Inhibitors of Peptidyl Proline Isomerases As Antivirals in Hepatitis C and Other Viruses

Viruses have small genomes with limited coding capacity. A common strategy by which viral genomes maximize their coding capacity is to express multifunctional proteins that promiscuously interact with various cellular partners to perform an array of essential functions. These interactions often involve flexible, and in some cases intrinsically disordered, viral domains or entire proteins that assume distinct conformations only upon binding cellular partners (see review, [1]). Viral coding capacity is further enhanced by relying on host factors and protein folding machinery to access different conformations and functions. These disordered peptide regions can be computationally recognized by features such as glycine, serine, and proline residues in contexts that are not conducive to β–strands or α–helices (reviewed by [2]). Bioinformatic analysis was used to predict the rigidity of proteins encoded by nearly 3,500 genomes from archaea, bacteria, eukaryotes, and viruses. This analysis suggests that almost all genomes with greater than 50% of their encoded residues in a predicted disordered state are viral genomes [3]. Thus, disordered proteins are enriched in the viral proteome and are common features to a large number of viruses. Flexible viral proteins and/or domains interact with the cellular folding machinery, including proline isomerases. While proline is traditionally thought of as being a rigid amino acid that can “kink” the polypeptide chain, prolines can slowly rotate between two energetically similar configurations, cis or trans. This rotation is only fast enough to be physiologically relevant when facilitated by proline isomerases (rotamases) such as mammalian cyclophilins [4]. At least four structurally distinct classes of cellular proline isomerases exist in bacteria and eukaryotes, and some viruses encode their own proline isomerase [4], [5]. Identification of the host isomerases exploited by viruses and the viral proteins that require them to perform essential viral functions for replication in culture, or more importantly, in animals, presents an obvious antiviral strategy. Whether or not inhibition of host proline isomerases could be an antiviral strategy for hepatitis C virus (HCV) was a subject of debate for several years.