In silico screening of small molecule libraries using the dengue virus envelope E protein has identified compounds with antiviral activity against multiple flaviviruses.
The flaviviruses comprise a large group of related viruses, many of which pose a significant global human health threat, most notably the dengue viruses (DENV), West Nile virus (WNV) and yellow fever virus (YFV). Flaviviruses enter host cells via fusion of the viral and cellular membranes, a process mediated by the major viral envelope protein E as it undergoes a low pH induced conformational change in the endosomal compartment of the host cell. This essential entry stage in the flavivirus life cycle provides an attractive target for the development of antiviral agents. We performed an in silico docking screen of the Maybridge chemical database within a previously described ligand binding pocket in the dengue E protein structure that is thought to play a key role in the conformational transitions that lead to membrane fusion. The biological activity of selected compounds identified from this screen revealed low micromolar antiviral potency against dengue virus for two of the compounds. Our results also provide the first evidence that compounds selected to bind to this ligand binding site on the flavivirus E protein abrogate fusion activity. Interestingly, one of these compounds also has antiviral activity against both WNV (kunjin strain) and YFV.
Kampmann
Thorsten
T
Centre for Infectious Disease Research, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
Yennamalli
Ragothaman
R
Campbell
Phillipa
P
Stoermer
Martin J
MJ
Fairlie
David P
DP
Kobe
Bostjan
B
Young
Paul R
PR
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001665:Binding Sites; D002522:Chlorocebus aethiops; D003716:Dengue Virus / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D005416:Flavivirus / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D018177:Flavivirus Infections / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D053586:Virus Internalization / Q000187:drug effects
D000998:Antiviral Agents; D054852:Small Molecule Libraries; D014759:Viral Envelope Proteins