The discovery of novel drug candidates with anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) potential is critical for the control of the global COVID-19 pandemic. Artemisinin, an old antimalarial drug derived from Chinese herbs, has saved millions of lives. Artemisinins are a cluster of artemisinin-related drugs developed for the treatment of malaria and have been reported to have multiple pharmacological activities, including anticancer, antiviral, and immune modulation. Considering the reported broad-spectrum antiviral potential of artemisinins, researchers are interested in whether they could be used to combat COVID-19. We systematically evaluated the anti-SARS-CoV-2 activities of nine artemisinin-related compounds in vitro and carried out a time-of-drug-addition assay to explore their antiviral mode of action. Finally, a pharmacokinetic prediction model was established to predict the therapeutic potential of selected compounds against COVID-19. Arteannuin B showed the highest anti-SARS-CoV-2 potential with an EC 50 of 10.28 ± 1.12 μM. Artesunate and dihydroartemisinin showed similar EC 50 values of 12.98 ± 5.30 μM and 13.31 ± 1.24 μM, respectively, which could be clinically achieved in plasma after intravenous administration. Interestingly, although an EC 50 of 23.17 ± 3.22 μM was not prominent among the tested compounds, lumefantrine showed therapeutic promise due to high plasma and lung drug concentrations after multiple dosing. Further mode of action analysis revealed that arteannuin B and lumefantrine acted at the post-entry step of SARS-CoV-2 infection. This research highlights the anti-SARS-CoV-2 potential of artemisinins and provides leading candidates for anti-SARS-CoV-2 drug research and development.

Highlights d O-GlcNAc transferase (OGT) deficiency impairs host defense against RNA virus d Mitochondrial antiviral-signaling protein (MAVS) is O-GlcNAcylated at multiple sites d O-GlcNAcylation of MAVS is critical for the activation of interferon signaling d D-glucosamine protects mice against lethal RNA viruses

Flaviviruses including Zika virus, Dengue virus, Japanese Encephalitis virus, and Yellow Fever virus cause heavy burdens to public health around the world. No specific antiviral drug is available in the clinic against these flavivirus infections. Heat-shock protein 70 (HSP70) has recently been proven to be a promising antiviral target against Zika virus and Dengue virus. Here, we report that Apoptozole, a small molecule inhibitor of ATPase activity of HSP70, has broad-spectrum anti-flavivirus potential. The mode of action analysis revealed that Apoptozole acted at the post-entry step. Transcriptome analysis revealed that genes related to cholesterol metabolism, fatty acid synthesis, and innate immunity were differentially expressed after treatment with Apoptozole. In vivo data suggested Apoptozole exerted protection effects against Zika virus (ZIKV) infection in a mouse model by enhancing the innate immune response, which suggested a novel anti-ZIKV mechanism of HSP70 inhibitors.

We report herein the design and synthesis of a series of novel Sinefungin (SIN) derivatives, based on the structures of SIN and its analogue EPZ004777. Our results reveal that target compounds 1ad-af, 1ba-bb and 1bf-bh show better activity (IC = 4.56-20.16 μM) than EPZ004777 (IC = 35.19 μM). Surprisingly, SIN was founded to be not as active (IC > 50 μM) as we and other research groups predicted. Interestingly, the intermediates 9a-b and 11b display potent anti-ZIKV potency (IC = 6.33-29.98 μM), and compound 9a also exhibits acceptable cytotoxicity (CC > 200 μM), suggesting their promising potential to be leads for further development.

Seasonal and pandemic influenza causes 650,000 deaths annually in the world. The emergence of drug resistance to specific anti-influenza virus drugs such as oseltamivir and baloxavir marboxil highlights the urgency of novel anti-influenza chemical entity discovery. In this study, we report a series of novel thiazolides derived from an FDA-approved drug, nitazoxanide, with antiviral activity against influenza and a broad range of viruses. The preferred candidates 4a and 4d showed significantly enhanced anti-influenza virus potentials, with 10-fold improvement compared to results with nitazoxanide, and were effective against a variety of influenza virus subtypes including oseltamivir-resistant strains. Notably, the combination using compounds 4a/4d and oseltamivir carboxylate or zanamivir displayed synergistic antiviral effects against oseltamivir-resistant strains. Mode-of-action analysis demonstrated that compounds 4a/4d acted at the late phase of the viral infection cycle through inhibiting viral RNA transcription and replication. Further experiments showed that treatment with compounds 4a/4d significantly inhibited influenza virus infection in human lung organoids, suggesting the druggability of the novel thiazolides. In-depth transcriptome analysis revealed a series of upregulated cellular genes that may contribute to the antiviral activities of 4a/4d. Together, the results of our study indicated the direction to optimize nitazoxanide as an anti-influenza drug and discovered two candidates with novel structures, compounds 4a/4d, that have relatively broad-spectrum antiviral potentials.