Novel antiviral strategies against known and emerging viruses

Viral infections represent a significant burden to societies worldwide, both in terms of morbidity and mortality and high economical toll. From a therapeutical standpoint, only a low number of antiviral drugs are approved, and most treatments are virus-specific and limited in safety. Thus, there is an urgent need to develop novel antiviral strategies. During the PhD program, I investigated different fields in the area of drug discovery and development for the treatment of infectious diseases, focusing on respiratory viruses (i.e., coronaviruses, rhinoviruses, adenoviruses, respiratory syncytial viruses) and herpetic viruses (i.e., herpes simplex viruses, cytomegalovirus). These multidisciplinary studies were performed in collaboration with national and international Universities and Institutions, following a translational approach. A major line of research focused on the discovery of novel antiviral molecules, starting from compounds/molecules/peptides produced or isolated in the context of collaborations with various groups of chemists. The antiviral activity of 4-(3-phenylsulfonylindol-2-yl)-1-(pyridin-2- yl)piperazinyl-methanones was demonstrated against beta-coronaviruses, via the putative inhibition of the highly conserved viral main protease (doi: 10.1021/acsinfecdis.4c00108). Moreover, the polyoxometalate Ti2PW10 was identified as potent inhibitor of various respiratory viruses, with good biocompatibility on cell lines and human nasal epithelia, broad-spectrum activity, and absence of antiviral resistance development (doi: 10.1016/j.antiviral.2024.105897). In addition, the peptide A-3302-B, isolated from a marine bacterium, was shown to exert inhibition against HSV- 2, preventing the egress of virus progeny from infected cells (doi: 10.3390/ijms23020947). A second line of study employed a drug repositioning approach to identify novel anti-coronavirus compounds. The active sites of coronaviral proteins were screened in silico against a public database of approved/investigational drugs, and the antipsychotic drug lurasidone was identified as an antiviral candidate against beta-coronaviruses (doi: 10.1016/j.antiviral.2021.105055). The follow-up study demonstrated that lurasidone acted via the inhibition of a viral protease conserved among human coronaviruses, and a specific additional inhibitory effect only against SARS-CoV-2 involving the spike:ACE2 interaction inhibition (doi: 10.3389/fcimb.2024.1487604). Against herpesviruses infections, a nanomedicinal approach was also employed, in view of a topical microbicide for genital herpes. The anti-herpetic drug valacyclovir was developed as nanodroplet formulation optimized for vaginal delivery, showing enhanced antiviral activity compared to the drug alone in in vitro cell models (doi: 10.3390/microorganisms11102460). A complementary research study focusing on COVID-19 vaccination showed that immunosuppressive drug-treated multiple sclerosis patients developed comparable levels of humoral and cellular immunity after vaccine booster compared to healthy subjects, lasting six months after vaccination (doi: 10.3389/fimmu.2023.1205879). Another complementary study on the anti-HCMV activity of pasteurized human milk (HM) demonstrated that a 2.5 °C reduction of heat treatment significantly preserved the IgA content and fully restored the anti-HCMV activity of HM, supporting this variant of pasteurization as a valid alternative for HM banks to preserve HM bioactivities (doi: 10.1038/s41390-023-02606-1). Overall, the data produced over the course of my PhD program contributed to the knowledge on the vast world of viruses, on the one hand proposing novel antiviral strategies to tackle common viral infections with high impact in humans, and on the other hand gaining insights on virus-related conditions to help and guide clinical practice and decision making.