Antiviral-hyperactivation limiting therapeutics for the treatment of viral diseases and cancer

Current anti-HIV drugs target several of viral enzymes that HIV requires to replicate and survive. Hyperactivation of the immune system is now recognized as the major driver of progression to AIDS and of the emergence of both AIDS-defining and non-AIDS events which negatively impact upon morbidity and mortality despite fully suppressive ART. AV-HALTs are a new class of antiretrovirals that both reduce HIV replication and excessive immune activation. By targeting a human rather than a viral enzyme the chances of the virus developing resistance are decreased, an improvement over traditional antiretroviral drugs. The proof of concept for this new class of drugs was achieved with a Phase IIa study in which the HU/ddI combination (first generation AV-HALTs) safely achieved the goals established for the AV-HALT class. The idea of AV-HALTs was further expanded in order to join both the antiproliferative and antiviral activities into a single molecule. CDK9 inhibitors were tested with the goal to identify second generation AV-HALTs. Compounds with good toxicity and activity profile were moved to preclinical development and were tested for ADME properties and preliminary in vivo experiments in rodent species. In addition, CDK9 inhibitors were found to be active against other viruses such as HSV-1, HSV-2, EBV and HPV. This class of compounds also proved to inhibit proliferation of tumor cells both in vitro and in vivo