Self-assembly Stability Compromises the Efficacy of Tryptophan-Containing Designed Anti-measles Virus Peptides.

The resurgence of several infectious diseases, like measles, has driven the search for new chemotherapeutics to prevent and treat viral infections. Self-assembling antiviral peptides are a promising class of entry inhibitors capable of meeting this need. Fusion inhibitory peptides derived from the heptad repeat of the C-terminal (HRC) of the measles fusion protein, dimerized and conjugated with lipophilic groups, were found to be efficacious against measles virus. The structures of the self-assembled nanoparticles formed by these peptides modulated their activity. Based on the analysis of a L454W mutation in the fusion protein of a naturally occurring measles viral isolate, HRC peptides bearing the tryptophan residue at position 454 (HRC-L454W) were synthesized with the goal of improving membrane anchoring and manipulating self-assembly. Monomeric and dimeric peptides, whether conjugated or not to a single lipophilic group, reduced infection in vivo. Bis-conjugation with lipophilic groups, in contrast, abrogated activity. Based on the physicochemical properties, self-assembly and membrane insertion kinetics of the HRC-L454W peptides we show that bis-conjugation increases the stability and order of the inner core of the spontaneously self-assembled nanoparticles, resulting in their compaction. The presence of the tryptophan residue also increases steric hindrance effects in the nanoparticle of the dimeric peptides, contributing to inter-peptide cluster meshing, but the same level of compaction is not achieved. We propose that the highly ordered packing and stability of molecular clusters forming the inner core of self-assembled nanoparticles prevent efficient dissociation of the peptides in vivo, hindering their release and therefore eliminating their antiviral efficacy.