Evolution of antiviral resistance captures a transient interdomain functional interaction between chikungunya virus envelope glycoproteins.

Abstract

CHIKV is a reemergent pathogen that has caused large outbreaks in the twenty years. There are no available antiviral therapies and a vaccine has only recently been approved. Here, we describe the mode of action of a novel inhibitor designed against CHIKV envelope proteins heterodimer that blocks entry at the stage of fusion between virus and host membranes. Fusion is common to the entry of enveloped viruses. Virus envelope proteins drive fusion undergoing a series of transitions from an initial metastable conformational state to a more stable post-fusion state. Intermediate conformations are transient and have mostly remained inaccessible to structure determination. In this study, directed evolution of resistance to antiviral inhibition of fusion uncovered a functional interaction between two residues residing in domains that are apart in both the pre-fusion and post-fusion states. Thus, our approach allowed gaining insight into the molecular detail of the inner working of virus fusion machinery.