Maria Antonietta Madeddu

Study of the biological activity of novel synthetic compounds with antiviral properties against human rhinoviruses.

Picornaviridae represent a very large family of small RNA viruses, some of which are the cause of important human and animal diseases. Since no specific therapy against any of these viruses currently exists, palliative symptomatic treatments are employed. The early steps of the picornavirus replicative cycle seem to be privileged targets for some antiviral compounds like disoxaril and pirodavir. Pirodavir’s main weakness is its cytotoxicity on cell cultures at relatively low doses. In this work some original synthetic compounds were tested, in order to find less toxic compounds with an improved protection index (PI) on infected cells. Using an amino group to substitute the oxygen atom in the central chain, such as that in the control molecule pirodavir, resulted in decreased activity against Rhinoviruses and Polioviruses. The presence of an -ethoxy-propoxy- group in the central chain (as in compound I-6602) resulted in decreased cell toxicity and in improved anti-Rhinovirus activity. This compound actually showed a PI >700 on HRV14, while pirodavir had a PI of 250. These results demonstrate that modification of pirodavir’s central hydrocarbon chain can lead to the production of novel derivatives with low cytotoxicity and improved PI against some strains of Rhinoviruses.

Autophagy activation and antiviral activity by a licorice triterpene

The triterpene glycyrrhizic acid (GRA), the main product from the Glycyrrhiza glabra medicinal plant, is known for its antiinflammatory and antimicrobial activity. In this work, GRA was studied for its ability to induce the autophagic process activator Beclin 1 in epithelial cells and to observe how this property could influence its antiviral activity. After 24 h of treatment, GRA induced a Beclin 1 production that was more than twofold higher than that produced by rapamycin, used as a reference compound. When the compounds were added to HeLa cells together with the viruses, GRA demonstrated a strong antiherpes simplex virus type 1 (HSV1) activity, whereas rapamycin had no activity. However, if the compounds were added to the cells 24 h before the viruses, GRA induced the production of an even higher amount of Beclin 1 and showed an improved antiviral effect; under these conditions, rapamycin was also able to exert a significant anti‐HSV1 activity. In conclusion, GRA is a strong inducer of the autophagy activator Beclin 1, which establishes a resistance state to HSV1 replication. Copyright

High Prevalence of Human Herpesvirus 8 Infection in Diabetes Type 2 Patients and Detection of a New Virus Subtype

The prevalence of Human Herpesvirus 8 (HHV8) DNA and antiviral antibodies in Diabetes type 2 (DM2) and control subjects was studied, in order to confirm a possible link between DM2 and HHV8 infection. The HHV8-DNA from diabetic patients was typed for detecting possible genomic differences with known HHV8 reference viruses.DM2 patients and healthy controls were examined for the presence of HHV8 DNA into the peripheral blood lymphocytes. Both anti-lytic and latent phase antibodies were detected in HHV8 positive and negative diabetic patients, as well in a number of controls. The HHV8 ORF K1 and ORF 26 genes from DM2 patients were typed and matched to reference strains.A significant prevalence of HHV8 DNA in DM2 subjects versus healthy controls was detected (about 58 % against 27 %). Anti-lytic phase, but not anti-latent phase antibodies, were significantly increased in DM2 patients versus controls. In addition, about 30 % of HHV8 strains isolated from DM2 lymphocytes showed consistent differences in the ORF 26 gene sequence, so that a new HHV8 subtype was proposed. These findings give additional support to the hypothesis that HHV8 could be considered an additional risk factor for DM2 onset.