Current standard-of-care antiviral regimens rely on direct-acting antivirals (DAAs) possessing inherent liabilities. DAAs are generally active against only one virus or a closely related, family of viruses. Because a viral protein is targeted, the virus can readily develop resistance mutations. To address the shortcomings of DAAs, FORGE Life Science is developing host-targeted antivirals (HTAs). HTAs have the potential to block the growth of multiple different viruses. Since a host-cell protein is targeted, viruses are much less likely to evolve drug resistance. Specifically, FORGE is developing small molecule drugs that target human sirtuin proteins. Sirtuins are a family of seven protein-deacylases that modulate many cellular processes critical for virus replication. This proposal seeks to develop a sirtuin-modulating drug that is simultaneously effective against multiple different opportunistic viruses causing life-threatening disease in immunosuppressed transplant patients. Initially, the program is focused on human cytomegalovirus (HCMV). In Phase 1, a chemical series of uncompetitive sirtuin 2 (SIRT2) inhibitors was developed that block the production of HCMV progeny in cultured human cells more potently than standard-of-care, ganciclovir. Strikingly, these SIRT2 inhibitors not only affect HCMV, but they also inhibited the growth of influenza A and B, hepatitis B and C viruses, and the polyomaviruses, BKV and JCV. The compound series demonstrates structure activity relationship to antiviral potency, excellent oral bioavailability, and good tolerability in mice. In vivo validation of anti-HCMV activity was achieved in immunosuppressed mice carrying human lung-tissue implants. This application proposes to move the program forward to SBIR Phase II to optimize a development candidate for progression into preclinical development.
Three aims will be pursued. (1) A mouse model supporting development of recently approved DAA letermovir will be adapted for use with SIRT2 inhibitors. This model allows for HCMV infection of human fibroblasts seeded to a Gelfoam implant placed into immunodeficient SCID mice. (2) A medicinal chemistry campaign will refine the current lead SIRT2 inhibitor to improve anti-HCMV activity in the Gelfoam/SCID mouse with a target to achieve a therapeutic index equivalent or better than oral-dosing valganciclovir and letermovir. The selected development candidate will additionally satisfy in vitro ADME and pharmaceutical criteria, including minimizing drug-drug interactions, for administration to transplant patients. (3) Compounds demonstrating sufficient efficacy in the Gelfoam/SCID mouse model will be validated with respect to providing a high barrier to acquired viral drug-resistance and to synergize with existing direct-acting antivirals. The pan-viral profile will be expanded to multiple opportunistic viruses. This project has the potential to produce a paradigm shift, introducing broad-spectrum antivirals that solve the problem of viral resistance.
An overwhelming number of Americans require immune suppression of variable duration at some point in their lives due to various diseases from asthma to HIV to rheumatologic diseases to organ transplant - during the time at which their immune system is being suppressed these individuals are at great risk for developing an opportunistic viral infection. Standard of care therapeutic interventions for these patients are restricted by highly focused targeting of only select pathogens, the emergence of drug resistant strains, drug:drug interactions and adverse side effects. Successful completion of this application will result in the development of broad based antiviral compounds that 1) provide protection against highly diverse viruses, 2) limit the acquisition of drug resistance and 3) limit the liabilities associated with adverse side effects observed with current antivirals.
