SARS-CoV-2, the causative agent of COVID-19, has caused an unprecedented global health crisis. The SARS-CoV-2 spike, a surface-anchored trimeric class-I fusion glycoprotein essential for viral entry, represents a key target for developing vaccines and therapeutics capable of blocking virus invasion. The emergence of SARS-CoV-2 spike variants that facilitate virus spread and may affect vaccine efficacy highlights the need to identify novel antiviral strategies for COVID-19 therapy. Here, we demonstrate that nitazoxanide, an antiprotozoal agent with recognized broad-spectrum antiviral activity, interferes with SARS-CoV-2 spike maturation, hampering its terminal glycosylation at an endoglycosidase H-sensitive stage. Engineering multiple SARS-CoV-2 variant-pseudoviruses and utilizing quantitative cell-cell fusion assays, we show that nitazoxanide-induced spike modifications hinder progeny virion infectivity as well as spike-driven pulmonary cell-cell fusion, a critical feature of COVID-19 pathology. Nitazoxanide, being equally effective against the ancestral SARS-CoV-2 Wuhan-spike and different emerging variants, including the Delta variant of concern, may represent a useful tool in the fight against COVID-19 infections. 

/pdf/impairment-of-sars-cov-2-spike-glycoprotein-maturation-and-2y97ppa3.pdf

Impairment of SARS-CoV-2 spike glycoprotein maturation and fusion activity by nitazoxanide: an effect independent of spike variants emergence

Repurposing regulatory agency approved drugs and investigational compounds with known safety profiles can significantly fast track the drug development timeline over de novo drug discovery, with lower investment requirements and improved attrition rate. These advantages are vital in any epidemic or pandemic situation, where hospital beds are occupied by patients for whom there is no known treatment. Here we examine drug repurposing in the context of human coronaviruses, SARS-CoV, MERS-CoV, and, in particular, SARS-CoV-2, the virus currently causing a continued widespread pandemic with substantial impacts on public health and economy. The key druggable targets explored were those involved in viral entry, viral replication, and viral-induced ARDS, as well as viral proteases, with a focus on the strategy by which the drugs were repurposed. 

Strategies for drug repurposing against coronavirus targets

Nitazoxanide, a US Food and Drug Administration-approved antiparasitic agent, was reported to be effective in treating coronavirus disease 2019 (COVID-19). The lack of effective and precise treatments for COVID-19 infection earlier in the pandemic forced us to depend on symptomatic, empirical, and supportive therapy, which overburdened intensive care units and exhausted hospital resources. Therefore, the aim of this systematic review and meta-analysis was to assess the efficacy and safety of nitazoxanide for COVID-19 treatment. A systematic review and meta-analysis synthesizing relevant randomized controlled trials from six databases (MedRxiv, WOS, SCOPUS, EMBASE, PubMed, and CENTRAL) until 17 May 2022 was conducted. Risk ratio (RR) for dichotomous outcomes was used and data with a 95% confidence interval (CI) are presented. The protocol was registered in PROSPERO with ID: CRD42022334658. Six randomized controlled trials with 1412 patients were included in the analysis. Nitazoxanide was effective in accelerating viral clearance compared with placebo (RR: 1.30 with 95% CI 1.08, 1.56, p = 0.006) and reducing oxygen requirements (RR: 0.48 with 95% CI 0.39, 0.59, p = 0.00001), but we found no difference between nitazoxanide and placebo in improving clinical resolution (RR: 1.01 with 95% CI 0.94, 1.08, p = 0.88), reducing the mortality rate (RR: 0.88 with 95% CI 0.4, 1.91, p = 0.74), and intensive care unit admission (RR: 0.69 with 95% CI 0.43, 1.13, p = 0.14). Moreover, nitazoxanide was as safe as placebo (RR: 0.9 with 95% CI 0.72, 1.12, p = 0.34). Compared with placebo, nitazoxanide was effective in expediting viral clearance and decreasing oxygen requirements. However, there was no difference between nitazoxanide and placebo regarding clinical response, all-cause mortality, and intensive care unit admission. Therefore, more large-scale studies are still needed to ascertain the clinical applicability of nitazoxanide in COVID-19. 

/pdf/the-effect-of-nitazoxanide-on-the-clinical-outcomes-in-7nss49al.pdf

The Effect of Nitazoxanide on the Clinical Outcomes in Patients with COVID-19: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is a novel strain of SARS coronavirus. The COVID-19 disease caused by this virus was declared a pandemic by the World Health Organization (WHO). SARS-CoV-2 mainly spreads through droplets sprayed by coughs or sneezes of the infected to a healthy person within the vicinity of 6 feet. It also spreads through asymptomatic carriers and has negative impact on the global economy, security and lives of people since 2019. Numerous lives have been lost to this viral infection; hence there is an emergency to build up a potent measure to combat SARS-CoV-2. In view of the non-availability of any drugs or vaccines at the time of its eruption, the existing antivirals, antibacterials, antimalarials, mucolytic agents and antipyretic paracetamol were used to treat the COVID-19 patients. Still there are no specific small molecule chemotherapeutics available to combat COVID-19 except for a few vaccines approved for emergency use only. Thus, the repurposing of chemotherapeutics with the potential to treat COVID-19 infected people is being used. The antiviral activity for COVID-19 and biochemical mechanisms of the repurposed drugs are being explored by the biological assay screening and structure-based in silico docking simulations. The present study describes the various US-FDA approved chemotherapeutics repositioned to combat COVID-19 along with their screening for biological activity, pharmacokinetic and pharmacodynamic evaluation.

Repurposing of chemotherapeutics to combat COVID-19.

Until December 2021, the COVID-19 pandemic has caused more than 5.5 million deaths. Vaccines are being deployed worldwide to mitigate severe disease and death, but continued transmission and the emergence of SARS-CoV-2 variants indicate that specific treatments against COVID-19 are still necessary. We screened 400 compounds from the Medicines for Malaria Venture (MMV) Pathogen Box seeking for molecules with antiviral activity against SARS-CoV-2 by using a high-throughput screening (HTS) infection assay in Vero CCL81 cells. On resupply of 15 selected hit compounds, we confirmed that 7 of them presented a dose-dependent cytoprotective activity against SARS-CoV-2-induced cytopathic effect (CPE) in the micromolar range. They were validated in low-throughput infection assays using four different cell lines, including the human lung Calu-3 cell line. MMV000063, MMV024937, MMV688279, and MMV688991 reduced viral load in cell culture, assessed by RT-qPCR and viral plaque assay, while MMV688279 and MMV688991 (also known as nitazoxanide) were the most promising, reducing SARS-CoV-2 load by at least 100-fold at 20 µM in almost all cell types tested. Our results indicate that active anti-SARS-CoV-2 molecules exist within the repertoire of antiviral, antiparasitic and antimicrobial compounds available to date. Although the mode of action by which MMV688279 and MMV688991 reduce SARS-CoV-2 replication is yet unknown, the fact that they were active in different cell types holds promise not only for the discovery of new therapeutic targets, but also for the development of novel antiviral medicines against COVID-19.

Identification of Compounds With Antiviral Activity Against SARS-CoV-2 in the MMV Pathogen Box Using a Phenotypic High-Throughput Screening Assay

The fast spread of COVID-19 has overcrowded Public Health Systems facilities in major countries due to the large number of seriously ill patients, particularly those requiring admission to intensive care units. Reducing viral load, along with other recommended epidemiological measures, such as social distancing and home confinement, can in time significantly help to reduce the infection R0 (Basic Reproductive Rate) and then mitigate disease burden. Early negativization or otherwise reduction of the viral load can potentially diminish disease severity, resulting in a better-controlled public health response, avoiding collapse of healthcare systems. Nitazoxanide, a widely used thiazolide approved by the FDA as an antiparasitic drug, also approved in Brazil for Norovirus and Rotavirus treatments, has an excellent safety record for a variety of indications. Nitazoxanide exhibits activity in vitro against MERS-CoV and other coronaviruses; and a specific antiviral effect (in micro molar doses) against SARS-CoV-2. The objective of this study was to evaluate the efficacy and safety of Nitazoxanide in reducing the SARS-COV 2 viral load within 7 days of treatment in respiratory samples from COVID-19-infected patients with mild to moderate disease, compared to placebo. An interim analysis showed that the ratio of patients with a viral load reduction [≥] 35% from baseline up to day 7 of treatment was significantly greater for Nitazoxanide compared to placebo (47.8% vs. 15.4%; {Delta} 34.6%; 95% CI: 64.7; 4.6: p = 0.037). KEY POINTSO_ST_ABSState of the ArtC_ST_ABSO_LIDifferent studies conclude that viral load (VL) would correlate with morbidity, mortality and contagiousness of COVID-19. C_LIO_LIEarly negativization or reduction of the viral load can potentially reduce the severity of this disease. C_LIO_LIIn vitro data demonstrated a specific antiviral effect of Nitazoxanide for SARS-CoV-2. C_LI Article contributionO_LINitazoxanide showed a statistically significant difference versus placebo in the number of patients who had their viral load reduced by at least 35% in mild to moderate COVID-19 disease. C_LIO_LIThe observed antiviral effect in vitro would seems to be verified in patients with mild to moderate COVID-19 infection, which should be confirmed by studies with a larger cohort of patients. C_LI

/pdf/efficacy-of-nitazoxanide-in-reducing-the-viral-load-in-covid-4g5ch2ul0w.pdf

Efficacy of Nitazoxanide in reducing the viral load in COVID-19 patients. Randomized, placebo-controlled, single-blinded, parallel group, pilot study.

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Efficacy of Nitazoxanide in reducing the viral load in COVID-19 patients. Randomized, placebo-controlled, single-blinded, parallel group, pilot study.