Understanding Dengue Virus Capsid Protein Interaction with Key Biological Targets

Abstract

Dengue virus (DENV) causes over 500,000 hospitalizations and 20,000 deaths worldwide every year. Dengue epidemics now reach temperate regions due to globalization of trade and travel and climate changes. Currently, there are no successful therapeutic or preventive approaches. We previously developed a peptide drug lead, pep14-23, that inhibits the biologically relevant interaction of DENV capsid (C) protein with lipid droplets (LDs). Surprisingly, pep14-23 also inhibits DENV C interaction with very low-density lipoproteins (VLDL). We thus investigated the similarity between the proposed DENV C molecular targets in LDs and VLDL, respectively, the proteins perilipin 3 (PLIN3) and apolipoprotein E (APOE). APOE N-terminal and PLIN3 C-terminal regions are remarkably similar, namely APOE α-helix 4 (APOEα4) and PLIN3 α-helix 5 (PLIN3α5) sequences, which are also highly superimposable structurally. Interestingly, APOE α-helical N-terminal sequence and structure superimposes with DENV C α-helices α1 and α2. Moreover, the DENV C hydrophobic cleft can accommodate the structurally analogous APOEα4 and PLIN3α5 helical regions. Mirroring DENV C-LDs interaction (previously shown experimentally to require PLIN3), we experimentally demonstrated that DENV C-VLDL interaction requires APOE. Thus, the results fit well with previous data and suggest future drug development strategies targeting the above mentioned α-helical structures.

Lipid droplet functions beyond energy storage

“…When this interaction is impaired (either through mutations that prevent capsid targeting to LDs or by reducing LDs via a FA synthase inhibitor), production of infectious viral particles is severely curtailed [140]. Because capsid binding to LDs is impaired after limited proteolysis of LDs, it is presumably mediated by protein-protein interactions with LD proteins [142, 143]. Rotaviruses are double-stranded RNA viruses and a leading cause of diarrhea in children.…”

Assembly and release of infectious hepatitis C virus involving unusual organization of the secretory pathway

“…The associations to lipoprotein particles and extracellular particles have been proposed as mechanisms to regulate vertebrate Hedgehog dispersion during development [79] . In addition, ApoE [25,80] and extracellular particles [47] are suspected to contribute also to the pathogenesis of viruses unrelated to HCV. Therefore, rather than having evolved a unique mechanism of viral propagation, HCV may have instead subverted existing cellular processes.…”

“…Potential mechanisms for WNV-conditioned BHK cells producing highly infectious HCV virions could relate to common genomic features between the Flavivirus and Hepacivirus genera within the Flaviviridae family [18] . In addition, several flaviviruses infect hepatocytes [19,20] and may use similar host factors as HCV for their production [21][22][23][24][25] . Our previous results showed that after curing BHK cells from the WNV subgenomic replicon, the production and release of infectious HCV particles were still observed for a while [8] .…”

Tracking cancer In vivo imaging techniques

“…11 It was also used for understanding the molecular determinants and identifying the ligand for the dengue virus capsid protein on intracellular lipid droplets and plasma lipoproteins (Figure 4 .3) . 17,[47][48][49][50] Glass surface…”