Targeting the proteases of arboviruses with cyclic and bicyclic peptides

Abstract

Arthropod-borne (arbo) viruses infect hundreds of millions of people annually. Many arboviruses and their mosquito vectors circulate in Australia and neighbouring regions. Recent years have shown that explosive outbreaks accompanied by life-threating symptoms such as encephalitis are unpredictable and increasingly common, particularly due to the effects of climate change. Two major genera of pathogenic viruses are flaviviruses and alphaviruses. Both require their own viral proteases to replicate and infect new cells. Viral proteases can be considered the Achilles heel of replication and are already long-established drug targets in the fight against chronic viral infectious diseases, for example, HIV/AIDS. We developed a large variety of high-affinity and proteolytically stable peptide inhibitors of flaviviral proteases using innovative chemical approaches. Our chemical strategies proceed under biocompatible conditions, enabling in situ access to constrained peptide ligands in presence of proteases and other drug targets. While cyclic and bicyclic peptides offer many advantages over small molecules used in conventional drug discovery, their limited bioavailability is a major challenge that still needs to be overcome.