Alkaloids and COVID-19

COVID-19 is a type of pneumonia caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which was first reported in Wuhan and then declared a pandemic by the World Health Organization in March 2020. Alkaloids, secondary metabolites of plant origin, possess many biological activities, including antiviral, antioxidative, and anticancer properties. Among these alkaloids are colchicine, tetrandrine, and berberine, which are being used as medicine for centuries. All these alkaloids have shown potential as a cure against COVID-19, albeit further studies are needed to ascertain their efficacy and safety before their adoption by the general population. © 2023 Elsevier Inc. All rights reserved.

COVID-19 Infection: A Review of Summarized Clinical Trials Study for the Treatment

Background: Coronavirus Disease 2019 (COVID-19) is a widely infectious and pathogenic viral infection. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was reported in Wu-han, China, and spread throughout the world. Coronavirus is indeed an enveloped RNA virus of the ge-nus Betacoronavirus, which is transmitted to birds, humans as well as other mammals. The fastest human to human transition has been generally established. On July 19, 2020, the WHO has reported total confirmed cases: 1,40, 43,176, total confirmed new cases: 1,66,735, total deaths: 5,97,583, and total new deaths: 4,496 globally. Material(s) and Method(s): In this review, the Clinical trial database is analyzed and systematically summarized drugs which are in the recruiting phase and the completion phase of the clinical trial. Result(s): Total 383 clinical trials are listed, involving more than 350 medicines such as Deferoxamine, Favipiravir, DAS181, Tocilizumab Injection, Sarilumab, Placebo, Sildenafil citrate tablets, Sargramo-stim, Lopinavir/ritonavir, Remdesivir, Bevacizumab, Tetrandrine, Fingolimod, Methylprednisolone, Plaquenil, Tocilizumab, Hydroxychloroquine, Abidol hydrochloride, Bevacizumab Injection, Methyl-prednisolone, Amoxicillin-clavulanate, Moxifloxacin, Sarilumab, Darunavir, Cobicistat, etc. Conclusion(s): There is no commercially authorized antiviral treatment or vaccine suitable for use against COVID-19. However, clinical trials represent an effective approach because they facilitate the development of new types of pharmaceutical drugs.Copyright © 2021 Bentham Science Publishers.

Antiviral effects and tissue exposure of tetrandrine against SARS-CoV-2 infection and COVID-19.

Tetrandrine (TET) has been used to treat silicosis in China for decades. The aim of this study was to facilitate rational repurposing of TET against SARS-CoV-2 infection. In this study, we confirmed that TET exhibited antiviral potency against SARS-CoV-2 in the African green monkey kidney (Vero E6), human hepatocarcinoma (Huh7), and human lung adenocarcinoma epithelial (Calu-3) cell lines. TET functioned during the early-entry stage of SARS-CoV-2 and impeded intracellular trafficking of the virus from early endosomes to endolysosomes. An in vivo study that used adenovirus (AdV) 5-human angiotensin-converting enzyme 2 (hACE2)-transduced mice showed that although TET did not reduce pulmonary viral load, it significantly alleviated pathological damage in SARS-CoV-2-infected murine lungs. The systemic preclinical pharmacokinetics were investigated based on in vivo and in vitro models, and the route-dependent biodistribution of TET was explored. TET had a large volume of distribution, which contributed to its high tissue accumulation. Inhaled administration helped TET target the lung and reduced its exposure to other tissues, which mitigated its off-target toxicity. Based on the available human pharmacokinetic data, it appeared feasible to achieve an unbound TET 90% maximal effective concentration (EC90) in human lungs. This study provides insights into the route-dependent pulmonary biodistribution of TET associated with its efficacy.

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.

Tetrandrine Treatment May Improve Clinical Outcome in Patients with COVID-19.

Background and objectives: The COVID-19 pandemic continues worldwide, and there is no effective treatment to treat it. Chinese medicine is considered the recommended treatment for COVID-19 in China. This study aimed to examine the effectiveness of tetrandrine in treating COVID-19, which is originally derived from Chinese medicine. Materials and Methods: A total of 60 patients, categorized into three types (mild, moderate, severe), from Daye Hospital of Chinese Medicine with a diagnosis of COVID-19 were included in this study. Demographics, medical history, treatment, and results were collected. We defined two main groups according to the clinical outcome between improvement and recovery. All underlying factors including clinical outcomes were assessed in the total number of COVID-19 patients and moderate-type patients. Results: In a total of 60 patients, there were significant differences in the clinical outcome underlying treatment with antibiotics, tetrandrine, and arbidol (p < 0.05). When the comparison was limited to the moderate type, treatment with tetrandrine further increased recovery rate (p = 0.007). However, the difference disappeared, and no association was indicated between the clinical outcome and the treatment with and without antibiotic (p = 0.224) and arbidol (p = 0.318) in the moderate-type patients. In all-type and moderate-type patients, tetrandrine improved the rate of improvement in cough and fatigue on day 7 (p < 0.05). Conclusions: Tetrandrine may improve clinical outcome in COVID-19 patientsand could be a promising potential natural antiviral agent for the prevention and treatment of COVID-19.

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.

Molecular Docking Studies for Protein-Targeted Drug Development in SARS-CoV-2

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic and emergency. Currently, there is no therapeutic agent that has been proven effective against the virus. Objective: We investigated and screened for 401 antiviral compounds that could inhibit one or more of the three protein targets in SARS-CoV-2 chymotrypsin-like (3CL) protease, RNA-dependent RNA polymerase, and spike glycoprotein) using the in-silico approach. Methods: Lipinski’s rule of five was used as an initial screening for relevant compounds. Ligand preparation was conducted using JChem software and Schrödinger’s LigPrep module, while protein elucidation was conducted using AutoDockTools-1.5.6. Molecular docking was analyzed using Au-toDockVina. Results: Five antiviral compounds were obtained from each SARS-CoV-2 protein with ideal and potential binding energy as a candidate for target protein inhibition on SARS-CoV-2, TAK-981;lopinavir, mefloquine, and sitagliptin were potent inhibitors of 3CL protease;imatinib, relacatib, AZD7986, imatinib, and TAK-981 proteins showed potential as inhibitors of RdRp tetrandrine, and, selinexor, imatinib, lopinavir, and ciclesonide, showed potential as inhibitors of glycoprotein AZD7986. These compounds have better binding energy than the three comparator drugs, remdesivir, chloroquine, and hydroxychloroquine. Conclusion: We obtained several antiviral compounds with reliable binding energies to the SARS-CoV-2 proteins and potentially better efficacy than the three comparator drugs. Furthermore, this research will help accelerate the development of Covid-19 drugs.