Dengue virus capsid proteins latch onto fat-filled droplets inside human cells to kickstart viral replication. This molecular handshake—between the virus’s disordered protein tail and a host protein called Perilipin 3—is the critical first step in assembling new virus particles. Without a clear picture of that interaction, researchers cannot design drugs to block it. Dengue infects hundreds of millions of people annually, and no effective treatments or vaccines exist. Climate change is pushing the mosquito vector into Europe and the UK, making this a growing threat to wealthy nations as well. The team will combine advanced peptide synthesis, biophysical models of lipid droplets, and computer simulations to map exactly which electrostatic or hydrophobic forces drive the binding. This is fundamental science: understanding a precise molecular mechanism inside a living cell. If successful, the work could reveal a new target for antiviral drugs that prevent dengue from replicating, potentially opening a pathway to treatments where none currently exist.
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Dengue virus (DENV), a member of the flaviviridae family, is the cause of mosquito-borne dengue fever. Endemic in 100 countries, it leads to over 400 million infections and 25k deaths annually worldwide. With no effective treatments or vaccines, it represents a major socio-economic burden for tropical and subtropical developing countries. Expansion of dengue Aedes mosquito vector due to climate change makes it increasingly a global threat, with over 4 billion people at risk, including EU and UK. There is an urgent need for detailed understanding of the DENV lifecycle for devising new pathways for tackling DENV infections. Central to DENV's lifecycle is its replication, a process that has been very recently linked with lipid droplets (LD; ubiquitous multifunctional intracellular organelles of 0.05-100 um in size), with DENV capsid proteins (DENV-C) found accumulating on LD, leading to nucleocapsid formation and viral particle self-assembly. Critically, this process is initiated by the adsorption of DENV-C onto the LD surface mediated by molecular interactions between DENV-C and the LD membrane and surface-anchored proteins, particularly Perilipin 3 (Plin3). Of particular interest to the molecular interactions is an intrinsically disordered region (IDR), i.e. the first 30 amino acid residues at the DENV-C N-terminus. Probing these fundamental molecular interactions, using a combination of physicochemical experimental and computer simulation methods, is the focus of this proposal. Our approach to designing the experimental programme is guided by the following considerations. The molecular interactions - electrostatic or hydrophobic - depend intricately on the amino acid sequence in DENV-C IDR. We thus will leverage advanced peptide synthesis to precisely tailor IDR-analogous viral peptide sequences and compare them with full IDR and C-proteins. The inherent complexity in LD obscures mechanistic probing of the underpinning molecular interactions. We thus will leverage biophysical methods to establish LD models, incorporating Plin3 and essential LD surface structural and compositional features. Going beyond phenomenological observations, we will bring to bear quantitative experimental and computational methods in biophysics and surface science to directly access molecular structures and interactions at complex interfaces.
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