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Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin ( HTT ) gene. Consequently, the mutant protein is ubiquitously expressed and drives pathogenesis of HD through a toxic gain-of-function mechanism. Animal models of HD have demonstrated that reducing huntingtin (HTT) protein levels alleviates motor and neuropathological abnormalities. Investigational drugs aim to reduce HTT levels by repressing HTT transcription, stability or translation. These drugs require invasive procedures to reach the central nervous system (CNS) and do not achieve broad CNS distribution. Here, we describe the identification of orally bioavailable small molecules with broad distribution throughout the CNS, which lower HTT expression consistently throughout the CNS and periphery through selective modulation of pre-messenger RNA splicing. These compounds act by promoting the inclusion of a pseudoexon containing a premature termination codon (stop-codon psiExon), leading to HTT mRNA degradation and reduction of HTT levels. Here the authors describe the discovery of a class of small molecule splicing modifiers which are orally bioavailable, cross the blood-brain barrier, and lower levels of huntingtin in a mouse model of Huntington’s disease (HD).

The nucleoside analogue ribavirin has antiviral activity against many distinct viruses both in vitro and in vivo. Five distinct mechanisms have been proposed to explain the antiviral properties of ribavirin. These include both indirect mechanisms (inosine monophosphate dehydrogenase inhibition, immunomodulatory effects) and direct mechanisms (interference with RNA capping, polymerase inhibition, lethal mutagenesis). Recent concerns about bioterrorism have renewed interest in exploring the antiviral activity of ribavirin against unique viruses. In this paper, we review the proposed mechanisms of action with emphasis on recent discoveries, as well as the implications of ribavirin resistance. Evidence exists to support each of the five proposed mechanisms of action, and distinct virus/host combinations may preferentially favour one or more of these mechanisms during antiviral therapy. Copyright © 2005 John Wiley & Sons, Ltd.

Despite advances in antiretroviral therapy, HIV-1 infection remains incurable in patients and continues to present a significant public health burden worldwide. While a number of factors contribute to persistent HIV-1 infection in patients, the presence of a stable, long-lived reservoir of latent provirus represents a significant hurdle in realizing an effective cure. One potential strategy to eliminate HIV-1 reservoirs in patients is reactivation of latent provirus with latency reversing agents in combination with antiretroviral therapy, a strategy termed \"shock and kill\". This strategy has shown limited clinical effectiveness thus far, potentially due to limitations of the few therapeutics currently available. We have identified a novel class of benzazole compounds effective at inducing HIV-1 expression in several cellular models. These compounds do not act via histone deacetylase inhibition or T cell activation, and show specificity in activating HIV-1 in vitro. Initial exploration of structure-activity relationships and pharmaceutical properties indicates that these compounds represent a potential scaffold for development of more potent HIV-1 latency reversing agents.

The coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-CoV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally available compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS CoV-2 replication (EC50 range, 2.0 to 31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known DHODH requirements for immunomodulatory cytokine production, PTC299 inhibited the production of interleukin (IL)-6, IL-17A (also called IL-17), IL-17F, and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and previously established favorable pharmacokinetic and human safety profiles render PTC299 a promising therapeutic for COVID-19. Competing Interest Statement J.L, E.M., S.B, C. S-D.-C., E.L.S., Y.W, and V.S. have no conflict of interest to declare. S.P. and R.S. received support from PTC Therapeutics for this work. J.D.G, L.C, M.W, C.T-L., N.A.N, J.M.C, M.P. E.M.W., K. O K., R.K, E.G., A.J. and S.P. are or were employed by PTC Therapeutic and have received salary compensation for time, effort, and hold or held financial interest in the company.

RNA viruses are responsible for numerous human diseases; some of these viruses are also potential agents of bioterrorism. In general, the replication of RNA viruses results in the incorporation of at least one mutation per round of replication, leading to a heterogeneous population, termed a qua-sispecies. The antiviral nucleoside ribavirin has been shown to cause an increase in the mutation frequency of RNA viruses. This increase in mutation frequency leads to a loss of viability due to error catastrophe. In this article, we review lethal mutagenesis as an antiviral strategy, emphasizing the challenges remaining for the development of lethal mutagenesis into a practical clinical approach.

HIV type-1 (HIV-1) can establish a state of latency in infected patients, most notably in resting CD4+ T-cells. This long-lived reservoir allows for rapid re-emergence of viraemia upon cessation of highly active antiretroviral therapy, even after extensive and seemingly effective treatment. Successful depletion of such latent reservoirs is probably essential to ‘cure’ HIV-1 infection and will require therapeutic agents that can specifically and efficiently act on cells harbouring latent HIV-1 provirus. The mechanisms underlying HIV-1 latency are not well characterized, and it is becoming clear that numerous factors, both cell- and virus-derived, are involved in the maintenance of proviral latency. The interplay of these various factors in the context of viral reactivation is still poorly understood. In this article, we review the current knowledge regarding the mechanisms underlying maintenance of HIV-1 latency, both transcriptional and post-transcriptional, with a focus on potential targets that might be exploited to therapeutically purge latent proviral reservoirs from infected patients.

RNA viruses exhibit increased mutation frequencies relative to other organisms. Recent work has attempted to exploit this unique feature by increasing the viral mutation frequency beyond an extinction threshold, an antiviral strategy known as lethal mutagenesis. A number of novel nucleoside analogs have been designed around this premise. Herein, we review the quasispecies nature of RNA viruses and survey the antiviral, biological and biochemical characteristics of mutagenic nucleoside analogs, including clinically-used ribavirin. Biological implications of modulating viral replication fidelity are discussed in the context of translating lethal mutagenesis into a clinically-useful antiviral strategy.

Viruses with RNA genomes constitute a broad class of medically important pathogens, including HIV and hepatitis C virus. Despite extensive research, few effective antiviral drugs exist to treat RNA virus infection. Thus, the development of new antiviral drugs, and, more importantly, new antiviral strategies, is an essential medical research goal. RNA viruses replicate at a high error frequency, resulting in the generation of a highly diverse virus population termed a quasispecies. It has been postulated that RNA viruses exist at or near the error rate that allows optimal evolutionary flexibility while still maintaining viability of the viral genome. However, it has been shown that increasing the inherent mutation rate just slightly can lead to \"genetic meltdown\", wherein the error rate is too high to maintain virus viability. This has led to the idea of \"lethal mutagenesis\" as an antiviral strategy, whereby drugs that can increase the mutation rate of an RNA virus can be administered in order to induce such a genetic meltdown in virus population, driving them to extinction. Work with the antiviral nucleoside ribavirin has suggested that such a mechanism may already be in clinical use. Furthermore, extensive research in the past decade has shown that lethal mutagenesis may be a broadly applicable strategy against a wide variety of RNA viruses. The work contained herein describes the synthesis and biological and biochemical evaluation of nucleoside analogs predicted to act as lethal mutagens of RNA viruses. Our hypothesis was that lethal mutagenesis is a viable broad-spectrum antiviral strategy for combating clinical RNA virus infection. As such, our goals were three-fold: (1) validate lethal mutagenesis as an antiviral strategy in vitro; (2) improve upon the mutagenic properties of ribavirin by developing more effective lethal mutagens as potential lead compounds for drug development; and (3) begin to understand the biological implications of lethal mutagenesis as an antiviral strategy. Our work in this regard is described in the following pages. Chapter 2 describes our efforts to synthesize novel mutagenic cytidine analogs as lethal mutagens, based on previous work with 2'-deoxyribonucleosides and HIV. Chapter 3 describes our antiviral investigations with the highly mutagenic pyrimidine analog, rP. Chapter 4 covers work with a series of substituted purine analogs that were found to be effective viral mutagens in cell culture. Chapter 5 explains the differences observed between related viruses in their susceptibility to lethal mutagenesis. Finally, Chapter 6 provides conclusions and future directions for work involving lethal mutagenesis as an antiviral strategy.