Immunity Modulators, Repurposed Drugs and Candidate Vaccines for COVID-19: A Review

COVID-19, a pandemic has led the whole globe through unprecedented times and unpre-dictability that has adversely affected the humanity as a whole. Although the severe acute respiratory syndrome was reported in the year 2002-2004 of zoonotic origin caused by SARS-CoV-1 strain. Now recently, in December 2019, SARS-CoV-2 virus has emerged and swiftly spread to the whole world, taking a heavy toll on life. Studies are being conducted worldwide to find antiviral drugs act-ing specifically on the virus and to develop the vaccine for the disease. The present review article summarizes the currently undergoing clinical trials of Indian Ayurvedic herbs and their role in promoting immunity. It also includes studies focused on repurposing the existing drugs and finding alternative treatment methods that can be opted for potential treatment/management of COVID-19. Last but not the least, this paper provides a background on the development of preventive vaccines and the various bioinformatic tools utilized in order to help accelerate the research on coronavirus. The manuscript gives a brief outline of all the possible strategies and therapeutics underway in India and at the global level to fight against the microscopic adversary and lead to an affordable and speedy remedy for COVID-19.Copyright © 2021 Bentham Science Publishers.

Antimalarial drugs inhibit the replication of SARS-CoV-2: An in vitro evaluation.

In December 2019, a new severe acute respiratory syndrome coronavirus (SARS-CoV-2) causing coronavirus diseases 2019 (COVID-19) emerged in Wuhan, China. African countries see slower dynamic of COVID-19 cases and deaths. One of the assumptions that may explain this later emergence in Africa, and more particularly in malaria endemic areas, would be the use of antimalarial drugs. We investigated the in vitro antiviral activity against SARS-CoV-2 of several antimalarial drugs. Chloroquine (EC50 = 2.1 µM and EC90 = 3.8 µM), hydroxychloroquine (EC50 = 1.5 µM and EC90 = 3.0 µM), ferroquine (EC50 = 1.5 µM and EC90 = 2.4 µM), desethylamodiaquine (EC50 = 0.52 µM and EC90 = 1.9 µM), mefloquine (EC50 = 1.8 µM and EC90 = 8.1 µM), pyronaridine (EC50 = 0.72 µM and EC90 = 0.75 µM) and quinine (EC50 = 10.7 µM and EC90 = 38.8 µM) showed in vitro antiviral effective activity with IC50 and IC90 compatible with drug oral uptake at doses commonly administered in malaria treatment. The ratio Clung/EC90 ranged from 5 to 59. Lumefantrine, piperaquine and dihydroartemisinin had IC50 and IC90 too high to be compatible with expected plasma concentrations (ratio Cmax/EC90 < 0.05). Based on our results, we would expect that countries which commonly use artesunate-amodiaquine or artesunate-mefloquine report fewer cases and deaths than those using artemether-lumefantrine or dihydroartemisinin-piperaquine. It could be necessary now to compare the antimalarial use and the dynamics of COVID-19 country by country to confirm this hypothesis.

Combining Computational and Experimental Evidence on the Activity of Antimalarial Drugs on Papain-Like Protease of SARS-CoV-2: A Repurposing Study.

The development of inhibitors that target the papain-like protease (PLpro) has the potential to counteract the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent causing coronavirus disease 2019 (COVID-19). Based on a consideration of its several downstream effects, interfering with PLpro would both revert immune suppression exerted by the virus and inhibit viral replication. By following a repurposing strategy, the current study evaluates the potential of antimalarial drugs as PLpro inhibitors, and thereby the possibility of their use for treatment of SARS-CoV-2 infection. Computational tools were employed for structural analysis, molecular docking and molecular dynamics simulations to screen antimalarial drugs against PLpro, and in silico data were validated by in vitro experiments. Virtual screening highlighted amodiaquine and methylene blue as the best candidates, and these findings were complemented by the in vitro results that indicated amodiaquine as a µM PLpro deubiquitinase inhibitor. The results of this study demonstrate that the computational workflow adopted here can correctly identify active compounds. Thus, the highlighted antimalarial drugs represent a starting point for the development of new PLpro inhibitors through structural optimization.

Review-Recent Advancements in Electrochemical Sensors for 4-Aminoquinoline Drugs Determination in Biological and Environmental Samples

4-Aminoquinoline including Hydroxychloroquine (HCQ), amodiaquine (AQ), Chloroquine (CQ) are a quinoline with an amino group at the 4th position with a basic side chain. They are generally used as antimalarial medications. HCQ and CQ are recommended by the World Health Organization on march 2020 the use as a possible treatment to coronavirus (COVID-19). Long-term of 4-aminoquinoline drugs administration can be associated with toxic side-effects on the outer retina and the retinal pigment epithelium. Therefore, their determination in biological samples is important. Several methods have been used for 4-Aminoquinoline compounds analysis, such as spectrophotometry, immunological, electrophoresis, chromatography and electroanalytical methods. Electrochemical methods are more preferable because they are simple, quick analysis and more sensitive performance. Up to now, numerous electrochemical methods have been used to detect those drugs. Nevertheless, the utilization of later techniques is limited. Therefore, this review describes different electrochemical sensors, which are used for 4-aminoquinoline electroanalysis in complex matrices such as pharmaceuticals and biological fluids. For this, the fundamental analytical performance of the chosen sensors is investigated. The selectivity and oxidation mechanisms for 4-aminoquinoline reported in the literature were discussed. Also, the application of these sensors for 4-aminoquinoline monitoring in biological and environmental samples is reported.

Re-orienting anti-malarial drug development to better serve pregnant women.

Malaria is one of the most serious infectious diseases affecting predominantly low- and middle-income countries, where pregnant women are among the populations at risk. There are limited options to prevent or treat malaria in pregnancy, particularly in the first trimester, and existing ones may not work optimally in areas where the threat of drug resistance is rising. As malaria elimination is a key goal of the global health community, the inclusion of pregnant women in the adult population to protect from malaria will be key to achieving success. New, safe, and effective options are needed but it can take decades of evidence-gathering before a medicine is recommended for use in pregnancy. This is because pregnant women are typically not included in pre-registration clinical trials due to fear of causing harm. Data to support dosing and safety in pregnancy are subsequently collected in post-licensure studies. There have been growing calls in recent years that this practice needs to change, amplified by the COVID-19 pandemic and increasing public awareness that newly developed medicines generally cannot be administered to pregnant women from the onset. The development of new anti-malarials should ensure that data informing their use in pregnancy and breastfeeding are available earlier. To achieve this, a mindset change and a different approach to medications for pregnant women are needed. Changes in non-clinical, translational, and clinical approaches in the drug development pathway, in line with recent recommendations from the regulatory bodies are proposed in this Comment. The new approach applies to any malaria-endemic region, regardless of the type of Plasmodium responsible for malaria cases. By incorporating intentional and systematic data collection from pre-registration stages of development through post-licensure, it will be possible to inform on the benefit/risk balance of a new anti-malarial earlier and help ensure that the needs of pregnant individuals are addressed in a more timely and equitable manner in the future.

In silico Drug Repurposing for the Identification of Antimalarial Drugs as Candidate Inhibitors of SARS-CoV-2

Background: Coronavirus disease (COVID-19) is a severe acute respiratory condition that has affected millions of people worldwide, indicating a global health emergency. Despite the deteriorating trends of COVID-19, no drugs are validated to have substantial efficacy in the potential treatment of COVID-19 patients in large-scale trials. Methods: This study aimed at identifying potential antimalarial candidate molecules for the treatment of COVID and evaluating the possible mechanism of action by in silico screening method. In silico screening studies on various antimalarial compounds, like amodiaquine, chloroquine, hydroxychloroquine, mefloquine, primaquine, and atovaquone, were conducted using PyRx and AutoDoc 1.5.6 tools against ACE 2 receptor, 3CL protease, hemagglutinin esterase, spike protein of SARS HR1 motif, and papain-like protease virus proteins. Results: Based on PyRx results, mefloquine and atovaquone were found to have higher docking affinity scores against virus proteins compared to other antimalarial compounds. Screening report of atovaquone exhibited affirmative inhibition constant for spike protein of SARS HR1 motif, 3CL protease, and papain-like protease. Conclusion: In silico analysis reported atovaquone as a promising candidate for COVID 19 therapy.

A Drug Repurposing Approach for Antimalarials Interfering with SARS-CoV-2 Spike Protein Receptor Binding Domain (RBD) and Human Angiotensin-Converting Enzyme 2 (ACE2).

Host cell invasion by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by the interaction of the viral spike protein (S) with human angiotensin-converting enzyme 2 (ACE2) through the receptor-binding domain (RBD). In this work, computational and experimental techniques were combined to screen antimalarial compounds from different chemical classes, with the aim of identifying small molecules interfering with the RBD-ACE2 interaction and, consequently, with cell invasion. Docking studies showed that the compounds interfere with the same region of the RBD, but different interaction patterns were noted for ACE2. Virtual screening indicated pyronaridine as the most promising RBD and ACE2 ligand, and molecular dynamics simulations confirmed the stability of the predicted complex with the RBD. Bio-layer interferometry showed that artemisone and methylene blue have a strong binding affinity for RBD (KD = 0.363 and 0.226 µM). Pyronaridine also binds RBD and ACE2 in vitro (KD = 56.8 and 51.3 µM). Overall, these three compounds inhibit the binding of RBD to ACE2 in the µM range, supporting the in silico data.

Phytocompounds of Rheum emodi, Thymus serpyllum, and Artemisia annua Inhibit Spike Protein of SARS-CoV-2 Binding to ACE2 Receptor: In Silico Approach.

COVID-19, the disease caused by SARS-CoV-2, has been declared as a global pandemic. Traditional medicinal plants have long history to treat viral infections. Our in silico approach suggested that unique phytocompounds such as emodin, thymol and carvacrol, and artemisinin could physically bind SARS-CoV-2 spike glycoproteins (6VXX and 6VYB), SARS-CoV-2 B.1.351 South Africa variant of Spike glycoprotein (7NXA), and even with ACE2 and prevent the SARS-CoV-2 binding to the host ACE2, TMPRSS2 and neutrapilin-1 receptors. Since Chloroquine has been looked as potential therapy against COVID-19, we also compared the binding of chloroquine and artemisinin for its interaction with spike proteins (6VXX, 6VYB) and its variant 7NXA, respectively. Molecular docking study of phytocompounds and SARS-CoV-2 spike protein was performed by using AutoDock/Vina software. Molecular dynamics (MD) simulation was performed for 50ns. Among all the phytocompounds, molecular docking studies revealed lowest binding energy of artemisinin with 6VXX and 6VYB, with Etotal -10.5 KJ mol-1 and -10.3 KJ mol-1 respectively. Emodin showed the best binding affinity with 6VYB with Etotal -8.8 KJ mol-1and SARS-CoV-2 B.1.351 variant (7NXA) with binding energy of -6.4KJ mol-1. Emodin showed best interactions with TMPRSS 2 and ACE2 with Etotal of -7.1 and -7.3 KJ mol-1 respectively, whereas artemisinin interacts with TMPRSS 2 and ACE2 with Etotal of -6.9 and -7.4 KJ mol-1 respectively. All the phytocompounds were non-toxic and non-carcinogenic. MD simulation showed that artemisinin has more stable interaction with 6VYB as compared to 6VXX, and hence proposed as potential phytochemical to prevent SARS-CoV-2 interaction with ACE-2 receptor. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40495-021-00259-4.

Antimalarial drugs-are they beneficial in rheumatic and viral diseases?-considerations in COVID-19 pandemic.

The majority of the medical fraternity is continuously involved in finding new therapeutic schemes, including antimalarial medications (AMDs), which can be useful in combating the 2019-nCoV: coronavirus disease (COVID-19). For many decades, AMDs have been widely used in the treatment of malaria and various other anti-inflammatory diseases, particularly to treat autoimmune disorders of the connective tissue. The review comprises in vitro and in vivo studies, original studies, clinical trials, and consensus reports for the analysis, which were available in medical databases (e.g., PubMed). This manuscript summarizes the current knowledge about chloroquine (CQ)/hydroxychloroquine (HCQ) and shows the difference between their use, activity, recommendation, doses, and adverse effects on two groups of patients: those with rheumatic and viral diseases (including COVID-19). In the case of connective tissue disorders, AMDs are prescribed for a prolonged duration in small doses, and their effect is observed after few weeks, whereas in the case of viral infections, they are prescribed in larger doses for a short duration to achieve a quick saturation effect. In rheumatic diseases, AMDs are well tolerated, and their side effects are rare. However, in some viral diseases, the effect of AMDs is questionable or not so noticeable as suggested during the initial prognosis. They are mainly used as an additive therapy to antiviral drugs, but recent studies have shown that AMDs can diminish the efficacy of some antiviral drugs and may cause respiratory, kidney, liver, and cardiac complications.

Treatment Approaches for COVID-19: A Critical Review.

BACKGROUND: Coronavirus disease 2019 (COVID-19) outbreak was declared as an emerging global public health concern on 30th January 2020. This novel coronavirus (SARS-CoV-2) outbreak was first identified in Wuhan city, China, which soon affected around 185 countries and territories all over the world through various transmission mechanisms. To date, no permanent cure has been found, due to which this pandemic threatens humanity for its very existence. OBJECTIVE: In light of the rising menace, this review aims at providing collective and prominent information on the current outbreak, covering its origin, structure, transmission, clinical features, potential treatment approaches, and clinical trial details. METHODS: The literature published in Scopus and PubMed indexed journals were reviewed, and clinical trial data was retrieved from the ClinicalTrials.gov database. RESULTS: Present review puts forth detailed insights on history, epidemiology, structure, genetic makeup, reservoirs, entry mechanisms, reproduction capacity, pathogenesis, routes of transmission, clinical features, diagnostics, the role of chloroquine in treatment, current promising therapies, and vaccination trials. CONCLUSION: At present, early detection, isolation of infected patients, and supportive care with a few recently USFDA approved alternative medications are being used as per the standard government guidelines. Due to insufficient availability of proof regarding current therapies to produce therapeutic activity against COVID-19, safety precautions, prevention methods, hygiene maintenance and management therapy with intensive care medicine is the only way to fight this current situation.

A pharmacovigilance study to quantify the strength of association between the combination of antimalarial drugs and azithromycin and cardiac arrhythmias: implications for the treatment of COVID-19.

Background: Hydroxychloroquine, an antimalarial drug, combined with azithromycin has been considered a potential treatment for COVID-19. However, these drugs may cause electrocardiogram QT prolongation (QTp) and torsade de Pointes (TdP). We examined potential safety signals for these cardiac arrhythmias. Methods: Using the OpenVigil 2.1 MedDRA platform, we mined data from the U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) from December 2019 to June 2020. We extracted individual case safety reports based on exposures of seven antimalarial drugs, azithromycin, and combinations. All other drugs in FAERS served as controls. Events of interest included QTp and TdP, with associations between drug exposures and events expressed as adjusted Reporting-Odds-Ratios (aRORs) and confidence intervals. The lower end of aROR 95% confidence interval >1 was used as the statistically significant signal detection threshold. Results: QTp safety signals were found for hydroxychloroquine[aROR:11.70 (10.40-13.16)], chloroquine[aROR:18.97 (11.30-31.87)], quinine[aROR:16.66 (10.18-27.25)], atovaquone[aROR:6.91 (4.14-11.56)], azithromycin alone [aROR:28.02 (22.87-34.32)] and hydroxychloroquine + azithromycin [aROR:75.23 (51.15-110.66)]. TdP safety signals were found for hydroxychloroquine [aROR: 5.62 (4.94-6.38)], chloroquine[aROR:49.37 (30.63-79.58)], and hydroxychloroquine + azithromycin[aROR:33.09 (21.22-51.61)]. Conclusion: Hydroxychloroquine/chloroquine and/or azithromycin was associated with QTp/TdP safety signals and their use should be monitored carefully.

What could explain the late emergence of COVID-19 in Africa?

At the end of November 2019, a novel coronavirus responsible for respiratory tract infections emerged in China. Despite drastic containment measures, this virus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spread in Asia and Europe. The pandemic is ongoing with a particular hotspot in southern Europe and America in spring 2020. Many studies predicted an epidemic in Africa similar to that currently seen in Europe and the USA. However, reported data do not confirm these predictions. Several hypotheses that could explain the later emergence and spread of the coronavirus disease 2019 (COVID-19) pandemic in African countries are being discussed, including the lack of health-care infrastructure capable of clinically detecting and confirming COVID-19 cases, the implementation of social distancing and hygiene, international air traffic flows, the climate, the relatively young and rural population, the genetic polymorphism of the angiotensin-converting enzyme 2 receptor, cross-immunity and the use of antimalarial drugs.

In silico Potential of Approved Antimalarial Drugs for Repurposing Against COVID-19.

Although the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is wreaking havoc and resulting in mortality and morbidity across the planet, novel treatments are urgently needed. Drug repurposing offers an innovative approach in this context. We report here new findings on the in silico potential of several antimalarial drugs for repurposing against COVID-19. We conducted analyses by docking the compounds against two SARS-CoV-2-specific targets: (1) the receptor binding domain spike protein and (2) the main protease of the virus (MPro) using the Schrödinger software. Importantly, the docking analysis revealed that doxycycline (DOX) showed the most effective binding to the spike protein of SARS-CoV-2, whereas halofantrine and mefloquine bound effectively with the main protease among the antimalarial drugs evaluated in the present study. The in silico approach reported here suggested that DOX could potentially be a good candidate for repurposing for COVID-19. In contrast, to decipher the actual potential of DOX and halofantrine against COVID-19, further in vitro and in vivo studies are called for. Drug repurposing warrants consideration as a viable research and innovation avenue as planetary health efforts to fight the COVID-19 continue.