Brain-penetrating viruses such as Zika (ZIKV), dengue or HIV pose a serious health problem because antiviral drugs with promising in vitro profiles become ineffective in vivo due to the restrictive permeability of the blood-brain barrier (BBB). ZIKV is a case in point: a mosquito-borne virus that spreads to people by insect bite and is particularly insidious due to its high potential to invade adult and fetus brains. When it infects pregnant women ZIKV can cause irreversible congenital brain abnormalities, fetal loss, preterm birth or other birth defects, and can also trigger Guillain-Barré syndrome. Porphyrins with antiviral activity are promising candidates to fight ZIKV in vitro but suffer from poor brain delivery. In recent years, blood-brain barrier peptide shuttles (BBBpS) have received increased attention for their ability to pass BBB and translocate diverse drug payloads. We have hypothesized that conjugating antiviral porphyrins to BBBpS is an effective approach to overcome brain delivery hurdles in fighting ZIKV.

We will present a comparative study of various on-resin conjugation strategies to generate peptide-porphyrin conjugates (PPCs) able to cross the BBB with good translocation rates and high in vitro antiviral activity. In total, twenty novel conjugates, combining six BBBpS (P1-P6), two porphyrins (MPIX and PPIX) and one PEG-like linker (O₂Oc), have been obtained in >90% purity. Most conjugates show high serum stability and do not alter cell viability at broad range of concentration tested. Eight conjugates, including PPIX-P1 (EU application EP22382150.5) are active against ZIKV, while four also inactivate HIV at micromolar range. Interestingly, when some PPCs were further elaborated into multimeric (juxtaposed or branched) arrangements, antiviral activity against ZIKV improved to low nanomolar range. Altogether, current results portray peptide-porphyrin conjugation as a promising strategy to tackle ZIKV and other brain-residing viruses.

Figure 1. The rationale behind synthesis of antiviral peptide-porphyrin conjugates.