作者: Gewirtz, Andrew T. ; Lieber, Carolin M. ; Sobolik, Elizabeth B. ; Suthar, Mehul S. ; Ngo, Vu L. ; Natchus, Michael G. ; Kolykhalov, Alexander A. ; Plemper, Richard K. ; Greninger, Alexander L. ; Sticher, Zachary M. ; Kang, Hae-Ji

ABSTRACT Immunocompromised people are at high risk of prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and progression to severe coronavirus disease 2019 (COVID-19). However, the efficacy of late-onset direct-acting antiviral (DAA) therapy with therapeutics in clinical use and experimental drugs to mitigate persistent viral replication is unclear. In this study, we employed an immunocompromised mouse model, which supports prolonged replication of SARS-CoV-2 to explore late-onset treatment options. Tandem immuno-depletion of CD4 + and CD8 + T cells in C57BL/6 mice followed by infection with SARS-CoV-2 variant of concern (VOC) beta B.1.351 resulted in prolonged infection with virus replication for 5 weeks after inoculation. Early-onset treatment with nirmatrelvir/ritonavir (paxlovid) or molnupiravir was only moderately efficacious, whereas the experimental therapeutic 4’-fluorouridine (4’-FlU, EIDD-2749) significantly reduced virus load in the upper and lower respiratory compartments 4 days postinfection (dpi). All antivirals significantly lowered virus burden in a 7-day treatment regimen initiated 14 dpi, but paxlovid-treated animals experienced rebound virus replication in the upper respiratory tract 7 days after treatment end. Viral RNA was detectable 28 dpi in paxlovid-treated animals, albeit not in the molnupiravir or 4’-FlU groups, when treatment was initiated 14 dpi and continued for 14 days. Low-level virus replication continued 35 dpi in animals receiving vehicle but had ceased in all treatment groups. These data indicate that late-onset DAA therapy significantly shortens the duration of persistent virus replication in an immunocompromised host, which may have implications for clinical use of antiviral therapeutics to alleviate the risk of progression to severe disease in highly vulnerable patients. IMPORTANCE Four years after the onset of the global coronavirus disease 2019 (COVID-19) pandemic, the immunocompromised are at greatest risk of developing life-threatening severe disease. However, specific treatment plans for this most vulnerable patient group have not yet been developed. Employing a CD4 + and CD8 + T cell-depleted immunocompromised mouse model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we explored therapeutic options of persistent infections with standard-of-care paxlovid, molnupiravir, and the experimental therapeutic 4’-fluorouridine (4’-FlU). Late-onset treatment initiated 14 days after infection was efficacious, but only 4’-FlU was rapidly sterilizing. No treatment-experienced viral variants with reduced susceptibility to the drugs emerged, albeit virus replication rebounded in animals of the paxlovid group after treatment end. This study supports the use of direct-acting antivirals (DAAs) for late-onset management of persistent SARS-CoV-2 infection in immunocompromised hosts. However, treatment courses likely require to be extended for maximal therapeutic benefit, calling for appropriately powered clinical trials to meet the specific needs of this patient group.

2024-06-12·mBio

4′-Fluorouridine inhibits alphavirus replication and infection in vitro and in vivo

Article

作者: Sticher, Zachary ; Kielian, Margaret ; Wang, Sainan ; Yin, Peiqi ; Merits, Andres ; Parks, M Guston ; Lello, Laura Sandra ; Fayed, Atef ; Morrison, Thomas E ; Kolykhalov, Alexander A ; Drobish, Adam M ; Painter, George R ; May, Nicholas A ; Natchus, Michael G ; Andrews, Meghan

ABSTRACT Chikungunya virus (CHIKV) is an enveloped, positive-sense RNA virus that has re-emerged to cause millions of human infections worldwide. In humans, acute CHIKV infection causes fever and severe muscle and joint pain. Chronic and debilitating arthritis and joint pain can persist for months to years. To date, there are no approved antivirals against CHIKV. Recently, the ribonucleoside analog 4′-fluorouridine (4′-FlU) was reported as a highly potent orally available inhibitor of SARS-CoV-2, respiratory syncytial virus, and influenza virus replication. In this study, we assessed 4′-FlU’s potency and breadth of inhibition against a panel of alphaviruses including CHIKV, and found that it broadly suppressed alphavirus production in cell culture. 4′-FlU acted on the viral RNA replication step, and the first 4 hours post-infection were the critical time for its antiviral effect. In vitro replication assays identified nsP4 as the target of inhibition. In vivo , treatment with 4′-FlU reduced disease signs, inflammatory responses, and viral tissue burden in mouse models of CHIKV and Mayaro virus infection. Treatment initiated at 2 hours post-infection was most effective; however, treatment initiated as late as 24–48 hours post-infection produced measurable antiviral effects in the CHIKV mouse model. 4′-FlU showed effective oral delivery in our mouse model and resulted in the accumulation of both 4′-FlU and its bioactive triphosphate form in tissues relevant to arthritogenic alphavirus pathogenesis. Together, our data indicate that 4′-FlU inhibits CHIKV infection in vitro and in vivo and is a promising oral therapeutic candidate against CHIKV infection. IMPORTANCE Alphaviruses including chikungunya virus (CHIKV) are mosquito-borne positive-strand RNA viruses that can cause various diseases in humans. Although compounds that inhibit CHIKV and other alphaviruses have been identified in vitro , there are no licensed antivirals against CHIKV. Here, we investigated a ribonucleoside analog, 4′-fluorouridine (4′-FlU), and demonstrated that it inhibited infectious virus production by several alphaviruses in vitro and reduced virus burden in mouse models of CHIKV and Mayaro virus infection. Our studies also indicated that 4′-FlU treatment reduced CHIKV-induced footpad swelling and reduced the production of pro-inflammatory cytokines. Inhibition in the mouse model correlated with effective oral delivery of 4′-FlU and accumulation of both 4′-FlU and its bioactive form in relevant tissues. In summary, 4′-FlU exhibits potential as a novel anti-alphavirus agent targeting the replication of viral RNA.

2024-04-16·Journal of Virology

Modeling Heartland virus disease in mice and therapeutic intervention with 4′-fluorouridine

Article

作者: Gowen, Brian B. ; Van Wettere, Arnaud J. ; Westover, Jonna B. ; Painter, George R. ; Kolykhalov, Alexander A. ; Ikegami, Tetsuro ; Jung, Kie Hoon ; Saindane, Manohar T. ; Mao, Shuli ; Rojas, Inioska ; Bluemling, Gregory R. ; Alkan, Cigdem ; Thomas, Aaron J. ; Bates, Paul ; Boardman, Kirsten M. ; Hicks, Philip ; Natchus, Michael G. ; Martens, Craig

ABSTRACTHeartland virus (HRTV) is an emerging tick-borne bandavirus that causes a febrile illness of varying severity in humans, with cases reported in eastern and midwestern regions of the United States. No vaccines or approved therapies are available to prevent or treat HRTV disease. Here, we describe the genetic changes, natural history of disease, and pathogenesis of a mouse-adapted HRTV (MA-HRTV) that is uniformly lethal in 7- to 8-week-old AG129 mice at low challenge doses. We used this model to assess the efficacy of the ribonucleoside analog, 4′-fluorouridine (EIDD-2749), and showed that once-daily oral treatment with 3 mg/kg of drug, initiated after the onset of disease, protects mice against lethal MA-HRTV challenge and reduces viral loads in blood and tissues. Our findings provide insights into HRTV virulence and pathogenesis and support further development of EIDD-2749 as a therapeutic intervention for HRTV disease.IMPORTANCEMore than 60 cases of HRTV disease spanning 14 states have been reported to the United States Centers for Disease Control and Prevention. The expanding range of the Lone Star tick that transmits HRTV, the growing population of at-risk persons living in geographic areas where the tick is abundant, and the lack of antiviral treatments or vaccines raise significant public health concerns. Here, we report the development of a new small-animal model of lethal HRTV disease to gain insight into HRTV pathogenesis and the application of this model for the preclinical development of a promising new antiviral drug candidate, EIDD-2749. Our findings shed light on how the virus causes disease and support the continued development of EIDD-2749 as a therapeutic for severe cases of HRTV infection.

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适应症	最高研发状态	国家/地区	公司	日期
沙粒病毒科感染	临床前	美国	Emory University	2022-10-27
新型冠状病毒感染	临床前	美国	Georgia State University	2022-01-14
新型冠状病毒感染	临床前	美国	Emory University	2022-01-14
呼吸道合胞体病毒感染	临床前	美国	Georgia State University	2022-01-14
呼吸道合胞体病毒感染	临床前	美国	Emory University	2022-01-14
基孔肯雅热	临床前	美国	Drug Innovation Ventures At Emory LLC	-