Search Results (7)

The replication machinery of SARS-CoV-2 is a primary target for therapeutic intervention, and has led to significant progress in antiviral medication discovery. This review consolidates contemporary molecular insights into viral replication and rigorously assesses treatment methods at different phases of viruses’ clinical development. Direct-acting antivirals, such as nucleoside analogs (e.g., remdesivir, molnupiravir) and protease inhibitors (e.g., nirmatrelvir), have shown clinical effectiveness in diminishing morbidity and hospitalization rates. Simultaneously, host-targeted medicines like baricitinib, camostat, and brequinar leverage critical host–virus interactions, providing additional pathways to reduce viral replication while possibly minimizing the development of resistance. Notwithstanding these advancements, constraints in distribution methods, antiviral longevity, and the risk of mutational evasion demand novel strategies. Promising investigational approaches encompass CRISPR-mediated RNA degradation systems, inhalable siRNA-nanoparticle conjugates, and molecular glue degraders that target host and viral proteins. Furthermore, next-generation treatments aimed at underutilized enzyme domains (e.g., NiRAN, ExoN) and host chaperone systems (e.g., TRiC complex) signify a transformative approach in antiviral targeting. The integration of high-throughput phenotypic screening, AI-driven medication repurposing, and systems virology is transforming the antiviral discovery field. An ongoing interdisciplinary endeavor is necessary to convert these findings into versatile, resistance-resistant antiviral strategies that are applicable beyond the present pandemic and in future coronavirus epidemics. Full article

Background/Objectives: Medulloblastoma (MB) is the most common high-grade paediatric brain tumour, with group 3 MB patients having the worst prognosis. A high prevalence of group 3 tumours shows overexpression of the MYC oncogene, making it a potential therapeutic target. However, attempts to directly inhibit MYC have so far demonstrated limited success. Dihydroorotate dehydrogenase (DHODH), a crucial enzyme of the pyrimidine biosynthesis process, has emerged as an up-and-coming target in oncology, as its inhibition has shown promise in several cancers. Methods: In this study, we investigated the efficacy of brequinar, a DHODH inhibitor, in MB, with a focus on group 3. In vitro, BRQ’s effects on cell viability and MYC expression were tested in seven MB cell lines. In vivo, a novel zebrafish xenograft model was used to evaluate BRQ’s impact on tumour growth and toxicity. Results: High DHODH expression was identified in group 3 and shh MB subgroups, correlating with poor survival and MYC expression. BRQ demonstrated nanomolar efficacy in inducing apoptosis and reducing MYC expression in group 3 MB cell lines. Finally, we established a novel zebrafish xenograft model and demonstrated that BRQ significantly inhibited tumour growth at non-toxic concentrations in vivo, particularly in the D458 metastatic MB cell line. Conclusions: Our findings indicate that DHODH is a promising therapeutic target in group 3 MBs. Furthermore, BRQ shows potential for clinical application, effectively reducing tumour growth and MYC expression in vitro and in vivo. Moreover, our newly established zebrafish xenograft model offers a promising avenue for rapid in vivo drug testing for use in MB. Full article

Ferroptosis exhibits a potent antitumor effect and dihydroorotate dehydrogenase (DHODH) has recently been identified as a novel ferroptosis defender. However, the role of DHODH inhibition in cervical cancer cells is unclear, particularly in synergy with cisplatin via ferroptosis. Herein, shRNA and brequinar were used to knock down DHODH and directly inhibit DHODH, respectively. Immunohistochemistry and Western blotting assays were performed to measure the expression of proteins. CCK-8 and colony formation assays were employed to assess the cell viability and proliferation. Ferroptosis was monitored through flow cytometry, the malondialdehyde assay kit and JC-1 staining analyses. The nude mouse xenograft model was generated to examine the effect of combination of DHODH inhibition and cisplatin on tumor growth in vivo. The expression of DHODH was increased in cervical cancer tissues. DHODH inhibition inhibited the proliferation and promoted the ferroptosis in cervical cancer cells. A combination of DHODH inhibition and cisplatin synergistically induced both in vitro and in vivo ferroptosis and downregulated the ferroptosis defender mTOR pathway. Therefore, the combination of DHODH inhibition and cisplatin exhibits synergistic effects on ferroptosis induction via inhibiting the mTOR pathway could provide a promising way for cervical cancer therapy. Full article

N-(2-(1H-Indol-3-yl)ethyl)-2-(2-fluoro-[1,1′-biphenyl]-4-yl)propanamide was prepared by a reaction between tryptamine and flurbiprofen, applying N,N’-Dicyclohexylcarbodiimide, as a coupling agent. The obtained new amide has a fragment similar to Brequinar, a compound used in SARS-CoV-2 treatment trials. The newly synthesized compound was fully analyzed and characterized via ¹H, ¹³C-NMR, UV, IR, and mass spectral data. Full article

Combination therapies have become a standard for the treatment for HIV and hepatitis C virus (HCV) infections. They are advantageous over monotherapies due to better efficacy, reduced toxicity, as well as the ability to prevent the development of resistant viral strains and to treat viral co-infections. Here, we identify new synergistic combinations against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), echovirus 1 (EV1), hepatitis C virus (HCV) and human immunodeficiency virus 1 (HIV-1) in vitro. We observed synergistic activity of nelfinavir with convalescent serum and with purified neutralizing antibody 23G7 against SARS-CoV-2 in human lung epithelial Calu-3 cells. We also demonstrated synergistic activity of nelfinavir with EIDD-2801 or remdesivir in Calu-3 cells. In addition, we showed synergistic activity of vemurafenib with emetine, homoharringtonine, anisomycin, or cycloheximide against EV1 infection in human lung epithelial A549 cells. We also found that combinations of sofosbuvir with brequinar or niclosamide are synergistic against HCV infection in hepatocyte-derived Huh-7.5 cells, and that combinations of monensin with lamivudine or tenofovir are synergistic against HIV-1 infection in human cervical TZM-bl cells. These results indicate that synergy is achieved when a virus-directed antiviral is combined with another virus- or host-directed agent. Finally, we present an online resource that summarizes novel and known antiviral drug combinations and their developmental status. Full article

Zika virus (ZIKV) was identified in 1947 in the Zika forest of Uganda and it has emerged recently as a global health threat, with recurring outbreaks and its associations with congenital microcephaly through maternal fetal transmission and Guillain-Barré syndrome. Currently, there are no United States (US) Food and Drug Administration (FDA)-approved vaccines or antivirals to treat ZIKV infections, which underscores an urgent medical need for the development of disease intervention strategies to treat ZIKV infection and associated disease. Drug repurposing offers various advantages over developing an entirely new drug by significantly reducing the timeline and resources required to advance a candidate antiviral into the clinic. Screening the ReFRAME library, we identified ten compounds with antiviral activity against the prototypic mammarenavirus lymphocytic choriomeningitis virus (LCMV). Moreover, we showed the ability of these ten compounds to inhibit influenza A and B virus infections, supporting their broad-spectrum antiviral activity. In this study, we further evaluated the broad-spectrum antiviral activity of the ten identified compounds by testing their activity against ZIKV. Among the ten compounds, Azaribine (SI-MTT = 146.29), AVN-944 (SI-MTT = 278.16), and Brequinar (SI-MTT = 157.42) showed potent anti-ZIKV activity in post-treatment therapeutic conditions. We also observed potent anti-ZIKV activity for Mycophenolate mofetil (SI-MTT = 20.51), Mycophenolic acid (SI-MTT = 36.33), and AVN-944 (SI-MTT = 24.51) in pre-treatment prophylactic conditions and potent co-treatment inhibitory activity for Obatoclax (SI-MTT = 60.58), Azaribine (SI-MTT = 91.51), and Mycophenolate mofetil (SI-MTT = 73.26) in co-treatment conditions. Importantly, the inhibitory effect of these compounds was strain independent, as they similarly inhibited ZIKV strains from both African and Asian/American lineages. Our results support the broad-spectrum antiviral activity of these ten compounds and suggest their use for the development of antiviral treatment options of ZIKV infection. Full article

Viruses are the major causes of acute and chronic infectious diseases in the world. According to the World Health Organization, there is an urgent need for better control of viral diseases. Repurposing existing antiviral agents from one viral disease to another could play a pivotal role in this process. Here, we identified novel activities of obatoclax and emetine against herpes simplex virus type 2 (HSV-2), echovirus 1 (EV1), human metapneumovirus (HMPV) and Rift Valley fever virus (RVFV) in cell cultures. Moreover, we demonstrated novel activities of emetine against influenza A virus (FLUAV), niclosamide against HSV-2, brequinar against human immunodeficiency virus 1 (HIV-1), and homoharringtonine against EV1. Our findings may expand the spectrum of indications of these safe-in-man agents and reinforce the arsenal of available antiviral therapeutics pending the results of further in vitro and in vivo tests. Full article