Harringtonine (HT), a potent Cephalotaxus ester alkaloid, was first isolated from the plant Cephalotaxus fortunei Hook. f. belonging to the Cephalotaxaceae family, as documented by Paudler and colleagues in 1963. This discovery marked the beginning of a series of significant research developments concerning this compound.
In 1972, Powell et al. identified the anti-leukemic properties of HT and its derivatives, including homoharringtonine (HHT), isoharringtonine, and deoxyharringtonine, which demonstrated inhibitory effects on the growth of mouse leukemia cells. This pioneering research paved the way for broader investigations into Cephalotaxus plants, leading to the isolation of a multitude of bioactive alkaloids over the subsequent years.
The clinical application of HT and HHT in China commenced in 1974, specifically targeting acute non-lymphocytic leukemia, as reported by Kato et al. in 1984. The successful therapeutic outcomes highlighted the potential of these compounds in clinical oncology, setting the stage for their further development and application in medicine.
The outbreak of the coronavirus disease 2019 (COVID-19) pandemic in late 2019 necessitated an urgent search for effective therapeutic agents. The reevaluation of existing natural cancer drugs derived from herbs, such as HT and HHT, for their antiviral properties became a priority. A series of studies in 2020 and 2021, including those by Sohrab et al., Wu and Wen, and Yousefi et al., highlighted the potential of HT and HHT as novel antiviral agents targeting the replication cycle of SARS-CoV-2 and other coronaviruses. These studies indicated that HHT could disrupt virus replication by interacting with ribosomal peptidyl transferases, a mechanism that was expected to play a crucial role in managing COVID-19.
One of the most promising breakthroughs came in 2021 when Wen et al. demonstrated that HHT could significantly reduce the viral load in SARS-CoV-2-infected transgenic mice. They observed a remarkable reduction in viral load by five orders of magnitude at extremely low concentrations of the drug. Furthermore, the adoption of nebulization as a delivery method for HHT, explored through a phase I/II clinical trial by Ma et al. in 2022, emphasized its potential not only in treating lung metastases but also in reducing viral load and preventing the progression of viral symptoms.
The molecular mechanism of SARS-CoV-2 infection involves the spike (S) protein binding to the angiotensin-converting enzyme 2 (ACE2) on the host cell surface, facilitated by the transmembrane serine protease 2 (TMPRSS2). Benton et al. in 2020 elucidated these interactions, which are critical for the virus’s entry into the host cells. Building on this understanding, Hu et al. in 2023 introduced a novel concept of “double blocking” the membrane fusion process of SARS-CoV-2. Their research provided detailed insights into how HT could bind to the S protein and TMPRSS2, disrupting the virus’s entry mechanism. This interaction was particularly effective against the Omicron BA.5 variant, which is known for its high transmissibility and immune evasion capabilities.
Despite the similar structural characteristics of HT and HHT, differences in their chemical structures have implications for their clinical use. HHT, with its higher extraction rate and broader application in clinical settings, has been the focus of much research. However, HT’s lower toxicity presents a compelling case for its use, particularly in the context of COVID-19, where medication safety is paramount.
The pharmacokinetics of HT have been studied extensively since the late 20th century. Early research by Ji et al. in the late 1970s and early 1980s utilized radioisotope technology to explore the absorption, distribution, and excretion of HT in rats and mice. These foundational studies were crucial for understanding the metabolic pathways and optimizing the clinical use of HT. Later studies by Levy et al. in 2001, and Lu et al. in the 1980s employed isotope labeling and high-performance liquid chromatography (HPLC) to monitor HT metabolism in various animal models and humans. These studies provided a comprehensive view of HT’s pharmacokinetics, essential for its therapeutic application.
However, the specific pharmacokinetic properties of HT in the lungs, especially given its potential application against SARS-CoV-2, remain underexplored. The recent study involving lung microsomes and advanced analytical techniques like UPLC-Q-TOF-MS aims to fill this gap. This research not only offers insights into the metabolic pathways of HT in lung tissues but also explores the dynamics of the metabolome under HT treatment, enhancing our understanding of its therapeutic potential against COVID-19.
In conclusion, the journey of HT from its initial discovery to its potential role in combating COVID-19 is a testament to the importance of reevaluating existing drugs for new therapeutic purposes. The ongoing research into the pharmacokinetics and molecular interactions of HT provides a hopeful outlook for its application in treating viral infections, particularly in the context of the current global health crisis.
reference link : https://www.sciencedirect.com/science/article/abs/pii/S0944711324002472
