While developing peptide drugs, activity and affinity to targets is often emphasized, other important aspects, like pharmacokinetics and biodistribution being frequently overlooked. We address one important issue in physiological clearance of peptide drugs (serum half-life) and one other important issue in biodistribution (translocation of the blood-brain barrier) to discover peptides with improved action as drug carriers to be used in peptide-drug conjugates.
Virus emergence/re-emergence can lead to devastating consequences, e.g., Zika outbreak in Brazil in 2015 and COVID-19 pandemics in 2019. In light of this, broad-spectrum antivirals, such as porphyrins, represent a key tool for outbreaks/pandemic preparedness and fast response. Viruses, such as Zika virus (ZIKV) and SARS-CoV-2, can invade the central nervous system (CNS), causing neurological complications, such as ZIKV-induced microcephaly. However, the blood-brain barrier (BBB) hinders the effective delivery of antiviral drugs to the CNS.
Using different porphyrins and BBB peptide shuttles (BBBpS), we developed peptide-porphyrin conjugates (PPCs) to translocate both BBB and the blood-placental barrier (BPB) to target viral infection in the brain of adults and/or foetuses during pregnancy. PPCs were ranked according to their toxicity, BBB and BPB translocation capacity, and antiviral activity (against DENV, ZIKV, SARS-CoV-2 and HIV) in vitro and the most promising PPCs were tested against ZIKV in vivo. PPCs impact on brain viral load and disease progression was monitored. Overall, our results show that PPCs treatment reduced viral load and cytokine expression in mice brain, mitigating disease progression and mortality.