Journal of Pharmaceutical Analysis Articles Spot Drug Targets for Key Pathophysiologies

­­­­­Researchers have unraveled key physiological mechanisms to pave the way for the discovery of novel therapeutics

XI'AN, China, March 23, 2023 /PRNewswire/ -- As the search for high-quality pharmaceutical drugs continues, researchers spend countless hours discovering the underlying mechanisms of drug action, thus expediting the drug discovery process. A recent example includes the discovery of the broad-spectrum anti-inflammatory effects of inosine, a nucleoside found in transfer RNAs, by researchers in China. These findings were made available online on 22 October 2022 and published in Volume 13, Issue 1 of Journal of Pharmaceutical Analysis (JPA) on 1^st January 2023.

Corresponding author, Yue Gao says, "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced cytokine storms constitute the primary cause of COVID-19 progression, severity, criticality, and death. Glucocorticoid and anti-cytokine therapies are frequently administered to treat COVID-19 but have limited clinical efficacy in severe and critical cases."

While attempting to develop effective treatment modalities for COVID-19, the researchers found that inosine downregulated the inflammation-promoting interleukin (IL)-6, upregulated the anti-inflammatory IL-10, and improved acute inflammatory lung injury.

Their study suggests that inosine appreciably improved survival in mice infected with SARS-CoV-2 and hindered TANK-binding kinase 1 (TBK1) phosphorylation by binding stimulator of interferon genes and glycogen synthase kinase-3b. It also inhibited the activation and nuclear translocation of the downstream transcription factors, interferon regulatory factor and nuclear factor kappa B, and downregulated IL-6 in the sera and lung tissues of mice infected with lipopolysaccharide, H1N1, or SARS-CoV-2.

Dr. Gao further adds, "Inosine is potentially an excellent broad-spectrum anti-inflammatory agent. Our study empirically demonstrated that inosine administration improved survival in severe SARS-CoV-2 infection through its immunomodulatory effects."

The researchers concluded that inosine therapy may exert distinct anti-inflammatory effects in patients with severe COVID-19, and identified TBK1 as a promising target for inhibiting cytokine storms and for mitigating acute inflammatory lung injury.

In another instance, Gu et al. demonstrated that compounds inhibiting disruptor of telomeric silencing-1-like (DOT1L) diminished the demethylation of histone H3 lysine 79 and inhibited the malignant behavior of uveal melanoma (UM) cells. This novel discovery can facilitate the development of the next generation of therapeutics targeting UM. As the author Xiang Gu, observes, "Our research reveals a novel targetable DOT1L-nicotinate phosphoribosyltransferase oncogenic mechanism, broadening the current understanding of UM therapies."

Similarly, Li and colleagues identified squalene epoxidase as a promising therapeutic target for combating drug-induced hepatotoxicity. The author Zhiqi Li says, "We elucidate the hepatotoxicity mechanism of Paris polyphylla, commonly used in traditional herbal medicines, and provide a reference for its safe clinical use. These results may help to modify the structure of related chemical components responsible for the toxicity of polyphyllin 1, the active ingredient of Paris polyphylla, and make its clinical use safer by reducing its toxicity."

In addition, Guo and co-authors demonstrated the promising antitumor efficacy of the supramolecular nanoreactor "DOC@TA-Fe³⁺" in a mouse model of colorectal cancer. The nanoreactor developed by the team rapidly accumulated at the tumor site following injection via the tail vein, attesting to its rapid transportability to the tumor tissue. Author Min Mu says, "The nanoreactor provides a new strategy for drug delivery and provides a reference for clinical research."

Collectively, these cutting-edge studies pave the way for the identification of novel pathophysiological pathways, strongly boosting the process of drug discovery.

Reference

Title of original paper: Inosine: A broad-spectrum anti-inflammatory against SARS-CoV-2 infection-induced acute lung injury via suppressing TBK1 phosphorylation
Journal: Journal of Pharmaceutical Analysis
DOI: https://doi.org/10.1016/j.jpha.2022.10.002

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SOURCE Journal of Pharmaceutical Analysis