ABSTRACT
The recent SARS-CoV-2 pandemic brought awareness to the permanent dangers of viral infections and outbreaks. Beyond its inherent infections, several viruses such as Dengue (DENV), Zika (ZIKV), HIV and even SARS-CoV-2 have the potential to infect the brain, causing more aggressive and irreversible injuries. These brain infections are particularly hard to treat not only because the number of efficient antiviral drugs against these viruses is scarce, but also due to the restrictive permeability of the blood- brain barrier (BBB) that hinders brain drug-intake. To overcome these issues, we designed peptide-drug conjugates formed by covalent attachment of a BBB peptide shuttle and a broad-spectrum antiviral porphyrin drug. We synthesized eighteen novel peptide-porphyrins conjugates (PPCs) and tested their activity in vitro, both in BBB-translocation and antiviral capacity against DENV, ZIKV, HIV and SARS-CoV-2. Cytotoxicity towards pharmacologic relevant cell lines was also studied. After careful fine-tuning of the on-resin synthetic chemistry, DIC/Oxyma coupling has emerged as preferred method, bearing a 99% conjugation yield. Ten PPCs inactivate at least two different viruses in vitro, a selection criterion for further evaluation, with IC50s ranging between 0.5 to 33 lM. Although all ten PPCs efficiently translocate the cellular BBB model in vitro, a set of seven stand out as the most druggable since they are not cytotoxic towards all cell lines tested. Overall, peptide-porphyrin conjugation shows to be an innovative and promising strategy to treat viral brain infections.