Cepharanthine Dry Powder Inhaler for the Treatment of Acute Lung Injury.

Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) induces a severe cytokine storm that may cause acute lung injury/acute respiratory distress syndrome (ALI/ARDS) with high clinical morbidity and mortality in infected individuals. Cepharanthine (CEP) is a bisbenzylisoquinoline alkaloid isolated and extracted from Stephania cepharantha Hayata. It exhibits various pharmacological effects, including antioxidant, anti-inflammatory, immunomodulatory, anti-tumor, and antiviral activities. The low oral bioavailability of CEP can be attributed to its poor water solubility. In this study, we utilized the freeze-drying method to prepare dry powder inhalers (DPI) for the treatment of acute lung injury (ALI) in rats via pulmonary administration. According to the powder properties study, the aerodynamic median diameter (Da) of the DPIs was 3.2 µm, and the in vitro lung deposition rate was 30.26; thus, meeting the Chinese Pharmacopoeia standard for pulmonary inhalation administration. We established an ALI rat model by intratracheal injection of hydrochloric acid (1.2 mL/kg, pH = 1.25). At 1 h after the model's establishment, CEP dry powder inhalers (CEP DPIs) (30 mg/kg) were sprayed into the lungs of rats with ALI via the trachea. Compared with the model group, the treatment group exhibited a reduced pulmonary edema and hemorrhage, and significantly reduced content of inflammatory factors (TNF-α, IL-6 and total protein) in their lungs (p < 0.01), indicating that the main mechanism of CEP underlying the treatment of ALI is anti-inflammation. Overall, the dry powder inhaler can deliver the drug directly to the site of the disease, increasing the intrapulmonary utilization of CEP and improving its efficacy, making it a promising inhalable formulation for the treatment of ALI.

Bench-to-bedside: Innovation of small molecule anti-SARS-CoV-2 drugs in China.

The ongoing COVID-19 pandemic has resulted in millions of deaths globally, highlighting the need to develop potent prophylactic and therapeutic strategies against SARS-CoV-2. Small molecule inhibitors (remdesivir, Paxlovid, and molnupiravir) are essential complements to vaccines and play important roles in clinical treatment of SARS-CoV-2. Many advances have been made in development of anti-SARS-CoV-2 inhibitors in China, but progress in discovery and characterization of pharmacological activity, antiviral mechanisms, and clinical efficacy are limited. We review development of small molecule anti-SARS-CoV-2 drugs (azvudine [approved by the NMPA of China on July 25, 2022], VV116 [approved by the NMPA of China on January 29, 2023], FB2001, WPV01, pentarlandir, and cepharanthine) in China and summarize their pharmacological activity, potential mechanisms of action, clinical trials and use, and important milestones in their discovery. The role of structural biology in drug development is also reviewed. Future studies should focus on development of diverse second-generation inhibitors with excellent oral bioavailability, superior plasma half-life, increased antiviral activity against SARS-CoV-2 and its variants, high target specificity, minimal side effects, reduced drug-drug interactions, and improved lung histopathology.

Simulation of pharmacokinetic drug-drug interaction and dosage regimens optimization of nelfinavir and cepharanthine as a potential combination against COVID-19

The pharmacokinetic (PK) drug-drug interactions (DDIs) of nelfinavir and cepharanthine combination is limited information in human. In addition, the dosage regimen of this combination is not available for COVID-19 treatment. The objective of this study was to perform in silico simulations using GastroPlusTM software to predict physicochemical properties, PK parameters using the physiologically based pharmacokinetic (PBPK) model of healthy adults in different dosage regimens. The DDIs analysis of nelfinavir and cepharanthine combination was carried out to optimize the dosage regimens as a potential against COVID-19. The Spatial Data File (SDF) format of nelfinavir and cepharanthine structures obtained from PubChem database were used to carry out in silico predictions for physicochemical properties and PK parameters using several aspects of modules such as ADMET Predictor, Metabolism and Transporter, PBPK model. Subsequently, all data were utilized in the DDIs simulations. The dynamic simulation feature was selected to calculate and investigate the Cmax, AUC0-120, AUC0-inf, Cmax ratio, AUC0-120 ratio, and AUC0-inf ratio. The victim or nelfinavir dosage regimens were used four oral administration regimens of 500 mg and 750 mg in every 8 and 12 hours for simulations. The perpetrator or cepharanthine oral dosage regimens were used in several regimens from 10 mg to 120 mg in every 8, 12, and 24 hours. From all predicted results, the dosage regimen as a potential combination against COVID-19 was nelfinavir 500 mg every 8 hours and cepharanthine 10 mg every 12 hours.Copyright © 2023 by Faculty of Pharmacy, Mahidol University, Thailand is licensed under CC BY-NC-ND 4.0. To view a copy of this license, visit https://www.creativecommons.org/licenses/by-nc-nd/4.0/.

Unraveling the mechanism of action of cepharanthine for the treatment of novel coronavirus pneumonia (COVID-19) from the perspectives of systematic pharmacology.

Natural products play an irreplaceable role in the treatment of SARS-CoV-2 infection. Nevertheless, the underlying molecular mechanisms involved remain elusive. To better understand their potential therapeutic effects, more validation studies are needed to explore underlying mechanisms systematically. This study aims to explore the potential targets of action and signaling pathways of cepharanthine for the treatment of COVID-19. This study revealed that a total of 173 potential targets of action for Cepharanthine and 86 intersectional targets for Cepharanthine against COVID-19 were screened and collected. Gene Ontology enrichment analysis suggested that inflammatory, immune cell and enzyme activities were the critical terms for cepharanthine against COVID-19. Pathway enrichment analysis showed that five pathways associated with COVID-19 were the main signaling pathways for the treatment of COVID-19 via cepharanthine. Molecular docking and molecular dynamics simulations suggested that 6 core targets were regarded as potential targets for cepharanthine against COVID-19. In brief, the study demonstrates that cepharanthine may play an important role in the treatment of SARS-CoV-2 infection through its harmonious activity against SARS-CoV-2 pathways and multiple related targets. This article provides valuable insights required to respond effectively to concerns of western medical community.

In silico analysis of phytochemicals and non-phytochemicals and comparing their potentiality on inhibiting nsp12 and nsp14 in SARS-CoV-2 variants

The spread of SARS-CoV-2 and its variants, leads to global pandemic endangering human life and health. The primary challenge for the scientific community is to find a potential cure for the disease which can act on the emerging variants of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). Due to the absence of effective medical treatment for the diseases, the healthcare system around the world was at a standstill. The nsp12 and nsp14 are one of the important proteins which are involved in the replication and proofreading of SARS-CoV-2 respectively. Both the non-structural proteins have highly conserved regions and served as a popular target for corona virus inhibitors for drug screening. In this study, the primary aim is to find the potential inhibitors, both phytochemical and nonphytochemical, which could act on variants to inhibit the activity of nsp12 and nsp14. Also to compare the binding affinity of nsp12 and nsp14 with phytochemicals and nonphytochemicals. A combination of mutational landscape, structure-based virtual screening and molecular dynamics (MD) simulation approaches were utilized in this work. From the mutational landscape, two functionally active mutations were observed in nsp12 and single mutation was observed in nsp14 of SARS CoV-2 Variants. The molecular simulation is performed for drugs Cepharanthine (phytochemical) and Hypericin (phytochemical) with top binding affinity for nsp12 variants and for molecules Hypericin (phytochemical) and conivaptan (non-Phytochemical) having top binding affinity with nsp14 wildtype and variants.

Drug Repurposing for SARS-COV-2 Using Molecular Docking

Drug repurposing is an unconventional approach that is used to investigate new therapeutic aids of existing and shelved drugs. Recent advancement in technologies and the availability of the data of genomics, proteomics, transcriptomics, etc., and with the accessibility of large and reliable database resources, there are abundantly of opportunities to discover drugs by drug repurposing in an efficient manner. The recent pandemic of SARS-COV-2, that caused the death of 6,245,750 human beings to date, has tremendously increase the exceptional usage of bioinformatics tools in interpreting the molecular characterizations of viral infections. In this paper, we have employed various bioinformatics tools such as AutoDock-Vina, PyMol etc. We have found a leading drug candidate Cepharanthine (CEP) that has shown better results and effectiveness than recently used antiviral drug candidates such as Favipiravir, IDX184, Remedesivir, Ribavirin and etc. This paper has analyzed CEP's potential therapeutic importance as a drug of choice in managing COVID-19 cases. It is anticipated that proposed study would be beneficial for researchers and medical practitioners in handling SARS-CoV-2 and its variant related diseases. © 2022 IEEE.

Drug Repurposing for CoVID-19 Spike Protein through Molecular Docking

Drug repurposing is the technique of finding new uses for currently used or under-researched drugs. Because this strategy requires less time and money, it is thought to be a particularly effective drug development strategy. Due to current technological breakthroughs, the accessibility of vast and reliable database resources, as well as data accessibility from genomes, proteomics, transcriptomics, etc., there are numerous opportunities to identify drugs by drug repurposing. The recent SARS-COV-2 epidemic, which has so far claimed 6,245,750 lives, has significantly increased the use of bioinformatics techniques in deciphering the characteristics of viral diseases. Using FDA-approved antiviral drugs that target the COVID-19 spike protein, we have used a bioinformatics approach to drug repurposing to find possible effective inhibitors against the Coronavirus (COVID-19). We used a variety of bioinformatics tools in this study, including AutoDock-Vina, PyMol, and Discovery Studio, to identify a promising drug called Cepharanthine (CEP), which demonstrates successful outcomes and efficacy compared to recently used antiviral drug candidates like arbidol, talampicillin, bromhexine, chloroquine, lycorine, bruceine A, reserpine, indinavir, galidesiver, doxycycline, methisazone, flupentixol, trifluoperazine and fluoxetine. The potential therapeutic value of cepharanthine as a drug for treating COVID-19 has been investigated in this study. It is expected that the proposed study will help medical professionals and researchers cure disorders linked to Severe acute respiratory and variations of it. © 2022 IEEE.

Cepharanthine Ameliorates Pulmonary Fibrosis by Inhibiting the NF-κB/NLRP3 Pathway, Fibroblast-to-Myofibroblast Transition and Inflammation.

Pulmonary fibrosis (PF) is one of the sequelae of Corona Virus Disease 2019 (COVID-19), and currently, lung transplantation is the only viable treatment option. Hence, other effective treatments are urgently required. We investigated the therapeutic effects of an approved botanical drug, cepharanthine (CEP), in a cell culture model of transforming growth factor-ß1 (TGF-ß1) and bleomycin (BLM)-induced pulmonary fibrosis rat models both in vitro and in vivo. In this study, CEP and pirfenidone (PFD) suppressed BLM-induced lung tissue inflammation, proliferation of blue collagen fibers, and damage to lung structures in vivo. Furthermore, we also found increased collagen deposition marked by α-smooth muscle actin (α-SMA) and Collagen Type I Alpha 1 (COL1A1), which was significantly alleviated by the addition of PFD and CEP. Moreover, we elucidated the underlying mechanism of CEP against PF in vitro. Various assays confirmed that CEP reduced the viability and migration and promoted apoptosis of myofibroblasts. The expression levels of myofibroblast markers, including COL1A1, vimentin, α-SMA, and Matrix Metallopeptidase 2 (MMP2), were also suppressed by CEP. Simultaneously, CEP significantly suppressed the elevated Phospho-NF-κB p65 (p-p65)/NF-κB p65 (p65) ratio, NOD-like receptor thermal protein domain associated protein 3 (NLRP3) levels, and elevated inhibitor of NF-κB Alpha (IκBα) degradation and reversed the progression of PF. Hence, our study demonstrated that CEP prevented myofibroblast activation and treated BLM-induced pulmonary fibrosis in a dose-dependent manner by regulating nuclear factor kappa-B (NF-κB)/ NLRP3 signaling, thereby suggesting that CEP has potential clinical application in pulmonary fibrosis in the future.

Current status and future challenges in extraction, purification and identification of Cepharanthine (a potential drug against COVID-19).

With the outbreak of the new coronavirus disease 2019 (COVID-19), the rapid spread of the virus has brought huge economic losses and life threats to the world. So far, we have entered the third year of the epidemic and there is an urgent need to provide more anti-viral treatment along with vaccination. Recent studies have confirmed that Cepharanthine (CEP) has strong antiviral efficacy, which is a potential drug against COVID-19. As a natural active alkaloid, the development of CEP-incorporated products is dependent on the extraction, purification and identification of CEP. This review gives a brief introduction of CEP, including its origin and classification, and its conventional and novel extraction techniques. In addition, the purification and identification techniques are summarized. In the last, the future research directions are proposed. It can be found from this review that the extraction from plants is still the main way to obtain CEP, and it is necessary to use innovative techniques and their hybrid extractions to extract CEP. More efficient extraction and purification techniques should be used to extract CEP in the future. This review provides a basis for the development of novel extraction and purification techniques and industrial utilization of CEP.

Pharmacological Effects and Clinical Prospects of Cepharanthine.

Cepharanthine is an active ingredient separated and extracted from Stephania cepharantha Hayata, a Menispermaceae plant. As a bisbenzylisoquinoline alkaloid, cepharanthine has various pharmacological properties, including antioxidant, anti-inflammatory, immunomodulatory, antitumoral, and antiviral effects. Following the emergence of coronavirus disease 2019 (COVID-19), cepharanthine has been found to have excellent anti-COVID-19 activity. In this review, the important physicochemical properties and pharmacological effects of cepharanthine, particularly the antiviral effect, are systematically described. Additionally, the molecular mechanisms and novel dosage formulations for the efficient, safe, and convenient delivery of cepharanthine are summarized.

The common regulatory pathway of COVID-19 and multiple inflammatory diseases and the molecular mechanism of cepharanthine in the treatment of COVID-19.

Background: Similar pathogenesis makes Corona Virus Disease 2019 (COVID-19) associated with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and gouty arthritis (GA), and it is possible to introduce common drugs for the treatment of RA, AS and GA into the treatment of COVID-19. That is, "homotherapy for heteropathy", especially cytokine inhibitors. But little is known about the specific link between the diseases. In addition, "new use of old drugs" is an important short-term strategy for the treatment of COVID-19. Cepharanthine (CEP), a monomer component of traditional Chinese medicine (TCM), is mainly used in the treatment of leukopenia and has recently been proved to have a good therapeutic effect on COVID-19, but its specific molecular mechanism has not been clearly explained. The purpose of this work is to explore the common targets and signaling pathways among COVID-19, RA, AS, and GA by means of network pharmacology (NP), and to infer the potential mechanism of CEP in the treatment of COVID-19. Methods: Firstly, SwissTargetPrediction was used to predict the targets of CEP, and the pathogenic targets of COVID-19, RA, AS and GA were searched in GeneCards, OMIM, TTD, PharmGKB database and literature, respectively. Then, the protein interaction network of CEP and COVID-19 cross targets and the common targets of COVID-19, RA, AS and GA was constructed. Cytosscape 3.7.2 software was used to construct CEP-common targets-signaling pathways-COVID-19 network, module function analysis, gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG). Finally, the molecular docking of hub targets and CEP was carried out by AutoDock software. Results: The results showed that the common targets of the four diseases were tumor necrosis factor (TNF), interleukin (IL)-6 and IL-1ß, and involved Coronavirus disease, IL-17 signaling pathway and TNF signaling pathway. CEP has a good binding force with AKT Serine/Threonine Kinase 1 (AKT1), phosphatidylinositol 3-kinase (PIK3) CA, PIK3CD and Angiotensin-converting enzyme 2 (ACE2), and plays a role in the treatment of COVID-19 by regulating PI3K-Akt signaling pathway, Relaxin signaling pathway, VEGF signaling pathway and HIF-1 signaling pathway. Conclusion: Therefore, this study not only confirmed the potential mechanism of CEP in the treatment of COVID-19 at the molecular level, but also found that TNF and IL-17 inhibitors, which are commonly used in the treatment of RA, AS and GA, may also affect the treatment of COVID-19, which provides new clues and theoretical basis for the rapid discovery of effective therapeutic drugs for COVID-19.

Dissecting the molecular mechanism of cepharanthine against COVID-19, based on a network pharmacology strategy combined with RNA-sequencing analysis, molecular docking, and molecular dynamics simulation.

OBJECTIVES: Recently, it has been reported that cepharanthine (CEP) is highly likely to be an agent against Coronavirus disease 2019 (COVID-19). In the present study, a network pharmacology-based approach combined with RNA-sequencing (RNA-seq), molecular docking, and molecular dynamics (MD) simulation was performed to determine hub targets and potential pharmacological mechanism of CEP against COVID-19. METHODS: Targets of CEP were retrieved from public databases. COVID-19-related targets were acquired from databases and RNA-seq datasets GSE157103 and GSE155249. The potential targets of CEP and COVID-19 were then validated by GSE158050. Hub targets and signaling pathways were acquired through bioinformatics analysis, including protein-protein interaction (PPI) network analysis and enrichment analysis. Subsequently, molecular docking was carried out to predict the combination of CEP with hub targets. Lastly, MD simulation was conducted to further verify the findings. RESULTS: A total of 700 proteins were identified as CEP-COVID-19-related targets. After the validation by GSE158050, 97 validated targets were retained. Enrichment results indicated that CEP acts on COVID-19 through multiple pathways, multiple targets, and overall cooperation. Specifically, PI3K-Akt signaling pathway is the most important pathway. Based on PPI network analysis, 9 central hub genes were obtained (ACE2, STAT1, SRC, PIK3R1, HIF1A, ESR1, ERBB2, CDC42, and BCL2L1). Molecular docking suggested that the combination between CEP and 9 central hub genes is extremely strong. Noteworthy, ACE2, considered the most important gene in CEP against COVID-19, binds to CEP most stably, which was further validated by MD simulation. CONCLUSION: Our study comprehensively illustrated the potential targets and underlying molecular mechanism of CEP against COVID-19, which further provided the theoretical basis for exploring the potential protective mechanism of CEP against COVID-19.

DNA intercalators alkaloids as Potential candidates to fight COVID-19 disease: Systematic review

The main objective of the current systematic review was to report the antiviral and anti-inflammatory effects of bioactive molecules class known as alkaloids against SARS-COV-2 disease. These bioactive compounds were characterized by their potential replication inhibitory ability by DNA intercalating effect, and might be powerful agents against infections caused by several viruses, therefore it can be a viable strategy for COVID-19 management. PubMed, ScienceDirect, Google Scholar and SpringerLink, databases have been chosen to look for keywords like DNA intercalators, alkaloids, antiviral activity, anti-inflammatory effect, coronavirus, SARS-CoV-2. Two reviewers have evaluated the quality of 60 articles extracted from the four databases till 15th of May 2021, using inclusions and exclusions criteria, 25 papers were accepted and treated in this systematic review, performed based on PRISMA protocol. Results disclosed that alkaloids have key roles in viral replication inhibition, quinine and emetine showed a noticeable therapeutic effect against SARS-COV-2 virus, however emetine revealed modifications in the electrocardiogram (ECG), unlike sanguinarine and berberine that showed low human toxicity. Tetrandrine, fangchinoline and cepharantine could be classified as remedies in case of Coronavirus ailment. Chelidonine, coptisine, skimmianine, protropine, palmatine, cinchonine, harmine and dictamine represented important agents for clinical researches or as precursors for antiviral drug’s formulation.

N-glycoproteomic profiling revealing novel coronavirus therapeutic targets potentially involved in Cepharanthine's intervention.

The Coronavirus disease 2019 (COVID-19) has posed a serious threat to global health and the world economy. Antiviral therapies targeting coronavirus are urgently required. The Cepharanthine (CEP) is a traditional Chinese herbal extract. Our previous research revealed that CEP has a very potent anti-coronavirus effect, but its mechanism of action was not fully understood. To investigate the effect of novel coronavirus on protein glycosylation in infected cells and to further investigate the mechanism of action of CEP against coronavirus, a cellular model using coronavirus GX_P2V infection of Vero E6 cells was established. The effect of coronavirus GX_P2V on host cell protein glycosylation was investigated by N-glycoproteomic analysis, and the antagonistic effect of CEP on the abnormal protein glycosylation caused by coronavirus was analyzed. The results showed that GX_P2V could cause abnormal changes in protein glycosylation levels in host cells, while CEP could partially antagonize the abnormal protein glycosylation caused by GX_P2V. In addition, we also found that CEP could regulate the glycosylation level of coronavirus S protein. In conclusion, this article provides important ideas about the infection mechanism of novel coronaviruses, providing evidence for CEP as a promising therapeutic option for coronavirus infection.

[Progress in the study of antiviral activity of cepharanthine against SARS-CoV-2].

As a member of the dibenzyl isoquinoline alkaloid family, cepharathine is an alkaloid from the traditional Chinese medicine cepharathine, which is mainly used for treatment of leukopenia and other diseases. Recent studies of the inhibitory effect of cepharathine against SARS-CoV-2 have attracted widespread attention and aroused heated discussion. As the original discoverer of the anti-SARS-CoV-2 activity of cepharanthine, here we briefly summarize the discovery of cepharanthine and review important progress in relevant studies concerning the discovery and validation of anti-SARS-CoV-2 activity of cepharathine, its antiviral mechanisms and clinical trials of its applications in COVID-19 therapy.

Cepharanthine: A Promising Old Drug against SARS-CoV-2.

Recently, the inhibiting effects of a clinically approved drug Cepharanthine on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have attracted widespread attention and discussion. However, the public does not understand the relevant research progress very well. This paper aims to introduce a brief history of studies on the effects of cepharanthine against SARS-CoV-2, including "discovery of anti-SARS-CoV-2 activity of cepharanthine in vitro", "potential mechanisms of cepharanthine against SARS-CoV-2", "confirmation of cepharanthine's anti-SARS-CoV-2 activity in vivo", "potential approaches for improving the druggability of cepharanthine" and "clinical trials of cepharanthine treating SARS-CoV-2 infection". Taken together, cepharanthine is believed to be a promising old drug for coronavirus disease-19 (COVID-19) therapy.

Bis-Benzylisoquinoline Alkaloids Inhibit Porcine Epidemic Diarrhea Virus In Vitro and In Vivo.

Porcine epidemic diarrhea virus (PEDV) belongs to the genus Alphacoronavirus of the family Coronaviridae that causes severe diarrhea and high mortality in neonatal suckling piglets. Currently, there is no effective medication against this pathogen. Cepharanthine (CEP), tetrandrine (TET), and fangchinoline (FAN) are natural bis-benzylisoquinoline alkaloids with anti-inflammatory, antitumor, and antiviral properties. Here, we first found that CEP, TET, and FAN had anti-PEDV activity with IC50 values of 2.53, 3.50, and 6.69 µM, respectively. The compounds could block all the processes of viral cycles, but early application of the compounds before or during virus infection was advantageous over application at a late stage of virus replication. FAN performed inhibitory function more efficiently through interfering with the virus entry and attachment processes or through attenuating the virus directly. CEP had a more notable effect on virus entry. With the highest SI index of 11.8 among the three compounds, CEP was chosen to carry out animal experiments. CEP in a safe dosage of 11.1 mg/kg of body weight could reduce viral load and pathological change of piglet intestinal tracts caused by PEDV field strain challenge, indicating that CEP efficiently inhibited PEDV infection in vivo. All of these results demonstrated that the compounds of bis-benzylisoquinoline alkaloids could inhibit PEDV proliferation efficiently and had the potential of being developed for PED prevention and treatment.

Therapeutic potential of plant secondary metabolites in treatment of respiratory viral diseases: A review

Respiratory viral infections are a major public health concern because of their global occurrence, ease of spread and considerable morbidity and mortality. Medical treatments for viral respiratory diseases primarily involve providing relief from symptoms like pain and discomfort rather than treating the infection. Very few antiviral medications have been approved with restrictive usage, high cost, unwanted side effects and limited availability. Plants with their unique metabolite composition and high remedial values offer unique preventive and therapeutic efficacy in treatment of viral infections. The present review is focused on the types and mode of action of plant secondary metabolites that have been used successfully ί in the treatment of infections caused by respiratory viruses like Influenza, SARS, MERS, RSV etc. Plant metabolites such as phenolics, alkaloids, terpenoids and oligosaccharides inhibit attachment and entry of the virus. Others such as flavonoids, viz quercetin and baicalein, alkaloids viz sanguinarine, berberine and emetine, specific lipids and fatty acids prevent viral replication and protein synthesis. These metabolites have the potential to be used as lead molecules that can be optimized to develop potent drugs for effectively combating pandemics caused by respiratory viruses.

Bioavailability Enhancement of Cepharanthine via Pulmonary Administration in Rats and Its Therapeutic Potential for Pulmonary Fibrosis Associated with COVID-19 Infection.

Cepharanthine (CEP) has excellent anti-SARS-CoV-2 properties, indicating its favorable potential for COVID-19 treatment. However, its application is challenged by its poor dissolubility and oral bioavailability. The present study aimed to improve the bioavailability of CEP by optimizing its solubility and through a pulmonary delivery method, which improved its bioavailability by five times when compared to that through the oral delivery method (68.07% vs. 13.15%). An ultra-performance liquid chromatography tandem-mass spectrometry (UPLC-MS/MS) method for quantification of CEP in rat plasma was developed and validated to support the bioavailability and pharmacokinetic studies. In addition, pulmonary fibrosis was recognized as a sequela of COVID-19 infection, warranting further evaluation of the therapeutic potential of CEP on a rat lung fibrosis model. The antifibrotic effect was assessed by analysis of lung index and histopathological examination, detection of transforming growth factor (TGF)-ß1, interleukin-6 (IL-6), α-smooth muscle actin (α-SMA), and hydroxyproline level in serum or lung tissues. Our data demonstrated that CEP could significantly alleviate bleomycin (BLM)-induced collagen accumulation and inflammation, thereby exerting protective effects against pulmonary fibrosis. Our results provide evidence supporting the hypothesis that pulmonary delivery CEP may be a promising therapy for pulmonary fibrosis associated with COVID-19 infection.

Advances in the development of therapeutic strategies against COVID-19 and perspectives in the drug design for emerging SARS-CoV-2 variants.

Since Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was identified in late 2019, the coronavirus disease 2019 (COVID-19) pandemic has challenged public health around the world. Currently, there is an urgent need to explore antiviral therapeutic targets and effective clinical drugs. In this study, we systematically summarized two main therapeutic strategies against COVID-19, namely drugs targeting the SARS-CoV-2 life cycle and SARS-CoV-2-induced inflammation in host cells. The development of above two strategies is implemented by repurposing drugs and exploring potential targets. A comprehensive summary of promising drugs, especially cytokine inhibitors, and traditional Chinese medicine (TCM), provides recommendations for clinicians as evidence-based medicine in the actual clinical COVID-19 treatment. Considering the emerging SARS-CoV-2 variants greatly impact the effectiveness of drugs and vaccines, we reviewed the appearance and details of SARS-CoV-2 variants for further perspectives in drug design, which brings updating clues to develop therapeutical agents against the variants. Based on this, the development of broadly antiviral drugs, combined with immunomodulatory, or holistic therapy in the host, is prior to being considered for therapeutic interventions on mutant strains of SARS-CoV-2. Therefore, it is highly acclaimed the requirements of the concerted efforts from multi-disciplinary basic studies and clinical trials, which improves the accurate treatment of COVID-19 and optimizes the contingency measures to emerging SARS-CoV-2 variants.