Characterization of new synthetic or natural compounds with broad spectrum or dual antiviral activity in HIV-1 treatment

Abstract

In recent years many advances have been made in the fight against HIV-1 infection. However, the lack of a vaccine, together with the increasing resistance to the highly active anti-retroviral therapy (HAART), make HIV-1 infection still a serious global emergency. Development of inhibitors that operate by a novel mechanism of action could expand the options for clinicians to address these unmet medical needs for the HIV-1-infected patient population or could represent novel options for an effective prevention. In this contest, one possibility is the development of single drug with multiple targets binding, such as the natural compound kuwanon-L. Derived from the computational identification of novel potential allosteric inhibitors of HIV integrase, in this thesis kuwanon-L has been further characterised in enzymatic assays to evaluate its activity in vitro. Moreover, kuwanon-L was tested in cellular-based assays to confirm its antiviral activity also on viral strains. Finally, its mechanism of action was further investigated through a time-of-addition (TOA) experiment and its innovative dual mode of action on both HIV integrase and reverse transcriptase was confirmed in enzymatic assays. On the other hand, compounds with novel mechanisms of action and targeting very early steps of viral life cycle, as the novel series of rhodanine derivatives investigated in the second part of this work, may represent potent anti-HIV-1 agents suitable for prevention approaches. Their activity not only on HIV but also on other sexually transmitted infections such as HSV-1/2 viruses, and their favourable pharmacokinetic profile further emphasize their usage as topical microbicides in pre-exposure prophylaxis (PrEP) approaches