Antiviral activity of chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine towards RNA-viruses. A review
Michał Otręba,a,∗ Leon Kośmider,b and Anna Rzepecka-Stojkoa
Eur J Pharmacol. 2020 Nov 15; 887: 173553.
Abstract
In 2020 the whole world focused on antivirus drugs towards SARS-CoV-2. Most of the researchers focused on drugs used in other viral infections or malaria. We have not seen such mobilization towards one topic in this century. The whole situation makes clear that progress needs to be made in antiviral drug development. The first step to do it is to characterize the potential antiviral activity of new or already existed drugs on the market. Phenothiazines are antipsychotic agents used previously as antiseptics, anthelminthics, and antimalarials. Up to date, they are tested for a number of other disorders including the broad spectrum of viruses. The goal of this paper was to summarize the current literature on activity toward RNA-viruses of such drugs like chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine. We identified 49 papers, where the use of the phenothiazines for 23 viruses from different families were tested. Chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine possess anti-viral activity towards different types of viruses. These drugs inhibit clathrin-dependent endocytosis, cell-cell fusion, infection, replication of the virus, decrease viral invasion as well as suppress entry into the host cells. Additionally, since the drugs display activity at nontoxic concentrations they have therapeutic potential for some viruses, still, further research on animal and human subjects are needed in this field to verify cell base research.
Inhibition of the replication of SARS-CoV-2 in human cells by the FDA-approved drug chlorpromazine
Marion Plaze, ProfileDavid Attali, ProfileMatthieu Prot, ProfileAnne-Cécile Petit, ProfileMichael Blatzer, ProfileFabien Vinckier, Laurine Levillayer, Florent Perin-Dureau, ProfileArnaud Cachia, ProfileGérard Friedlander, ProfileFabrice Chrétien, ProfileEtienne Simon-Loriere, ProfileRaphaël Gaillard
doi: https://doi.org/10.1101/2020.05.05.079608
This article is a preprint
Abstract
Urgent action is needed to fight the ongoing COVID-19 pandemic by reducing the number of infected people along with the infection contagiousness and severity. Chlorpromazine (CPZ), the prototype of typical antipsychotics from the phenothiazine group, is known to inhibit clathrin-mediated endocytosis and acts as an antiviral, in particular against SARS-CoV-1 and MERS-CoV. In this study, we describe the in vitro testing of CPZ against a SARS-CoV-2 isolate in monkey and human cells. We evidenced an antiviral activity against SARS-CoV-2 with an IC50 of ∼10μM. Because of its high biodistribution in lung, saliva and brain, such IC50 measured in vitro may translate to CPZ dosage used in clinical routine. This extrapolation is in line with our observations of a higher prevalence of symptomatic and severe forms of COVID-19 infections among health care professionals compared to patients in psychiatric wards. These preclinical findings support the repurposing of CPZ, a largely used drug with mild side effects, in COVID-19 treatment.
https://www.biorxiv.org/content/10.1101/2020.05.05.079608v1
Cannabinoid Receptor Type 2: A Possible Target in SARS-CoV-2 (CoV-19) Infection?
Francesca Rossi,1,* Chiara Tortora,1 Maura Argenziano,2 Alessandra Di Paola,2 and Francesca Punzo1
Int J Mol Sci. 2020 Jun; 21(11): 3809.
Abstract
In late December 2019, a novel coronavirus (SARS-CoV-2 or CoV-19) appeared in Wuhan, China, causing a global pandemic. SARS-CoV-2 causes mild to severe respiratory tract inflammation, often developing into lung fibrosis with thrombosis in pulmonary small vessels and causing even death. COronaVIrus Disease (COVID-19) patients manifest exacerbated inflammatory and immune responses, cytokine storm, prevalence of pro-inflammatory M1 macrophages and increased levels of resident and circulating immune cells. Men show higher susceptibility to SARS-CoV-2 infection than women, likely due to estrogens production. The protective role of estrogens, as well as an immune-suppressive activity that limits the excessive inflammation, can be mediated by cannabinoid receptor type 2 (CB2). The role of this receptor in modulating inflammation and immune response is well documented in fact in several settings. The stimulation of CB2 receptors is known to limit the release of pro-inflammatory cytokines, shift the macrophage phenotype towards the anti-inflammatory M2 type and enhance the immune-modulating properties of mesenchymal stromal cells. For these reasons, we hypothesize that CB2 receptor can be a therapeutic target in COVID-19 pandemic emergency.
Curcumin: a Wonder Drug as a Preventive Measure for COVID19 Management
Yamuna Manoharan,#1 Vikram Haridas,2,3 K. C. Vasanthakumar,corresponding author#1 Sundaram Muthu,1 Fathima F. Thavoorullah,1 and Praveenkumar Shetty4,5
Indian J Clin Biochem. 2020 Jul; 35(3): 373–375.
A major outbreak of highly contagious disease novel coronavirus (COVID19) that has recently emerged as epidemic in China in December 2019, spreads across the globe and becoming a pandemic [1]. The disease is caused by novel Corona virus SARS-COV-2 (severe acute respiratory syndrome coronavirus 2) belonging to the family coronaviridae. Coronaviruses are single stranded positive sense RNA viruses, transmitted to humans via respiratory droplets. Majority of the severe SARS-CoV2 infected patients develop acute respiratory distress due to the elevated levels of proinflammatory cytokines and other clinical conditions like diarrhoea, when infection is transmitted through food [1–3]. Globally, it is reported that 6,057,853 positive cases with 371,166 deaths thus far. In India over 190,000 confirmed COVID19 positive cases have been reported, the virus claimed 5577 lives so far suggesting a low mortality rate in Indian population as compared to other ethnics.
Till date there is no specific antiviral therapy available to treat COVID-19 patients. Combination therapy has been considered by the clinicians which include antiviral agents, antibiotics and anti-inflammatory drugs [2] including hydroxychloroquine are widely used in developed countries. In the context of preventive and supportive therapy, several polyphenolic compounds extracted from natural products were identified with varied antiviral mechanisms such as targeting virus host specific interactions, viral entry, replication, and assembly. In line with these findings, curcumin, is one of the natural compounds that had been widely investigated for its antiviral effects [4]. Curcumin, a natural polyphenolic compound extracted from roots of rhizome plant Curcuma longa (family Zingiberaceae), exhibits wide range of therapeutic properties including antioxidant, anti-microbial, anti-proliferative, anti-inflammatory, neuroprotective and cardioprotective properties. Curcumin, the yellow pigment of turmeric is extensively used in our Indian traditional herbal medicines to cure many diseases associated with infection and inflammation for many decades [5]. It is reported that, curcumin exerts antiviral activities against broad spectrum of viruses including HIV, HSV-2, HPV viruses, Influenza virus, Zikavirus, Hepatitis virus and Adenovirus [3, 4].
Recent studies have indicated that alike original SARS-CoV, the SARS-COV2 also invades human host cells by targeting Angiotensin Converting Enzyme 2(ACE2) membrane receptor, an entry site for coronavirus. The binding of viral S protein to ACE2 receptor present on mucus membrane mediates the viral and membrane fusion and subsequent viral replication in host [1, 5]. A recent study showed that expression of ACE2 was detected in nasal epithelial cells, alveolar epithelial type II cells (AECII) of lungs and luminal surface of intestinal epithelial cells. Hence nasopharynx, lungs and intestine facilitate viral entry and serve as potential site of viral invasion [6]. Most studies have shown that Angiotensin II exerts its biological activities by binding to two receptors namely angiotensin 2 type 1 receptor (AT1R) and angiotensin 2 type 2 receptor (AT2R). Angiotensin-converting enzyme 2 (ACE2) a homologue of ACE, sharing 61% sequence similarity with the ACE catalytic domain, hydrolyses Angiotensin II to Angiotensin (1–7) and attenuates Angiotensin II-ATIR axis mediated vasoconstriction effects, thereby reducing the blood pressure through vasodilation [7].
In line with the growing evidences of therapeutic properties of the curcumin, here we propose a hypothetical treatment strategy of using curcumin as (1) potential inhibitory agent blocking the host viral interaction (viral spike protein—ACE2 receptor) at an entry site in humans and (2) as an attenuator via modulating the proinflammatory effects of Angiotensin II-AT1 receptor-signalling pathways reducing respiratory distress in the treatment of COVID19.
A study using Insilico approach involving docking and stimulation, demonstrated the dual binding affinity of polyphenolic compoundsin which both the viral S protein and ACE2 binds to curcumin. Binding of curcumin to receptor-binding domain (RBD) site of viral S protein and also to the viral attachment sites of ACE2 receptor, demonstrated that curcumin can act as potential inhibitory agent antagonizing the entry of SARS-CoV2 viral protein [3]. Moreover, emulsion form of topical application of curcumin may effectively prevent the SARS-CoV2 infection in humans, as the viral entry site of ACE2 receptor is predominantly distributed at the nasal cells, mucosal surface of respiratory tract and eyes [6].
Further, curcumin has been extensively studied for its role in the regulation of RAAS (renin–angiotensin–aldosterone system) components through which it is known to exert anti-oxidant, anti-inflammatory and antihypertensive effects. Animal studies have implicated the role of curcumin in the downregulation of ACE and AT1R receptor expression in brain tissue and vascular smooth muscle cells, respectively resulting inhibition of Angiotensin II-AT1R mediated effects of hypertension and oxidative stress in animals [8, 10]. Previous studies revealed high level of AT2R and ACE2 expression in myocardial cells treated with curcumin thus exhibiting the protective mechanism of curcumin via modulationof effects mediated by Angiotensin II receptors AT1R and AT2R. Upregulation of AT2R induces suppression of AT1R expression leading to Angiotensin II-AT2R mediated anti-inflammatory effects involving an inhibition of NF-κB activity and oxidative stress. Hence, treatment with curcumin attenuated the proinflammatory effects induced by Angiotensin II-AT1R axis leading to significant decrease in the level of proinfammatory cytokines TNF-α, IL-6 and reactive oxygen species [5, 10].
Nutritional supplements of curcumin with vitamin C and zinc have showed promising results in boosting the natural immunity and protective defense against the CoV infections have been noted in many hospitalized patients in Indian setting. It is also noted that pharmacological formulation of curcumin in nanoemulsion system proved increased solubility and bioavailability and with enhanced antihypertensive effect [9].
Henceforth, it is clear that the biological properties including advance mode of drug delivery system of curcumin could be considered while formulating the pharmaceutical products and its application as preventive measure in the inhibition of transmission of SARS-COV2 infection among humans. However, further large scale clinical trials are warranted to understand the usefulness of curcumin for the pharmacological application in nanoemulsion system. In conclusion, we propose that curcumin could be used as a supportive therapy in the treatment of COVID19 disease in any clinical settings to circumvent the lethal effects of SARS-CoV-2.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299138/
Potential effects of curcumin in the treatment of COVID-19 infection
Fatemeh Zahedipour 1, Seyede Atefe Hosseini 1, Thozhukat Sathyapalan 2, Muhammed Majeed 3, Tannaz Jamialahmadi 4 5 6, Khalid Al-Rasadi 7, Maciej Banach 8 9, Amirhossein Sahebkar 9 10 11
Phytother Res. 2020 Nov;34(11):2911-2920. doi: 10.1002/ptr.6738. Epub 2020 Jun 23.
Abstract
Coronavirus disease 2019 (COVID-19) outbreak is an ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with considerable mortality worldwide. The main clinical manifestation of COVID-19 is the presence of respiratory symptoms, but some patients develop severe cardiovascular and renal complications. There is an urgency to understand the mechanism by which this virus causes complications so as to develop treatment options. Curcumin, a natural polyphenolic compound, could be a potential treatment option for patients with coronavirus disease. In this study, we review some of the potential effects of curcumin such as inhibiting the entry of virus to the cell, inhibiting encapsulation of the virus and viral protease, as well as modulating various cellular signaling pathways. This review provides a basis for further research and development of clinical applications of curcumin for the treatment of newly emerged SARS-CoV-2.
https://pubmed.ncbi.nlm.nih.gov/32430996/
Targeting the SARS-CoV-2 Main Protease to Repurpose Drugs for COVID-19
Erol C. Vatansever,a,† Kai Yang,a,† Kaci C. Kratch,a,† Aleksandra Drelich,b Chia-Chuan Cho,a Drake M. Mellot,c Shiqing Xu,a Chien-Te K. Tseng,b and Wenshe Ray Liua,c,*
Version 1. bioRxiv. Preprint. 2020 May 23. doi: 10.1101/2020.05.23.112235
Abstract
Guided by a computational docking analysis, about 30 FDA/EMA-approved small molecule medicines were characterized on their inhibition of the SARS-CoV-2 main protease (MPro). Of these tested small molecule medicines, six displayed an IC50 value in inhibiting MPro below 100 μM. Three medicines pimozide, ebastine, and bepridil are basic small molecules that are expected to exert a similar effect as hydroxychloroquine in raising endosomal pH for slowing down the SARS-CoV-2 entry into human cell hosts. Bepridil has been previously explored in a high dose as 100 mg/kg for treating diseases. Its high dose use will likely achieve dual functions in treating COVID-19 by both raising the endosomal pH to slow viral entry and inhibiting MPro in infected cells. Therefore, the current study urges serious considerations of using bepridil in COVID-19 clinical tests.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263498.1/
FDA approved calcium channel blockers inhibit SARS-CoV-2 infectivity in epithelial lung cells
ProfileMarco R. Straus, Miya Bidon, Tiffany Tang, Gary R. Whittaker, Susan Daniel
doi: https://doi.org/10.1101/2020.07.21.214577 This article is a preprint
Abstract
COVID-19 has infected more than 22 million people worldwide causing over 750.000 deaths. The disease is caused by the severe acute respiratory syndrome coronavirus (CoV) 2 (SARS-CoV-2), which shares a high sequence similarity to SARS-CoV. Currently there are no vaccinations available to provide protection and the only antiviral therapy in active use in patients is remdesivir, which currently provides only limited benefit. Hence, there is an urgent need for antiviral therapies against SARS-CoV2. SARS-CoV requires Ca2+ ions for host cell entry and based on the similarity between SARS-CoV and SARS-CoV-2 it is highly likely that the same requirements exist for the two viruses. Here, we tested whether FDA-approved calcium channel blocker (CCB) drugs are efficacious to inhibit the spread of SARS-CoV-2 in cell culture. Our data shows that amlodipine, felodipine, and nifedipine limit the growth of SARS-CoV-2 in epithelial kidney (Vero E6) and epithelial lung (Calu-3) cells. We observed some differences in the inhibition efficacy of the drugs in the two different cell lines, but with felodipine and nifedipine having the greatest effect. Overall, our data suggest that CCBs have a high potential to treat SARS-CoV-2 infections and their current FDA approval would allow for a fast repurposing of these drugs.
https://www.biorxiv.org/content/10.1101/2020.07.21.214577v2
Repurposing FDA-Approved Drugs for COVID-19 Using a Data-Driven Approach
Preprint submitted on 17.04.2020, 19:37 and posted on 21.04.2020, 13:36 by Rodrigo R. R. Duarte, Dennis C. Copertino Jr., Luis P. Iñiguez, Jez L. Marston, Douglas F. Nixon, Timothy R. Powell
Abstract
There have been more than 116,000 recorded deaths worldwide to-date caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the etiological agent of the Coronavirus Disease 2019 (COVID-19), and over 1.8 million individuals are currently infected. Although there are now hundreds of clinical trials for COVID-19, there are currently no effective licensed treatments, while the numbers of infected individuals continue to rise at an exponential rate in many parts of the world. Here, we used a data-driven approach utilizing connectivity mapping and the transcriptional signature of lung carcinoma cells infected with SARS-CoV-2, to search for drugs across the spectrum of medicine that have repurposing potential for treating COVID-19. We also performed chemoinformatic analyses to test whether the identified compounds were predicted to physically interact with the SARS-CoV-2 RNA-dependent RNA polymerase or main protease enzymes. Our study identified commonly prescribed FDA-approved molecules as important candidates for drug repositioning against COVID-19, including flupentixol, reserpine, fluoxetine, trifluoperazine, sunitinib, atorvastatin, raloxifene, butoconazole, and metformin. These drugs should not be taken for treating or preventing COVID-19 without a doctor’s advice, as further research and clinical trials are now needed to elucidate their efficacy for this purpose.
Insights into the biased activity of dextromethorphan and haloperidol towards SARS-CoV-2 NSP6: in silico binding mechanistic analysis
Preeti Pandey,1 Kartikay Prasad,2 Amresh Prakash,corresponding author3 and Vijay Kumarcorresponding author2
J Mol Med (Berl). 2020 Sep 23 : 1–15.
Abstract
The outbreak of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus continually led to infect a large population worldwide. SARS-CoV-2 utilizes its NSP6 and Orf9c proteins to interact with sigma receptors that are implicated in lipid remodeling and ER stress response, to infect cells. The drugs targeting the sigma receptors, sigma-1 and sigma-2, have emerged as effective candidates to reduce viral infectivity, and some of them are in clinical trials against COVID-19. The antipsychotic drug, haloperidol, exerts remarkable antiviral activity, but, at the same time, the sigma-1 benzomorphan agonist, dextromethorphan, showed pro-viral activity. To explore the potential mechanisms of biased binding and activity of the two drugs, haloperidol and dextromethorphan towards NSP6, we herein utilized molecular docking–based molecular dynamics simulation studies. Our extensive analysis of the protein-drug interactions, structural and conformational dynamics, residual frustrations, and molecular switches of NSP6-drug complexes indicates that dextromethorphan binding leads to structural destabilization and increase in conformational dynamics and energetic frustrations. On the other hand, the strong binding of haloperidol leads to minimal structural and dynamical perturbations to NSP6. Thus, the structural insights of stronger binding affinity and favorable molecular interactions of haloperidol towards viral NSP6 suggests that haloperidol can be potentially explored as a candidate drug against COVID-19.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509052/
Nature Publication Presents New ‘Blueprint’ Revealing How SARS-CoV-2 Virus Hijacks Human Cells
Research April 30, 2020
An international team of more than 120 scientists has detailed the impact of 75 over-the-counter prescription and development-stage drug compounds on SARS-CoV-2, the virus that causes COVID-19. Several of these agents show promise in blocking SARS-CoV-2 replication in laboratory experiments. One compound investigated in the research, a common ingredient in over-the-counter cough medicines, appears to have the potential to promote the growth of the virus.
The collaborative study, published in Nature on April 30, 2020, was assembled and led by Nevan Krogan, PhD, director of the Quantitative Biosciences Institute at UC San Francisco and a senior investigator at Gladstone Institutes. As the first hints of the pandemic emerged in January, over a matter of just a few weeks, Krogan formed a rapid-response research team of dozens of scientists and clinicians – hailing from UCSF, Gladstone, Icahn School of Medicine at Mount Sinai in New York, and Institut Pasteur in Paris – to search for potential treatments for COVID-19.
Repurposed Compounds Show Promise for Fighting COVID-19; Further Research Needed
Looking at a list of drugs that interact with the protein blueprint, UCSF researchers Brian Shoichet, PhD, professor of pharmaceutical chemistry, and Kevan Shokat, PhD, professor of cellular and molecular pharmacology and a Howard Hughes Medical Institute investigator, led studies employing chemical biology and computational approaches. Two drug categories emerged as promising agents to effectively reduce viral infectivity: protein translation inhibitors (including zotatifin and ternatin-4), and drugs that modulate proteins inside the cell known as Sigma1 and Sigma2 receptors (including progesterone, PB28, PD-144418, hydroxychloroquine; the antipsychotic drugs haloperidol and cloperazine; siramesine, an antidepressant and anti-anxiety drug; and the antihistamines clemastine and cloperastine).
Drug Repurposing Screen for Compounds Inhibiting the Cytopathic Effect of SARS-CoV-2
Catherine Z. Chen,1,* Paul Shinn,1 Zina Itkin,1 Richard T. Eastman,1 Robert Bostwick,2 Lynn Rasmussen,2 Ruili Huang,1 Min Shen,1 Xin Hu,1 Kelli M. Wilson,1 Brianna Brooks,1 Hui Guo,1 Tongan Zhao,1 Carleen Klump-Thomas,1 Anton Simeonov,1 Samuel G. Michael,1 Donald C. Lo,1 Matthew D. Hall,1 and Wei Zheng1,*
bioRxiv. Preprint. 2020 Aug 18. doi: 10.1101/2020.08.18.255877
Abstract
Drug repurposing is a rapid approach to identifying therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for treatment options, we carried out a quantitative high-throughput screen using a SARS-CoV-2 cytopathic assay with a compound collection of 8,810 approved and investigational drugs, mechanism-based bioactive compounds, and natural products. Three hundred and nineteen compounds with anti-SARSCoV-2 activities were identified and confirmed, including 91 approved drug and 49 investigational drugs. Among these confirmed compounds, the anti-SARS-CoV-2 activities of 230 compounds, including 38 approved drugs, have not been previously reported. Chlorprothixene, methotrimeprazine, and piperacetazine were the three most potent FDA approved drugs with anti-SARS-CoV-2 activities. These three compounds have not been previously reported to have anti-SARS-CoV-2 activities, although their antiviral activities against SARS-CoV and Ebola virus have been reported. These results demonstrate that this comprehensive data set of drug repurposing screen for SARS-CoV-2 is useful for drug repurposing efforts including design of new drug combinations for clinical trials.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444282/