Biochemical and x-ray structural studies show that the drug binds to sirtuin 2 and allosterically inhibits its deacetylase activity. We have developed a family of compounds that modulate sirtuin 2, an NAD+-dependent deacylase, and now report the properties of a member of that family, FLS-359. The broad-spectrum activity achieved by host targeting can be especially useful in combating emerging viruses and for treatment of diseases caused by multiple viral pathogens, such as opportunistic agents in immunosuppressed patients. Host-targeted antivirals can overcome these limitations. They inhibit a single virus or virus family, and the pathogen can readily evolve resistance.

Most drugs used to treat viral disease target a virus-coded product. Thus, in sharp contrast to PARP9 enhancement of type I IFN production in viral infections, this member of the MAR family plays a protective role by limiting type I IFN responses during TB. tuberculosis susceptibility is type I IFN dependent, as blockade of IFN α receptor (IFNAR) signaling reversed the enhanced susceptibility of Parp9–/– mice. Thus, Parp9-deficient mice were susceptible to Mycobacterium tuberculosis infection and exhibited increased TB disease, cGAS and 2′3′-cyclic GMP-AMP (cGAMP) expression, and type I IFN production, along with upregulation of complement and coagulation pathways. Here, we show that PARP9 mRNA encoding the MARylating PARP9 enzyme was upregulated during TB in humans and mice and provide evidence of a critical modulatory role for PARP9 in DNA damage, cyclic GMP–AMP synthase (cGAS) expression, and type I IFN production during TB. Although PARP9 mRNA expression is significantly increased in progressive tuberculosis (TB) in humans, its participation in host immunity to TB is unknown. PARPs are classified on the basis of their ability to catalyze poly-ADP-ribosylation (PARylation) or mono-ADP-ribosylation (MARylation). The ADP ribosyltransferases (PARPs 1–17) regulate diverse cellular processes, including DNA damage repair. Despite limited clinical success to date, as we continue to refine our understanding of tau’s pathogenic mechanism(s) in different neurodegenerative diseases, we remain optimistic that tau-targeting therapies will eventually play a central role in the treatment of tauopathies. Innovative approaches to human clinical trials can help address some of the difficulties that have plagued our field’s development of tau-targeting therapies thus far. We discuss possible reasons for failures of these therapies, such as use of imperfect nonclinical models that do not predict human effects for drug development heterogeneity of human tau pathologies which may lead to variable responses to therapy and ineffective therapeutic mechanisms, such as targeting of the wrong tau species or protein epitope. We review what is known about tau biology, genetics, and therapeutic mechanisms that have been tested in clinical trials to date. However, a number of tau-targeting therapies with various mechanisms of action have shown little promise in clinical trials in different tauopathies. Multiple lines of evidence from human disease, as well as nonclinical translational models, suggest that tau has a central pathologic role in these disorders, historically thought to be primarily related to tau gain of toxic function. Tauopathies are disorders associated with tau protein dysfunction and insoluble tau accumulation in the brain at autopsy.

Cyclic amp signaling pathway