*Article* **Targeting Zika Virus with New Brain- and Placenta-Crossing Peptide–Porphyrin Conjugates**

**Toni Todorovski 1,† , Diogo A. Mendonça 2,† , Lorena O. Fernandes-Siqueira <sup>3</sup> , Christine Cruz-Oliveira <sup>2</sup> , Giuseppina Guida <sup>1</sup> , Javier Valle <sup>1</sup> , Marco Cavaco <sup>2</sup> , Fernanda I. V. Limas <sup>3</sup> , Vera Neves <sup>2</sup> , Íris Cadima-Couto <sup>2</sup> , Sira Defaus <sup>1</sup> , Ana Salomé Veiga <sup>2</sup> , Andrea T. Da Poian 3,\* , Miguel A. R. B. Castanho 2,\* and David Andreu 1,\***


**Abstract:** Viral disease outbreaks affect hundreds of millions of people worldwide and remain a serious threat to global health. The current SARS-CoV-2 pandemic and other recent geographicallyconfined viral outbreaks (severe acute respiratory syndrome (SARS), Ebola, dengue, zika and everrecurring seasonal influenza), also with devastating tolls at sanitary and socio-economic levels, are sobering reminders in this respect. Among the respective pathogenic agents, Zika virus (ZIKV), transmitted by *Aedes* mosquito vectors and causing the eponymous fever, is particularly insidious in that infection during pregnancy results in complications such as foetal loss, preterm birth or irreversible brain abnormalities, including microcephaly. So far, there is no effective remedy for ZIKV infection, mainly due to the limited ability of antiviral drugs to cross blood–placental and/or blood– brain barriers (BPB and BBB, respectively). Despite its restricted permeability, the BBB is penetrable by a variety of molecules, mainly peptide-based, and named BBB peptide shuttles (BBBpS), able to ferry various payloads (e.g., drugs, antibodies, etc.) into the brain. Recently, we have described peptide– porphyrin conjugates (PPCs) as successful BBBpS-associated drug leads for HIV, an enveloped virus in which group ZIKV also belongs. Herein, we report on several brain-directed, low-toxicity PPCs capable of targeting ZIKV. One of the conjugates, PP-P1, crossing both BPB and BBB, has shown to be effective against ZIKV (IC<sup>50</sup> 1.08 µM) and has high serum stability (t1/2 ca. 22 h) without altering cell viability at all tested concentrations. Peptide–porphyrin conjugation stands out as a promising strategy to fill the ZIKV treatment gap.

**Keywords:** peptide-drug conjugates; blood–brain barrier; blood–placental barrier; Zika virus; BBB shuttles; porphyrins; antivirals
