmann M.G.
Isern S.
Samudrala R.
Michael S.F.
Keywords: antivirus agent
peptide 1OAN1
peptide DN57opt
unclassified drug
virus envelope protein
peptide
virus antibody
virus envelope protein
animal cell
antiviral activity
article
cell assay
concentration response
controlled study
cryoelectron microscopy
cytotoxicity test
Dengue virus 2
drug design
drug mechanism
drug protein binding
drug research
drug screening
drug structure
in vitro study
incubation time
interferometry
nonhuman
nucleotide sequence
process optimization
protein domain
structure activity relation
structure analysis
virus culture
virus entry
virus expression
virus inhibition
virus morphology
virus particle
virus strain
amino acid sequence
analysis of variance
animal
biology
blood
cell line
chemical structure
chemistry
Dengue virus
drug effect
genetics
human
Macaca
metabolism
methodology
molecular genetics
physiology
polymerase chain reaction
virus attachment
virus entry
Amino Acid Sequence
Analysis of Variance
Animals
Antibodies, Viral
Cell Line
Computational Biology
Cryoelectron Microscopy
Dengue Virus
Humans
Interferometry
Macaca mulatta
Models, Molecular
Molecular Sequence Data
Peptides
Polymerase Chain Reaction
Viral Envelope Proteins
Virus Attachment
Virus Internalization
Issue Date: 2010
Citation: Costin J.M., Jenwitheesuk E., Lok S.-M., Hunsperger E., Conrads K.A., Fontaine K.A., Rees C.R., Rossmann M.G., Isern S., Samudrala R., Michael S.F. (2010). Structural optimization and de novo design of dengue virus entry inhibitory peptides. PLoS Neglected Tropical Diseases 4 (6) : e721. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pntd.0000721
Abstract: 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 ?M 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.
Source Title: PLoS Neglected Tropical Diseases
URI: https://scholarbank.nus.edu.sg/handle/10635/161662
ISSN: 19352727
DOI: 10.1371/journal.pntd.0000721
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