Viral DNA and RNA polymerases are two kinds of very important enzymes that synthesize the genetic materials of the virus itself, and they have become extremely favorable targets for the development of antiviral drugs because of their relatively conserved characteristics. There are many similarities in the structure and function of different viral polymerases, so inhibitors designed for a certain viral polymerase have acted as effective universal inhibitors on other types of viruses. The present review describes the development of classical antiviral drugs targeting polymerases, summarizes a variety of viral polymerase inhibitors from the perspective of chemically synthesized drugs and natural product drugs, describes novel approaches, and proposes promising development strategies for antiviral drugs.

Epitranscriptomic modifications can affect every aspect of RNA biology, including stability, transport, splicing, and translation, participate in global intracellular mRNA metabolism, and regulate gene expression and a variety of biological processes. N6-methyladenosine (m6A) as the most prevalent modification contributes to normal embryonic brain development and memory formation. However, changes in the level of m6A modification and the expression of its related proteins cause abnormal nervous system functions, including brain tissue development retardation, axon regeneration disorders, memory changes, and neural stem cell renewal and differentiation disorders. Recent studies have revealed that m6A modification and its related proteins play key roles in the development of various neuropsychiatric disorders, such as depression, Alzheimer’s disease, and Parkinson’s disease. In this review, we summarize the research progresses of the m6A modification regulation mechanism in the central nervous system and discuss the effects of gene expression regulation mediated by m6A modification on the biological functions of the neuropsychiatric disorders, thereby providing some insight into new research targets and treatment directions for human diseases.

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Hypericin, one of the major antidepressant constituents of St. John’s wort, was shown to exert antidepressant effects by affecting cerebral CYP enzymes, serotonin homeostasis, and neuroinflammatory signaling pathways. However, its exact mechanisms are unknown. Previous clinical studies reported that the mRNA modification N6-methyladenosine (m6A) interferes with the neurobiological mechanism in depressed patients, and it was also found that the antidepressant efficacy of tricyclic antidepressants (TCAs) is related to m6A modifications. Therefore, we hypothesize that the antidepressant effect of hypericin may relate to the m6A modification of epitranscriptomic regulation. We constructed a UCMS mouse depression model and found that hypericin ameliorated depressive-like behavior in UCMS mice. Molecular pharmacology experiments showed that hypericin treatment upregulated the expression of m6A-modifying enzymes METTL3 and WTAP in the hippocampi of UCMS mice. Next, we performed MeRIP-seq and RNA-seq to study m6A modifications and changes in mRNA expression on a genome-wide scale. The genome-wide m6A assay and MeRIP-qPCR results revealed that the m6A modifications of Akt3, Ntrk2, Braf, and Kidins220 mRNA were significantly altered in the hippocampi of UCMS mice after stress stimulation and were reversed by hypericin treatment. Transcriptome assays and qPCR results showed that the Camk4 and Arhgdig genes might be related to the antidepressant efficacy of hypericin. Further gene enrichment results showed that the differential genes were mainly involved in neurotrophic factor signaling pathways. In conclusion, our results show that hypericin upregulates m6A methyltransferase METTL3 and WTAP in the hippocampi of UCMS mice and stabilizes m6A modifications to exert antidepressant effects via the neurotrophin signaling pathway. This suggests that METTL3 and WTAP-mediated changes in m6A modifications may be a potential mechanism for the pathogenesis of depression and the efficacy of antidepressants, and that the neurotrophin signaling pathway plays a key role in this process.

COVID-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel highly contagious and pathogenic coronavirus that emerged in late 2019. SARS-CoV-2 spreads primarily through virus-containing droplets and small particles of air pollution, which greatly increases the risk of inhaling these virus particles when people are in close proximity. COVID-19 is spreading across the world, and the COVID-19 pandemic poses a threat to human health and public safety. To date, there are no specific vaccines or effective drugs against SARS-CoV-2. In this review, we focus on the enzyme targets of the virus and host that may be critical for the discovery of chemical compounds and natural products as antiviral drugs, and describe the development of potential antiviral drugs in the preclinical and clinical stages. At the same time, we summarize novel emerging technologies applied to the research on new drug development and the pathological mechanisms of COVID-19.