Pyrimidine biosynthesis inhibitors synergize with nucleoside analogs to block SARS-CoV-2 infection

The ongoing COVID-19 pandemic has highlighted the dearth of approved drugs to treat viral infections, with only ~90 FDA approved drugs against human viral pathogens. To identify drugs that can block SARS-CoV-2 replication, extensive drug screening to repurpose approved drugs is underway. Here, we screened ~18,000 drugs for antiviral activity using live virus infection in human respiratory cells. Dose-response studies validate 122 drugs with antiviral activity and selectivity against SARS-CoV-2. Amongst these drug candidates are 16 nucleoside analogs, the largest category of clinically used antivirals. This included the antiviral Remdesivir approved for use in COVID-19, and the nucleoside Molnupirivir, which is undergoing clinical trials. RNA viruses rely on a high supply of nucleoside triphosphates from the host to efficiently replicate, and we identified a panel of host nucleoside biosynthesis inhibitors as antiviral, and we found that combining pyrimidine biosynthesis inhibitors with antiviral nucleoside analogs synergistically inhibits SARS-CoV-2 infection in vitro and in vivo suggesting a clinical path forward.

Download Full-text

In vitro activity of human recombinant alpha-2b interferon against SARS-CoV-2 virus

Voprosy Virusologii ◽

10.36233/0507-4088-13 ◽

2021 ◽

Vol 66 (2) ◽

pp. 123-128

Author(s):

S. Ya. Loginova ◽

V. N. Shсhukina ◽

S. V. Savenko ◽

S. V. Borisevich

Keyword(s):

Cell Culture ◽

Antiviral Activity ◽

Viral Infections ◽

Complete Suppression ◽

Antiviral Efficacy ◽

Prevention And Treatment ◽

Proven Efficacy ◽

High Antiviral Activity

Introduction. The pandemic spread of a new coronavirus infection, COVID-19, has caused a global emergency and attracted the attention of public health professionals and the population of all countries. A significant increase in the number of new cases of SARS-CoV-2 infection demonstrates the urgency of finding drugs effective against this pathogen.The aim of this work was to evaluate the in vitro antiviral efficacy of human recombinant alpha-2b interferon (IFN-α2b) against SARS-CoV-2 virus.Material and methods. The experiments had been carried out on Vero Cl008, the continuous line of African green monkey (Chlorocebus sabaeus) kidney cells. The effectiveness of the drugs was assessed by the suppression of viral reproduction in vitro. The biological activity was determined using titration of a virus-containing suspension in a Vero Cl008 cell culture by the formation of negative colonies.Results. The antiviral efficacy of the IFN-α2b-based medications, which have a high safety profile and proven efficacy in the prevention and treatment of influenza and acute respiratory viral infections (ARVI), has been studied against the new pandemic SARS-CoV-2 virus in vitro experiments in Vero C1008 cell culture. IFN-α2b effectively inhibits the reproduction of the virus when applied both 24 hrs before and 2 hrs after infection. In the IFN-α2b concentration range 102–106 IU/ml a complete suppression of the reproduction of the SARS-CoV-2 virus had been demonstrated.Discussion. IFN-α2b demonstrated in vitro high antiviral activity against SARS-CoV-2. In addition, the substance has a high chemotherapeutic index (>1000).Conclusion. Medications for intranasal use based on IFN-α2b have high antiviral activity and are promising drugs for in vivo study in terms of prevention and treatment of COVID-19.

Download Full-text

A narrative review of herbal preparations against RNA viruses

Journal of Contemporary Medical Sciences ◽

10.22317/jcms.v7i1.896 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Eghbal Jasemi ◽

Saeideh Momtaz ◽

Reza Ghaffarzadegan ◽

Amir Hossein Abdolghaffari ◽

Mohammad Abdollahi

Keyword(s):

Infectious Diseases ◽

Viral Infections ◽

Therapeutic Potential ◽

Synthetic Compound ◽

Novel Approach ◽

Plant Families ◽

Approved Drugs ◽

Almost All

Background: Throughout history, the plant kingdom has been a source of medicine in almost all cultures. Nowadays, ensuring the safety, quality, and effectiveness of medicinal herbs and their products has become an essential issue in industrialized and developing countries. Phytochemicals are usually involved in pharmacological actions and are used worldwide for various purposes, including the treatment of infectious diseases. Objectives: Although several therapeutics were designed to control infectious diseases, viral infections are still fatal. Currently, evidence extracted from in vivo, in vitro, and silico studies support the antiviral activity of many herbs scientifically; however, the therapeutic potential of many other herbs is still unknown. Plants and their products may potentially control the propagation of viruses in a variety of conditions. Methods: Data were extracted from PubMed, Scopus, Google Scholar, and Science Direct from 1983-2020. We gathered a list of plant extracts, phytochemicals, and herbal formulations that can inhibit RNA viral infections, mainly those are originated from the coronaviruses family. We also provided an overview of their inhibitory mechanism of actions. Results: Plant families, including Lamiaceae, Asteraceae, and Myrtaceae, contain the highest number of species with anti-coronaviruses activities, respectively. Conclusion: It can be suggested that the combination of these antiviral ingredients with each other, any synthetic compound, or already approved drugs or inhibitors can be a novel approach for antiviral therapies.

Download Full-text

Hydrotalcite–Niclosamide Nanohybrid as OralFormulation towards SARS-CoV-2 Viral Infections

Pharmaceuticals ◽

10.3390/ph14050486 ◽

2021 ◽

Vol 14 (5) ◽

pp. 486

Author(s):

Goeun Choi ◽

Huiyan Piao ◽

N. Sanoj Rejinold ◽

Seungjin Yu ◽

Ki yeok Kim ◽

...

Keyword(s):

Therapeutic Strategy ◽

Viral Infections ◽

Methyl Cellulose ◽

Oral Formulation ◽

Drug Candidates ◽

Ic50 Value ◽

Great Relevance ◽

Tween 60

COVID-19 has been affecting millions of individuals worldwide and, thus far, there is no accurate therapeutic strategy. This critical situation necessitates novel formulations for already existing, FDA approved, but poorly absorbable drug candidates, such as niclosamide (NIC), which is of great relevance. In this context, we have rationally designed NIC-loaded hydrotalcite composite nanohybrids, which were further coated with Tween 60 or hydroxypropyl methyl cellulose (HPMC), and characterized them in vitro. The optimized nanohybrids showed particle sizes <300 nm and were orally administrated to rats to determine whether they could retain an optimum plasma therapeutic concentration of NIC that would be effective for treating COVID-19. The pharmacokinetic (PK) results clearly indicated that hydrotalcite-based NIC formulations could be highly potential options for treating the ongoing pandemic and we are on our way to understanding the in vivo anti-viral efficacy sooner. It is worth mentioning that hydrotalcite–NIC nanohybrids maintained a therapeutic NIC level, even above the required IC50 value, after just a single administration in 8–12 h. In conclusion, we were very successfully able to develop a NIC oral formulation by immobilizing with hydrotalcite nanoparticles, which were further coated with Tween 60 or HPMC, in order to enhance their emulsification in the gastrointestinal tract.

Download Full-text

Broad anti-coronaviral activity of FDA approved drugs against SARS-CoV-2 in vitro and SARS-CoV in vivo

10.1101/2020.03.25.008482 ◽

2020 ◽

Cited By ~ 31

Author(s):

Stuart Weston ◽

Christopher M. Coleman ◽

Rob Haupt ◽

James Logue ◽

Krystal Matthews ◽

...

Keyword(s):

Antiviral Activity ◽

Rapid Development ◽

Drug Repurposing ◽

Ic50 Values ◽

Human Use ◽

Approved Drugs ◽

Fda Approved Drugs

AbstractSARS-CoV-2 emerged in China at the end of 2019 and has rapidly become a pandemic with roughly 2.7 million recorded COVID-19 cases and greater than 189,000 recorded deaths by April 23rd, 2020 (www.WHO.org). There are no FDA approved antivirals or vaccines for any coronavirus, including SARS-CoV-2. Current treatments for COVID-19 are limited to supportive therapies and off-label use of FDA approved drugs. Rapid development and human testing of potential antivirals is greatly needed. A quick way to test compounds with potential antiviral activity is through drug repurposing. Numerous drugs are already approved for human use and subsequently there is a good understanding of their safety profiles and potential side effects, making them easier to fast-track to clinical studies in COVID-19 patients. Here, we present data on the antiviral activity of 20 FDA approved drugs against SARS-CoV-2 that also inhibit SARS-CoV and MERS-CoV. We found that 17 of these inhibit SARS-CoV-2 at a range of IC50 values at non-cytotoxic concentrations. We directly follow up with seven of these to demonstrate all are capable of inhibiting infectious SARS-CoV-2 production. Moreover, we have evaluated two of these, chloroquine and chlorpromazine, in vivo using a mouse-adapted SARS-CoV model and found both drugs protect mice from clinical disease.

Download Full-text

In Vitro Antiviral Activity of Doxycycline against SARS-CoV-2

Molecules ◽

10.3390/molecules25215064 ◽

2020 ◽

Vol 25 (21) ◽

pp. 5064 ◽

Cited By ~ 2

Author(s):

Mathieu Gendrot ◽

Julien Andreani ◽

Priscilla Jardot ◽

Sébastien Hutter ◽

Océane Delandre ◽

...

Keyword(s):

Antiviral Activity ◽

Broad Spectrum ◽

In Vitro Study ◽

Experimental Models ◽

In Vivo Evaluation ◽

Study Results ◽

Anti Inflammatory ◽

Approved Drugs

In December 2019, a new severe acute respiratory syndrome coronavirus (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), emerged in Wuhan, China. Despite containment measures, SARS-CoV-2 spread in Asia, Southern Europe, then in America and currently in Africa. Identifying effective antiviral drugs is urgently needed. An efficient approach to drug discovery is to evaluate whether existing approved drugs can be efficient against SARS-CoV-2. Doxycycline, which is a second-generation tetracycline with broad-spectrum antimicrobial, antimalarial and anti-inflammatory activities, showed in vitro activity on Vero E6 cells infected with a clinically isolated SARS-CoV-2 strain (IHUMI-3) with median effective concentration (EC50) of 4.5 ± 2.9 µM, compatible with oral uptake and intravenous administrations. Doxycycline interacted both on SARS-CoV-2 entry and in replication after virus entry. Besides its in vitro antiviral activity against SARS-CoV-2, doxycycline has anti-inflammatory effects by decreasing the expression of various pro-inflammatory cytokines and could prevent co-infections and superinfections due to broad-spectrum antimicrobial activity. Therefore, doxycycline could be a potential partner of COVID-19 therapies. However, these results must be taken with caution regarding the potential use in SARS-CoV-2-infected patients: it is difficult to translate in vitro study results to actual clinical treatment in patients. In vivo evaluation in animal experimental models is required to confirm the antiviral effects of doxycycline on SARS-CoV-2 and more trials of high-risk patients with moderate to severe COVID-19 infections must be initiated.

Download Full-text

Pharmacophore Investigations of Potential COVID-19 RNA Polymerase (Rdrp) Inhibitors: Repurposing FDA-Approved Drugs

Microbiology & Infectious Diseases ◽

10.33425/2639-9458.1108 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Valentina L. Kouznetsova ◽

Caroline Kellogg ◽

Aidan Zhang ◽

Mahidhar Tatineni ◽

Mark A. Miller ◽

...

Keyword(s):

Rna Polymerase ◽

Hydrophobic Interactions ◽

Pharmacophore Model ◽

In Vivo Studies ◽

Drug Candidates ◽

Promising Target ◽

Approved Drugs ◽

Fda Approved Drugs

Authors: Valentina L. Kouznetsova, Caroline Kellogg, Aidan Zhang, Mahidhar Tatineni, Mark A. Miller, Igor F. Tsigelny Background: SARS-CoV-2 has caused tens of millions of infections worldwide and millions of deaths. Currently, no effective treatment has been identified against the virus. Of its viral proteins, the RNA-dependent RNA polymerase (RdRp) is a promising target for drug design because of its importance in the replication of the virus. Material and Methods: After the identification of an RdRp pocket site based on the crystal structure of the RdRp– nsp7–nsp8 complex and the triphosphate form of remdesivir (PDB ID: 7BV2), we created a pharmacophore model consisting of 11 different features. These features include two acceptors, three donors, one acceptor and donor, three donor or acceptor, and one hydrophobic; an excluded volume of R=1.1 Å was also added. We then ran a pharmacophore search on our conformational database (DB) of approximately 2500 FDA-approved drugs and 600 000 conformations to identify potential drug-candidates. To determine the drugs that bound the best, we conducted multi conformational docking of these results to the previously identified pocket site. Results: The pharmacophore search found 315 different potential inhibitors of RdRp, of which 85 were chosen based on the number of H-bonds and hydrophobic interactions in the best docking pose. Several of the drugs selected, including ritonavir, dasatinib, imatinib, and sofosbuvir, have previously been shown to be effective against other viruses. Conclusions: These findings highlight compounds that could lead to both in vitro and in vivo studies to identify potential treatments against SARS-CoV-2.

Download Full-text

Broad Anti-coronavirus Activity of Food and Drug Administration-Approved Drugs against SARS-CoV-2 In Vitro and SARS-CoV In Vivo

Journal of Virology ◽

10.1128/jvi.01218-20 ◽

2020 ◽

Vol 94 (21) ◽

Cited By ~ 12

Author(s):

Stuart Weston ◽

Christopher M. Coleman ◽

Robert Haupt ◽

James Logue ◽

Krystal Matthews ◽

...

Keyword(s):

Antiviral Activity ◽

Fast Track ◽

Rapid Development ◽

Clinical Disease ◽

Off Label Use ◽

Human Use ◽

Approved Drugs ◽

Fda Approved Drugs

ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China at the end of 2019 and has rapidly caused a pandemic, with over 20 million recorded COVID-19 cases in August 2020 (https://covid19.who.int/). There are no FDA-approved antivirals or vaccines for any coronavirus, including SARS-CoV-2. Current treatments for COVID-19 are limited to supportive therapies and off-label use of FDA-approved drugs. Rapid development and human testing of potential antivirals is urgently needed. Numerous drugs are already approved for human use, and subsequently, there is a good understanding of their safety profiles and potential side effects, making them easier to fast-track to clinical studies in COVID-19 patients. Here, we present data on the antiviral activity of 20 FDA-approved drugs against SARS-CoV-2 that also inhibit SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). We found that 17 of these inhibit SARS-CoV-2 at non-cytotoxic concentrations. We directly followed up seven of these to demonstrate that all are capable of inhibiting infectious SARS-CoV-2 production. Moreover, we evaluated two of these, chloroquine and chlorpromazine, in vivo using a mouse-adapted SARS-CoV model and found that both drugs protect mice from clinical disease. IMPORTANCE There are no FDA-approved antivirals for any coronavirus, including SARS-CoV-2. Numerous drugs are already approved for human use that may have antiviral activity and therefore could potentially be rapidly repurposed as antivirals. Here, we present data assessing the antiviral activity of 20 FDA-approved drugs against SARS-CoV-2 that also inhibit SARS-CoV and MERS-CoV in vitro. We found that 17 of these inhibit SARS-CoV-2, suggesting that they may have pan-anti-coronaviral activity. We directly followed up seven of these and found that they all inhibit infectious-SARS-CoV-2 production. Moreover, we evaluated chloroquine and chlorpromazine in vivo using mouse-adapted SARS-CoV. We found that neither drug inhibited viral replication in the lungs, but both protected against clinical disease.

Download Full-text

African and Asian Medicinal Plants as a Repository for Prospective Antiviral Metabolites Against HIV-1 and SARS CoV-2: A Mini Review

Frontiers in Pharmacology ◽

10.3389/fphar.2021.703837 ◽

2021 ◽

Vol 12 ◽

Author(s):

Godwin Anywar ◽

Muhammad Akram ◽

Muhammad Amjad Chishti

Keyword(s):

Medicinal Plants ◽

Plant Species ◽

Viral Infections ◽

Antiviral Agents ◽

Natural Compounds ◽

Drug Candidates ◽

Novel Coronavirus ◽

Hiv 1

Introduction: The worldwide burden of viral infections has triggered a resurgence in the search for new and more efficient antiviral drugs. Scientists are also repurposing existing natural compounds such as the antimalarial drug artemisinin from Artemesia annua L. as potential drug candidates for some of the emerging and re-emerging viral infections such as covid-19Aim: The aim of this review was to analyse the existing literature to explore the actual or potential natural antiviral compounds from African and Asian medicinal plants as lead compounds in the drug discovery process.Methods: We searched the literature on African and Asian medicinal plant species as antiviral agents for HIV-1 and the novel coronavirus (SARS-CoV-2) in various databases and search engines such as Web of Science, Google Scholar and PubMed. The search was limited to in vitro, in vivo, and clinical studies and excluded in silico studies.Results: We present 16 plant species with actual or potential antiviral activity against HIV-1 and SARS-CoV-2. These plant species span the continents of Africa and Asia where they are widely used for treating several other ailments.Conclusion: Natural compounds from plants can play a significant role in the clinical management of HIV/AIDS and the covid-19 pandemic. More research needs to be conducted to investigate the potential toxicities of the various compounds and their efficacies in clinical settings.

Download Full-text

Flavonoids as P-gp Inhibitors: A Systematic Review of SARs

Current Medicinal Chemistry ◽

10.2174/0929867325666181001115225 ◽

2019 ◽

Vol 26 (25) ◽

pp. 4799-4831 ◽

Cited By ~ 4

Author(s):

Jiahua Cui ◽

Xiaoyang Liu ◽

Larry M.C. Chow

Keyword(s):

Molecular Mechanisms ◽

Metastatic Cancer ◽

Drug Candidates ◽

Chemical Structures ◽

Transporter Family ◽

Promising Area ◽

New Generation ◽

Nontoxic Inhibitors

P-glycoprotein, also known as ABCB1 in the ABC transporter family, confers the simultaneous resistance of metastatic cancer cells towards various anticancer drugs with different targets and diverse chemical structures. The exploration of safe and specific inhibitors of this pump has always been the pursuit of scientists for the past four decades. Naturally occurring flavonoids as benzopyrone derivatives were recognized as a class of nontoxic inhibitors of P-gp. The recent advent of synthetic flavonoid dimer FD18, as a potent P-gp modulator in reversing multidrug resistance both in vitro and in vivo, specifically targeted the pseudodimeric structure of the drug transporter and represented a new generation of inhibitors with high transporter binding affinity and low toxicity. This review concerned the recent updates on the structure-activity relationships of flavonoids as P-gp inhibitors, the molecular mechanisms of their action and their ability to overcome P-gp-mediated MDR in preclinical studies. It had crucial implications on the discovery of new drug candidates that modulated the efflux of ABC transporters and also provided some clues for the future development in this promising area.

Download Full-text

Current Approaches to Drug Discovery for Chagas Disease: Methodological Advances

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207322666191010144111 ◽

2019 ◽

Vol 22 (8) ◽

pp. 509-520

Author(s):

Cauê B. Scarim ◽

Chung M. Chin

Keyword(s):

Drug Discovery ◽

Chagas Disease ◽

Drug Candidates ◽

Lead Compounds ◽

New Drug ◽

Compound Libraries ◽

Screening Assays ◽

Cruzi Infection

Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.

Download Full-text