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Antiviral drugs can substantially reduce illness and deaths from human infections. For example, antiretroviral therapy has prevented millions of HIV/AIDS deaths globally since the late 1980s (1). During the 2009 [...]

We evaluated the population-level benefits of expanding treatment with the antiviral drug Paxlovid (nirmatrelvir/ritonavir) in the United States for SARS-CoV-2 Omicron variant infections. Using a multiscale mathematical model, we found that treating 20% of symptomatic case-patients with Paxlovid over a period of 300 days beginning in January 2022 resulted in life and cost savings. In a low-transmission scenario (effective reproduction number of 1.2), this approach could avert 0.28 million (95% CI 0.03-0.59 million) hospitalizations and save US $56.95 billion (95% CI US $2.62-$122.63 billion). In a higher transmission scenario (effective reproduction number of 3), the benefits increase, potentially preventing 0.85 million (95% CI 0.36-1.38 million) hospitalizations and saving US $170.17 billion (95% CI US $60.49-$286.14 billion). Our findings suggest that timely and widespread use of Paxlovid could be an effective and economical approach to mitigate the effects of COVID-19. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.tips.2009.03.002 Byline: Robert M. Krug (1), James M. Aramini (2) Abstract: The potential threat of a pandemic caused by H5N1 influenza A viruses has stimulated increased research on developing new antivirals against influenza A viruses. Current antivirals are directed against the M2 protein (named adamantanes) and the neuraminidase (named zanamivir and oseltamivir). However, both seasonal and H5N1 influenza A viruses have developed resistance to adamantanes and oseltamivir. Accordingly, new antivirals directed at the M2 and neuraminidase proteins, and against the hemagglutinin protein, are being developed. In addition, elucidation of the structural basis for several crucial functions of other viral proteins (specifically the non-structural NS1A protein, the nucleoprotein and the viral polymerase) has identified novel targets for the development of new antivirals. Here, we describe how functional and structural studies led to the discovery of these novel targets and also how structural information is facilitating the rational design of new drugs against previously identified targets. Author Affiliation: (1) Institute for Cellular and Molecular Biology, Section of Molecular Genetics and Microbiology, University of Texas at Austin, Austin, TX 78712, USA (2) Center for Advanced Biotechnology and Medicine, Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA

Ubiquitin- (Ub) like proteins (Ubls) are conjugated to their targets by an enzymatic cascade involving an E1 activating enzyme, an E2 conjugating enzyme, and in some cases an E3 ligase. ISG15 is a Ubl that is conjugated to cellular proteins after IFN-[alpha]/[beta] stimulation. Although the E1 enzyme for ISG15 (Ube1L/[E1.sup.ISG15]) has been identified, the identities of the downstream components of the ISG15 conjugation cascade have remained elusive. Here we report the purification of an E2 enzyme for ISG15 and demonstrate that it is UbcH8, an E2 that also functions in Ub conjugation. In vitro assays with purified Ub E2 enzymes and in vivo RNA interference assays indicate that UbcH8 is a major E2 enzyme for ISG15 conjugation. These results indicate that the ISG15 conjugation pathway overlaps or converges with the Ub conjugation pathway at the level of a specific E2 enzyme. Furthermore, these results raise the possibility that the ISG15 conjugation pathway might use UbcH8competent Ub ligases in vivo. As an initial test of this hypothesis, we have shown that a UbcH8-competent Ub ligase conjugates ISG15 to a specific target in vitro. These results challenge the concept that Ub and Ubl conjugation pathways are strictly parallel and nonoverlapping and have important implications for understanding the regulation and function of ISG15 conjugation in the IFN-[alpha]/[beta] response.