Journal of Nanomedicine & Nanotechnology

Abstract

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

Diogo A. Mendonça, Tiago N. Figueira, Manuel N. Melo, Olivia Harder, Stefan Niewiesk, Anne Moscona, Matteo Porotto and Ana Salomé Veiga

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.