Targeting enveloped virus entry into cells : self-delivery and other strategies against HIV and Measles virus

Viruses infect host cells through invasive entry mechanisms, ubiquitous to all viral families. Pathogenic enveloped viruses, such as the Human immunodeficiency virus (HIV) and the Measles virus (MV), depend on the interplay between viral envelope glycoproteins, cellular receptors and membrane lipids to infect cells. It is possible to block enveloped virus entry with entry inhibitors (EIs) which act prior to viral invasion and outside the cellular environment with considerable prophylactic and therapeutic potential. However, these remain largely underused or unexplored for the treatment of HIV and MV, respectively, as well as their associated pathologies. Taking advantage of drug synergy, liposomal transport and nanoparticle selfdelivery, the present work addresses innovative drug delivery strategies for EIs developed against HIV and MV. In addition, the work is focused on the role of lipid membranes as potential carriers (liposomes) and targets (cell membranes) for EIs, towards the improvement of associated pharmacokinetics and efficacy. Liposomal nanocarrier systems, designed for the delivery of two anti-HIV EI, were found to enhance their synergistic action against HIV entry, in vitro. These systems consisted of small-molecule protoporphyrin IX and peptide enfuvirtide, coloaded within the lipid bilayer of immune-evasive unilamellar vesicles. The intrinsic lipophilicity of the EI allowed their spontaneous incorporation in lipid bilayers. Likewise, the synthetic single domain antibody F63, specifically developed against HIV entry, was also found to interact with lipids, highlighting the role of membrane partition in the mode of action and efficacy of EI. The same principles were applied in the design of anti-MV EI peptide amphiphiles, engineered with lipid membrane affinity through hydrophobic domains conjugation. Additionally, these EI self-assembled into nanoparticles deliverable through the intranasal route, leading to improved biodistribution and efficacy against MV entry, compared to unconjugated peptides. The findings suggest that self-assembly and lipid partition/retention are closely related in modulating the EI self-delivery and antiviral properties. In sum, EI-lipid membranes interactions, exploited in favour of targeting and delivery systems development, represent a valuable strategy for the enhancement of EI against HIV, MV and other emerging viruses