The pandemic of COVID-19 has ignited a global race to locate effective therapies with drug repositioning emerging as a leading strategy due to its cost-effectiveness and established safety profiles. Remdesivir, Favipiravir, Hydroxychloroquine, and Chloroquine have been the focus of rigorous clinical trials to determine their therapeutic potential against SARS-CoV-2. This article delves into the innovative synthetic strategies behind these drugs, providing a blueprint for researchers navigating the complex landscape of antiviral development. Beyond synthesis, we explore the fascinating mechanisms of action: hydroxychloroquine and chloroquine elevate lysosomal pH to impede autophagy and viral replication; favipiravir, a nucleoside analogue, induces lethal mutagenesis or RNA chain termination and remdesivir disrupts viral RNA synthesis through delayed chain termination. By merging synthetic methodologies with mechanistic insights, this article offers a comprehensive resource aimed at accelerating the development of potent COVID-19 therapies and underscores the crucial part that chemistry in addressing global health emergencies. It also underscores the vital function of chemistry in addressing global health emergencies and highlights how innovative drug design and repurposing can provide rapid responses to emerging infectious diseases. This fusion of chemistry and virology not only advances our understanding of drug action but also paves the way for the discovery of new therapeutic agents crucial in future pandemics.

Although the SARS-CoV-2 epidemic worldwide has gradually decreased, in some areas, the situation has not yet been stamped and has become a global health emergency. It is quite possible that we could again be threatened by a new coronavirus. Therefore, new nucleotide analog drugs and vaccines or using drug repositioning for SARS-CoV-2 still has been developed, yet their safety and efficacy against COVID-19 remains underexplored. Malabaricone C is 2,6-dihydroxyphenyl acylphenol found in edible plants such as the mace spice of nutmeg derived from the seeds of Myristica fragrans. In this study, we identified malabaricone C as the first inhibitor of SARS-CoV-2 from natural food with a safe alternative for drugs. Malabaricone C and its chemical derivatives showed EC50 values of 1-1.5 μM against SARS-CoV-2 (WK-521, ancestral strain) and its variant strains in mammalian cells (HEK293T and Vero E6). In addition, we have successfully established novel evaluation system for the inhibition of SARS virus cell fusion by visualization for providing a versatile tool for study SARS-CoV-2 mediated fusion. Furthermore, our experiments suggested that malabaricone C could affect the distribution of sphingomyelin on the plasma membrane, which involves in viral infections. Thus, in light of the beneficial effect of malabaricone C on viral infection, the nontoxic malabaricone C is a suitable candidate as a drug that can be employed in the treatment and prevention of COVID-19. Moreover, it may potentially be used to treat acute infections of other enveloped viruses.

A new series of acyl hydrazones have been synthesized from 4-chloro-8-nitro-1,2-dihydroquinoline-3-carbaldehyde. These compounds were characterized using various spectroscopic techniques. Density functional theoretical (DFT) studies were conducted to understand the correlation between electronic parameters and biological activity. The biological activity of the compounds was theoretically examined through molecular docking and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analysis. The compounds demonstrated high absorption rates and were found to be non-hepatotoxic. Preliminary cytotoxicity screenings against HeLa cell lines identified compound 7 as the most potent, with an IC50 value of 18.8 μM. This compound was further selected for bioimaging studies. The results indicate that compound 7 induces apoptosis at its IC50 concentration, suggesting its potential as an anticancer agent.

THSWD has the effect of reducing inflammation, improving microcirculation, and regulating immune status in patients with hepatocellular carcinoma. Regardless of its clear therapeutic effect, the underlying mechanism of action against hepatocellular carcinoma is not clear. To identify critical gut microbiota and its associated metabolites related to THSWD inhibition against hepatocellular carcinoma progression, we assessed the microbe-dependent anti-hepatocellular carcinoma effects of THSWD through 16 s rRNA gene sequencing, fecal microbial transplantation and antibiotic treatment. Metabolic analyses, transcriptomic analyses, and molecular experiments were performed to explore how THSWD modulates the gut microbiota against hepatocellular carcinoma progression. As confirmed by in vivo and in vitro assays, THSWD reduced tumour growth rate and promoted apoptosis in hepatocellular carcinoma cells in hepatocellular carcinoma model mice, and liver and kidney indexes were detected and confirmed the safety of THSWD. Transcriptomic analysis revealed that the targets of THSWD were significantly enriched in multiple lysosomal autophagy signalling pathways, suggesting that lysosomal autophagy is probably associated with THSWD's therapeutic effect. Based on the integrated data analysis, THSWD delays hepatocellular carcinoma progression by increasing the intestinal microbiota Duncaniella and augmenting the metabolite glabrol, and the joint analysis of metabolic and genomic data suggests that this metabolite is associated with lysosomal autophagy, and cellular experiments confirmed that the The differential metabolite glabrol induces apoptosis in hepatocellular carcinoma cells by triggering the lysosomal autophagy-mediated apoptosis signalling pathway. Supplementation with glabrol metabolites up regulates the LTF/AMPK/mTOR/Beclin1 axis and promotes hepatocellular carcinoma cells with lysosomal autophagy and induced apoptosis in hepatocellular carcinoma cells.

Various repurposing drugs have been tested for their efficacy on coronavirus disease 2019 (COVID-19), including antimalarial drugs. During the pandemic, Chloroquine (CQ) and Hydroxychloroquine (HCQ) demonstrated good potential against COVID-19, but further studies showed both drugs had side effects that were more dangerous than the efficacy. This made World Health Organization (WHO) ban the usage for COVID-19 patients. In this context, there is a need to explore other antimalarial drugs as potential therapies for COVID-19. This study provides a descriptive synthesis of clinical trials evaluating antimalarial drugs for COVID-19 treatment conducted after the withdrawal of CQ and HCQ. The method was a literature study using the keywords "antimalarial", "COVID-19", "SARS-CoV-2", "clinical trial", and "randomized controlled trial" on the MEDLINE, Scopus, and Cochrane databases. Inclusion criteria were published clinical trials with randomized controlled trials (RCTs) on the efficacy and safety of single antimalarial drugs for COVID-19, published in English and excluding combination therapies. The results showed 3 antimalarial drugs, namely Quinine Sulfate (QS), Atovaquone (AQ), and Artemisinin-Piperaquine (AP), had gone through clinical trial to assess efficacy and safety against COVID-19 patients. Out of the 3 drugs, only AP showed significant results in the primary outcome, which was the time required to reach undetectable levels of SARS-CoV-2. Furthermore, the intervention group took 10.6 days, and the control group took 19.3 days (p=0.001). Based on this review, AP showed significant potential as a therapy in the fight against COVID-19.

One of the most significant threats to global public health in the 21st century is the novel coronavirus disease (COVID-19) caused by SARS-CoV-2. It rapidly turned into a global pandemic after it was identified in late 2019, and the World Health Organization announced the end of the pandemic on May 5, 2023. Current strategies for managing this disease include vaccination and repurposing antimalarial and antibiotic medications to alleviate symptoms like fever and throat pain, which are associated with acute respiratory distress syndrome (ARDS). Antiviral drugs such as chloroquine, hydroxychloroquine, azithromycin, remdesivir, and favipiravir have been repurposed for the treatment of COVID-19. They were previously recommended for treating SARS-CoV and MERS-CoV. However, the inefficacy and adverse side effects of these repurposed drugs led to a decrease in their widespread use in treating COVID-19 patients. The lack of approved drugs for combating this coronavirus and its unpredictable variants remains a significant challenge.

Four years after the beginning of the COVID-19 pandemic, it is important to reflect on the events that have occurred during that time and the knowledge that has been gained. The response to the pandemic was rapid and highly resourced; it was also built upon a foundation of decades of federally funded basic and applied research. Laboratories in government, pharmaceutical, academic, and non-profit institutions all played roles in advancing pre-2020 discoveries to produce clinical treatments. This perspective provides a summary of how the development of high-throughput screening methods in a biosafety level 3 (BSL-3) environment at Southern Research Institute (SR) contributed to pandemic response efforts. The challenges encountered are described, including those of a technical nature as well as those of working under the pressures of an unpredictable virus and pandemic.

Chloroquine (CQ) is a 4-aminoquinoline derivative largely employed in the management of malaria. CQ treatment exploits the drug's ability to cross the erythrocyte membrane, inhibiting heme polymerase in malarial trophozoites. Accumulation of CQ prevents the conversion of heme to hemozoin, causing its toxic buildup, thus blocking the survival of Plasmodium parasites. Recently, it has been reported that CQ is able to exert antiviral properties, mainly against HIV and SARS-CoV-2. This renewed interest in CQ treatment has led to the development of new studies which aim to explore its side effects and long-term outcome. Our study focuses on the effects of CQ in non-parasitized red blood cells (RBCs), investigating hemoglobin (Hb) functionality, the anion exchanger 1 (AE1) or band 3 protein, caspase 3 and protein tyrosine phosphatase 1B (PTP-1B) activity, intra and extracellular ATP levels, and the oxidative state of RBCs. Interestingly, CQ influences the functionality of both Hb and AE1, the main RBC proteins, affecting the properties of Hb oxygen affinity by shifting the conformational structure of the molecule towards the R state. The influence of CQ on AE1 flux leads to a rate variation of anion exchange, which begins at a concentration of 2.5 μM and reaches its maximum effect at 20 µM. Moreover, a significant decrease in intra and extracellular ATP levels was observed in RBCs pre-treated with 10 µM CQ vs. erythrocytes under normal conditions. This effect is related to the PTP-1B activity which is reduced in RBCs incubated with CQ. Despite these metabolic alterations to RBCs caused by exposure to CQ, no signs of variations in oxidative state or caspase 3 activation were recorded. Our results highlight the antithetical effects of CQ on the functionality and metabolism of RBCs, and encourage the development of new research to better understand the multiple potentiality of the drug.

In this study, we aim to describe the demographic, clinical and imaging characteristics, treatment course and subsequent outcomes of the first 116 cases presenting to a tertiary Dublin hospital with COVID-19 infection and to compare whether ethnic minority background was a risk factor for poorer disease outcomes in this cohort. Of 116 cases analysed, 100 (86%) patients presented from the community, 6 (5%) from care homes and 10 (9%) were existing inpatients. Fifty-four (46%) patients identified as being from an ethnic minority group. One hundred fourteen (98%) patients reported two or more symptoms at time of diagnosis with 81 (70%) patients having confirmed radiological findings of COVID-19 infection. Median duration of symptoms prior to hospital presentation was 6 days (IQR 3-10 days). The median age at presentation was 52 years (IQR 43-65). Co-morbidities recorded included hypertension, hyperlipidaemia, type 2 diabetes mellitus, underlying respiratory disease, previous or current malignancy and current smoker. Twenty-six patients (22%) required ICU admission, 20 (76.9%) of these were from all other ethnic groups combined and 6 (10%) from White Irish group. Adjusting for variables of age, ethnicity and gender, all other ethnic groups combined were five times more likely to require ICU admission than White Irish group (Table 5). Patients from all other ethnic groups combined admitted to ICU were significantly younger than patients from White Irish group (OR 50.85 vs 62.83, P = 0.012). Our hospital's catchment area serves a wide-ranging and diverse population with many ethnic minority groups represented. Our data demonstrated that there was a significant overrepresentation of a younger cohort of patients from ethnic minority groups admitted to ICU with COVID-19 infection with less co-morbidities than that of the White Irish group.

The Coronavirus disease of 2019 (COVID-19) pandemic undoubtedly ranks among the most health-impacting pandemics throughout medical history. Although the COVID-19 global public health emergency has ended, lessons need to be learned to be more ready to face similar pandemics in the future. Few studies in Saudi Arabia discuss the impact of the COVID-19 pandemic on autoimmune rheumatic disease (AIRD) patients. Thus, this study was conducted to elaborate on the effects of the COVID-19 pandemic on AIRD patients and rheumatology practices in Saudi Arabia.  Methods: This observational cross-sectional study was conducted among patients aged over 14 with AIRD using a pre-designed validated survey questionnaire. Data were collected from AIRD patients who were following up between November 2021 to April 2022 at the Rheumatology Clinic of King Fahad General Hospital in Madinah City, Saudi Arabia. This center was chosen as being the main hospital in the city following patients of AIRD.

A total of 324 patients were included in our study, with the majority (n=264, 81.5%) being females. The mean age was 44.42±14.4 years. Clinical data revealed that 115 (35.5%) of our patients experienced mild COVID-19 infection, 19 (5.9%) suffered from respiratory insufficiency, and seven (2.2%) required admission to the intensive care unit (ICU). Non-compliance to medication was recorded at 25.2%. There were 115 (35.5%) patients who had an AIRD flare that was significantly higher among those who were not adherent to the medications (p<0.001). Disease flare was also significantly seen among patients who were not on prednisone or were on low doses of prednisone (p<0.001). The majority (n=33, 97.1%) of the 34 infected patients who had an AIRD flare had their flare-up at the same time as their COVID-19 infection (p<0.001). COVID-19 vaccination rate was 87.7% (n=284). The most common reason for non-vaccination in 40 (12.3%) patients was the patients' concern about disease flare-ups by the vaccine or interference of the vaccine with their medication (n=16, 4.9%).

Our study showed a 35.5% (n=115) COVID-19 infection rate. The majority of our AIRD patients sustained minor infections that did not require hospitalization or ICU admission. The majority of the patients who underwent a severe COVID-19 infection course were not on prednisolone or were on low-dose prednisone. Due to COVID-19 restrictions and drug shortages, one in four patients (25.3%) stopped taking their medications and was significantly found to have a high prevalence of underlying AIRD flare. Despite the high vaccination rate, disease flare was the biggest concern for those who were not immunized. Although the COVID-19 pandemic has ended, doctors should be aware of risk factors associated with severe AIRD outcomes that should be balanced based on the infection severity, underlying disease flares, and patient-centered education about medication adherence and vaccination.

Pharmaceutical transformation products (TPs) generated during wastewater treatment have become an environmental concern. However, there is limited understanding regarding the TPs produced from pharmaceuticals during wastewater treatment. In this study, chloroquine (CQ), which was extensively used for treating coronavirus disease-19 (COVID-19) infections during the pandemic, was selected for research. We identified and fractionated the main TP produced from CQ during chlorine disinfection and investigated the neurotoxic effects of CQ and its main TP on zebrafish (Danio rerio) embryos. Halogenated TP353 was observed as one of the main TPs produced from CQ during chlorine disinfection. Zebrafish embryos test revealed that TP353 caused higher neurotoxicity in zebrafish larvae, as compared to the CQ, and that was accompanied by significantly decreased expression levels of the genes related to central nervous system development (e.g., gfap, syn2a, and elavl3), inhibited activity of acetylcholinesterase (AChE), reduced GFP fluorescence intensity of motor neuron axons in transgenic larvae (hb9-GFP), and reduced total swimming distance and swimming velocity of larvae during light-dark transition stimulation. The results of this study can potentially be utilized as a theoretical reference for future evaluations of environmental risks associated with CQ and its related TPs. This work presents a methodology for assessing the environmental hazards linked to the discharge of pharmaceutical TPs after wastewater treatment.

The rapid spread of the SARS-CoV-2 virus during the early phase of the pandemic led to an unprecedented global health crisis. Various factors have influenced self-medication practices among the general population and unsubstantiated prescribing practices among healthcare professionals.

This study aimed to describe trends in the purchase and sale of medicines during the COVID-19 pandemic period (2020-2022) in Ecuador, by comparing them with pre-pandemic periods.

In this study, a cross-sectional design was employed to conduct a comprehensive analysis of 28 pharmacological groups, categorized according to the Anatomical Therapeutic Chemical Classification (ATC). Utilizing an integrated drug consumption database, the study examined physician prescribing data, medicine usage, and spending levels in Ecuador during the COVID-19 pandemic. The analysis involved computing absolute differences in monthly resolution, calculating excessive expenditure in comparison to previous yearly averages, and using Defined Daily Dose (DDD) methodology for internationally comparable results. Furthermore, a correlation analysis was performed to investigate potential associations between prescribed and consumed medicines and the number of new cases and deaths.

In Ecuador, the average yearly expenditure among these groups prior to the pandemic (2017-2019) amounted to $150,646,206 USD, whereas during 2020 and 2021, the same groups represented a total expenditure of $228,327,210, reflecting a significant increase. The excess expenditure during this period reached 51.4%, equivalent to $77,681,004 USD. Notably, 13% of this expenditure consisted of Over the Counter (OTC) Medicines. The study also identified a remarkable surge in sales of ivermectin, which increased by 2,057%, and hydroxychloroquine, which increased by 171%, as measured by DDD.

This study highlights the substantial consumption of medicines by the population in Ecuador during the pandemic. It is concerning that many medications were sold without proven therapeutic indications, indicating that misinformation and desperation may have led to improper prescribing by physicians and patients resorting to ineffective drugs. Moreover, since the sale of these therapeutic drugs requires a prescription, poor regulation, and a lack of control within pharmacies likely contributed to such practices.

Many of the 2020 COVID-19 clinical trials included an (hydroxy)chloroquine ((H)CQ) arm. We aimed to juxtapose the state of science before April 2020 regarding the benefits of (H)CQ for viral infections with the number and size of the clinical trials studying (H)CQ and the volume of (H)CQ dispensed in France.

We identified and analysed published scientific material regarding the antiviral activity of (H)CQ and publicly available data regarding clinical trials and drug dispensation in France.

We conducted a review of scientific publications available before April 2020 and a systematic analysis of COVID-19 clinical trials featuring (H)CQ registered on clinicaltrials.gov.

Before April 2020, 894 scientific publications mentioning (H)CQ for viruses other than coronaviruses were available, including 35 in vitro studies (reporting an inconstant inhibition of viral replication), 11 preclinical studies (reporting no or disputable positive effects), and 32 clinical trials (reporting no or disputable positive effects). Moreover, 67 publications on (H)CQ and coronavirus infections were available, including 12 in vitro studies (reporting an inconstant inhibition of viral replication), two preclinical studies (reporting contradictory results), and no clinical trials. Meanwhile, 253 therapeutic clinical trials featuring an HCQ arm were registered in 2020, intending to enrol 246,623 patients.

The number and size of (H)CQ clinical trials for COVID-19 launched in 2020 were not supported by the literature published before April 2020.

This study describes the cell-free biomanufacturing of a broad-spectrum antiviral protein, griffithsin (GRFT) such that it can be produced in microgram quantities with consistent purity and potency in less than 24 h. We demonstrate GRFT production using two independent cell-free systems, one plant and one microbial. Griffithsin purity and quality were verified using standard regulatory metrics. Efficacy was demonstrated in vitro against SARS-CoV-2 and HIV-1 and was nearly identical to that of GRFT expressed in vivo. The proposed production process is efficient and can be readily scaled up and deployed wherever a viral pathogen might emerge. The current emergence of viral variants of SARS-CoV-2 has resulted in frequent updating of existing vaccines and loss of efficacy for front-line monoclonal antibody therapies. Proteins such as GRFT with its efficacious and broad virus neutralizing capability provide a compelling pandemic mitigation strategy to promptly suppress viral emergence at the source of an outbreak.

Cell death is a fundamental physiological process that occurs in all organisms and is crucial to each organism's evolution, ability to maintain a stable internal environment, and the development of multiple organ systems. Disulfidptosis is a new mode of cell death that is triggered when cells with high expression of solute carrier family 7 member 11 (SLC7A11) are exposed to glucose starvation to initiate the process of cell death. The disulfidptosis mechanism is a programmed cell death mode that triggers cell death through reduction-oxidation (REDOX) reactions and disulfur bond formation. In disulfidptosis, disulfur bonds play a crucial role and cause the protein in the cell to undergo conformational changes, eventually leading to cell death. This mode of cell death has unique characteristics and regulatory mechanisms in comparison with other modes of cell death. In recent years, an increasing number of studies have shown that the disulfidptosis mechanism plays a key role in the occurrence and development of a variety of diseases. For example, cancer, cardiovascular diseases, neurodegenerative diseases, and liver diseases are all closely related to cell disulfidptosis mechanisms. Therefore, it is of paramount clinical significance to conduct in-depth research regarding this mechanism. This review summarizes the research progress on the disulfidptosis mechanism, including its discovery history, regulatory mechanism, related proteins, and signaling pathways. Potential applications of the disulfidptosis mechanism in disease therapy and future research directions are also discussed. This mechanism represents another subversive discovery after ferroptosis, and provides both a fresh perspective and an innovative strategy for the treatment of cancer, as well as inspiration for the treatment of other diseases.

This study aimed to evaluate whether individualized homeopathic medicines have a greater adjunctive effect than adjunctive placebos in the treatment of moderate and severe cases of coronavirus disease 2019 (COVID-19).

The study was a randomized, single-blind, prospective, placebo-controlled clinical trial set in the clinical context of standard care.

Patients of either sex, admitted in a tertiary care hospital, suffering from moderate or severe COVID-19 and above 18 years of age were included. In total, 150 patients were recruited and then randomly divided into two groups to receive either individualized homeopathic medicines or placebos, in addition to the standard treatment of COVID-19.

The primary outcome was time taken to achieve RT-PCR-confirmed virus clearance for COVID-19. Secondary outcomes were changes in the Clinical Ordinal Outcomes Scale (COOS) of the World Health Organization, the patient-reported MYMOP2 scale, and several biochemical parameters. Parametric data were analyzed using unpaired t-test. Non-parametric data were analyzed using the Wilcoxon signed rank test. Categorical data were analyzed using Chi-square test.

In total, 72 participants of the add-on homeopathy (AoH) group showed conversion of RT-PCR status to negative, in an average time of 7.53 ± 4.76 days (mean ± SD), as compared with 11.65 ± 9.54 days in the add-on placebo (AoP) group (p = 0.001). The mean COOS score decreased from 4.26 ± 0.44 to 3.64 ± 1.50 and from 4.3 ± 0.46 to 4.07 ± 1.8 in the AoH and AoP groups respectively (p = 0.130). The mortality rate for the AoH group was 9.7% compared with 17.3% in the AoP group. The MYMOP2 scores between the two groups differed significantly (p = 0.001), in favor of AoH. Inter-group differences in the pre- and post- mean values of C-reactive protein, fibrinogen, total leukocyte count, platelet count and alkaline phosphatase were each found to be statistically significant (p <0.05), favoring AoH; six other biochemical parameters showed no statistically significant differences.

The study suggests homeopathy may be an effective adjunct to standard care for treating moderate and severe COVID-19 patients. More rigorous, including double-blinded, studies should be performed to confirm or refute these initial findings.

The Penn Medicine COVID-19 Therapeutics Committee-an interspecialty, clinician-pharmacist, and specialist-front line primary care collaboration-has served as a forum for rapid evidence review and the production of dynamic practice recommendations during the 3-year coronavirus disease 2019 public health emergency. We describe the process by which the committee went about its work and how it navigated specific challenging scenarios. Our target audiences are clinicians, hospital leaders, public health officials, and researchers invested in preparedness for inevitable future threats. Our objectives are to discuss the logistics and challenges of forming an effective committee, undertaking a rapid evidence review process, aligning evidence-based guidelines with operational realities, and iteratively revising recommendations in response to changing pandemic data. We specifically discuss the arc of evidence for corticosteroids; the noble beginnings and dangerous misinformation end of hydroxychloroquine and ivermectin; monoclonal antibodies and emerging viral variants; and patient screening and safety processes for tocilizumab, baricitinib, and nirmatrelvir-ritonavir.

The coronavirus disease 2019 (COVID-19) pandemic has affected a large portion of the global population, both physically and mentally. Current evidence suggests that the rapidly evolving coronavirus subvariants risk rendering vaccines and antibodies ineffective due to their potential to evade existing immunity, with enhanced transmission activity and higher reinfection rates that could lead to new outbreaks across the globe. The goal of viral management is to disrupt the viral life cycle as well as to relieve severe symptoms such as lung damage, cytokine storm, and organ failure. In the fight against viruses, the combination of viral genome sequencing, elucidation of the structure of viral proteins, and identifying proteins that are highly conserved across multiple coronaviruses has revealed many potential molecular targets. In addition, the time- and cost-effective repurposing of preexisting antiviral drugs or approved/clinical drugs for these targets offers considerable clinical advantages for COVID-19 patients. This review provides a comprehensive overview of various identified pathogenic targets and pathways as well as corresponding repurposed approved/clinical drugs and their potential against COVID-19. These findings provide new insight into the discovery of novel therapeutic strategies that could be applied to the control of disease symptoms emanating from evolving SARS-CoV-2 variants.

At the beginning of the coronavirus disease (COVID-19) pandemic, hydroxychloroquine (HCQ) was widely used as a possible antiviral agent. Current knowledge indicates that HCQ has little or no effect on individual clinical outcomes of COVID-19, but populational effects on disease transmissibility are still unknown.

This study investigates the hypothesis that massive HCQ consumption by a population may contribute to reducing the transmissibility of SARS-CoV-2 and COVID-19 spread by reducing the viral load of infected individuals.

Public database of seven states from Brazil in 2020 were assessed, before the start of COVID-19 vaccination. The daily values of the COVID-19 effective reproduction number (Rt) were obtained. Associations between Rt values and the proposed predictor variables (prevalence of COVID-19 as a marker of collective immunity; social isolation indices; consumption of HCQ) were tested using multiple linear regression analysis.

In all seven states, consumption of HCQ was a significant negative predictor of Rt (β ranged from -0.295 to -0.502, p = 0.001). Furthermore, the mean derivative of Rt during the declining period of the COVID-19 incidence (the mean rate of variation) was also significantly negatively related to the mean HCQ consumption in that period (R2 = 0.895; β = -0.783; p = 0.011), meaning that the higher the HCQ consumption, the faster the decline of COVID-19 Rt. It suggests a dose-response phenomenon and a causal relationship in this association.

The results of this study are compatible with the hypothesis that HCQ has small but significant in vivo antiviral effects that are able to reduce SARS-CoV-2 transmissibility at the populational level.

A new series of 4-((7-methoxyquinolin-4-yl) amino)-N-(substituted) benzenesulfonamide 3(a-s) was synthesized via the reaction of 4-chloro-7-methoxyquinoline 1 with various sulfa drugs. The structural elucidation was verified based on spectroscopic data analysis. All the target compounds were screened for their antimicrobial activity against Gram-positive bacteria, Gram-negative bacteria, and unicellular fungi. The results revealed that compound 3l has the highest effect on most tested bacterial and unicellular fungal strains. The highest effect of compound 3l was observed against E. coli and C. albicans with MIC = 7.812 and 31.125 µg/mL, respectively. Compounds 3c and 3d showed broad-spectrum antimicrobial activity, but the activity was lower than that of 3l. The antibiofilm activity of compound 3l was measured against different pathogenic microbes isolated from the urinary tract. Compound 3l could achieve biofilm extension at its adhesion strength. After adding 10.0 µg/mL of compound 3l, the highest percentage was 94.60% for E. coli, 91.74% for P. aeruginosa, and 98.03% for C. neoformans. Moreover, in the protein leakage assay, the quantity of cellular protein discharged from E. coli was 180.25 µg/mL after treatment with 1.0 mg/mL of compound 3l, which explains the creation of holes in the cell membrane of E. coli and proves compound 3l's antibacterial and antibiofilm properties. Additionally, in silico ADME prediction analyses of compounds 3c, 3d, and 3l revealed promising results, indicating the presence of drug-like properties.

Antiviral transformation products (TPs) generated during wastewater treatment are an environmental concern, as their discharge, in considerable amounts, into natural waters during a pandemic can pose possible risks to the aquatic environment. Identification of the hazardous TPs generated from antivirals during wastewater treatment is important. Herein, chloroquine phosphate (CQP), which was widely used during the coronavirus disease-19 (COVID-19) pandemic, was selected for research. We investigated the TPs generated from CQP during water chlorination. Zebrafish (Danio rerio) embryos were used to assess the developmental toxicity of CQP after water chlorination, and hazardous TPs were estimated using effect-directed analysis (EDA). Principal component analysis revealed that the developmental toxicity induced by chlorinated samples could be relevant to the formation of some halogenated TPs. Fractionation of the hazardous chlorinated sample, along with the bioassay and chemical analysis, identified halogenated TP387 as the main hazardous TP contributing to the developmental toxicity induced by chlorinated samples. TP387 could also be formed in real wastewater during chlorination in environmentally relevant conditions. This study provides a scientific basis for the further assessment of environmental risks of CQP after water chlorination and describes a method for identifying unknown hazardous TPs generated from pharmaceuticals during wastewater treatment.

The fusion of viral and cell membranes is one of the basic processes in the life cycles of viruses. A number of enveloped viruses confer fusion of the viral envelope and the cell membrane using surface viral fusion proteins. Their conformational rearrangements lead to the unification of lipid bilayers of cell membranes and viral envelopes and the formation of fusion pores through which the viral genome enters the cytoplasm of the cell. A deep understanding of all the stages of conformational transitions preceding the fusion of viral and cell membranes is necessary for the development of specific inhibitors of viral reproduction. This review systematizes knowledge about the results of molecular modeling aimed at finding and explaining the mechanisms of antiviral activity of entry inhibitors. The first section of this review describes types of viral fusion proteins and is followed by a comparison of the structural features of class I fusion proteins, namely influenza virus hemagglutinin and the S-protein of the human coronavirus.

In November 2021, variant B.1.1.529 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified by the World Health Organization (WHO) and designated Omicron. Omicron is characterized by a high number of mutations, thirty-two in total, making it more transmissible than the original virus. More than half of those mutations were found in the receptor-binding domain (RBD) that directly interacts with human angiotensin-converting enzyme 2 (ACE2). This study aimed to discover potent drugs against Omicron, which were previously repurposed for coronavirus disease 2019 (COVID-19). All repurposed anti-COVID-19 drugs were compiled from previous studies and tested against the RBD of SARS-CoV-2 Omicron.

As a preliminary step, a molecular docking study was performed to investigate the potency of seventy-one compounds from four classes of inhibitors. The molecular characteristics of the best-performing five compounds were predicted by estimating the drug-likeness and drug score. Molecular dynamics simulations (MD) over 100 ns were performed to inspect the relative stability of the best compound within the Omicron receptor-binding site.

The current findings point out the crucial roles of Q493R, G496S, Q498R, N501Y, and Y505H in the RBD region of SARS-CoV-2 Omicron. Raltegravir, hesperidin, pyronaridine, and difloxacin achieved the highest drug scores compared with the other compounds in the four classes, with values of 81%, 57%, 18%, and 71%, respectively. The calculated results showed that raltegravir and hesperidin had high binding affinities and stabilities to Omicron with ΔGbinding of - 75.7304 ± 0.98324 and - 42.693536 ± 0.979056 kJ/mol, respectively. Further clinical studies should be performed for the two best compounds from this study.

Excitation-contraction (E-C) coupling, the interaction of action potential duration (APD) and contractility, plays an essential role in arrhythmogenesis. We aimed to investigate the arrhythmogenic role of E-C coupling in the right ventricular outflow tract (RVOT) in the chloroquine-induced long QT syndrome.

Conventional microelectrodes were used to record electrical and mechanical activity simultaneously under electrical pacing (cycle lengths from 1000-100 ms) in rabbit RVOT tissue preparations before and after chloroquine with and without azithromycin. KB-R7943 (a Na⁺-Ca²⁺ exchanger [NCX] inhibitor), ranolazine (a late sodium current inhibitor), or MgSO₄ were used to assess their pharmacological responses in the chloroquine-induced long QT syndrome.

Sequential infusion of chloroquine and chloroquine plus azithromycin triggered ventricular tachycardia (VT) (33.7%) after rapid pacing compared to baseline (6.7%, p = 0.004). There were greater post-pacing increases of the first occurrence of contractility (ΔContractility) in the VT group (VT vs. non-VT: 521.2 ± 50.5% vs. 306.5 ± 26.8%, p < 0.001). There was no difference in the first occurrence of action potential at 90% repolarization (ΔAPD₉₀) (VT vs. non-VT: 49.7 ± 7.4 ms vs. 51.8 ± 13.1 ms, p = 0.914). Pacing-induced VT could be suppressed to baseline levels by KB-R7943 or MgSO₄. Ranolazine did not suppress pacing-induced VT in chloroquine-treated RVOT. ΔContractility was reduced by KB-R7943 and MgSO₄, but not by ranolazine.

ΔContractility (but not ΔAPD) played a crucial role in the genesis of pacing-induced VT in the long QT tissue model, which can be modulated by NCX (but not late sodium current) inhibition or MgSO₄.

A new coronavirus has been identified as the contributing agent of the severe acute respiratory syndrome (SARS). The main viral protease (Mpro), which controls the activities of the coronavirus replication complex, which is an essential target for the treatment of coronavirus disease. With the primary objective of targeting this receptor, we designed a new series of pyrrolo [3,2-c] pyrroles, synthesized and characterized using various analytical techniques including FT-IR, UV-Vis and NMR spectroscopic studies. The biological descriptors of the synthesized compounds were investigated using DFT calculation. The mode of binding and reactivity of the target compounds with SARS-CoV-2 main protease (Mpro) were studied using molecular docking and molecular dynamics (MD) simulation. Molecular docking of the compounds (4a and 5a) showed a promising binding affinity towards Mpro protein with the binding energy of -7.8 kcal/mol and -7.0 kcal/mol, respectively. The results of MD simulation and prime MM-GBSA calculation were consistent with molecular docking. The absorption, distribution, metabolism and excretion (ADME) properties of the compounds are in the acceptable range, as they are orally active and obey Lipinski's rule of five without violation. In addition, in silico toxicity prediction using the Pro-Tox II revealed the non-toxic nature of the compounds. Hence the obtained results suggest that these compounds could be a possible anti-viral candidate and highlight this series of compounds for further drug design and development against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

The global spread of SARS-CoV-2 has resulted in millions of fatalities worldwide, making it crucial to identify potent antiviral therapeutics to combat this virus. We employed structure-assisted virtual screening to identify phytochemicals that can target the two proteases which are essential for SARS-CoV-2 replication and transcription, the main protease and papain-like protease. Using virtual screening and molecular dynamics, we discovered new phytochemicals with inhibitory activity against the two proteases. Isoginkgetin, kaempferol-3-robinobioside, methyl amentoflavone, bianthraquinone, podocarpusflavone A, and albanin F were shown to have the best affinity and inhibitory potential among the compounds, and can be explored clinically for use as inhibitors of novel coronavirus SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

Hydroxychloroquine (HCQ) and its derivatives have recently gained tremendous attention as a probable medicinal agent in the COVID-19 outbreak caused by SARS-CoV-2. An efficient agent to act directly in inhibiting the SARS-CoV-2 replication is yet to be achieved. Thus, the goal is to investigate the dynamic nature of HCQ derivatives against SARS-CoV-2 main protease and spike proteins. Molecular docking studies were also performed to understand their binding affinity in silico methods using the vital protein domains and enzymes involved in replicating and multiplying SARS-CoV-2, which were the main protease and spike protein. Molecular Dynamic simulations integrated with MM-PBSA calculations have identified In silico potential inhibitors ZINC05135012 and ZINC59378113 against the main protease with -185.171 ± 16.388, -130.759 ± 15.741 kJ/mol respectively, ZINC16638693 and ZINC59378113 against spike protein -141.425 ± 22.447, -129.149 ± 11.449 kJ/mol. Identified Hit molecules had demonstrated Drug Likeliness features, PASS values and ADMET predictions with no violations. Communicated by Ramaswamy H. Sarma.

This study describes the cell-free biomanufacturing of a broad-spectrum antiviral protein, griffithsin (GRFT) such that it can be produced with consistent purity and potency in less than 24 hours. We demonstrate GRFT production using two independent cell-free systems, one plant and one microbial. Griffithsin purity and quality were verified using standard regulatory metrics. Efficacy was demonstrated in vitro against SARS-CoV-2 and HIV-1 and was nearly identical to that of GRFT expressed in vivo . The proposed production process is efficient and can be readily scaled up and deployed anywhere in the world where a viral pathogen might emerge. The current emergence of viral variants has resulted in frequent updating of existing vaccines and loss of efficacy for front-line monoclonal antibody therapies. Proteins such as GRFT with its efficacious and broad virus neutralizing capability provide a compelling pandemic mitigation strategy to promptly suppress viral emergence at the source of an outbreak.

The novel coronavirus SARS-CoV-2, responsible for the present COVID-19 global pandemic, is known to bind to the angiotensin converting enzyme-2 (ACE2) receptor in human cells. A possible treatment of COVID-19 could involve blocking ACE2 and/or disabling the spike protein on the virus. Here, molecular dynamics simulations were performed to test the binding affinities of nine candidate compounds. Of these, three drugs showed significant therapeutic potential that warrant further investigation: SN35563, a ketamine ester analogue, was found to bind strongly to the ACE2 receptor but weakly within the spike receptor-binding domain (RBD); in contrast, arbidol and hydroxychloroquine bound preferentially with the spike RBD rather than ACE2. A fourth drug, remdesivir, bound approximately equally to both the ACE2 and viral spike RBD, thus potentially increasing risk of viral infection by bringing the spike protein into closer proximity to the ACE2 receptor. We suggest more experimental investigations to test that SN35563-in combination with arbidol or hydroxychloroquine-might act synergistically to block viral cell entry by providing therapeutic blockade of the host ACE2 simultaneous with reduction of viral spike receptor-binding; and that this combination therapy would allow the use of smaller doses of each drug.Communicated by Ramaswamy H. Sarma.

Hypericum perforatum and Echinacea are reported to have antiviral activities against several viral infections. In this study, H. perforatum (St. John's Wort) and Echinacea were tested in vitro using Vero E6 cells for their anti-viral effects against the newly identified Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) through its infectious cycle from 0 to 48 h post infection. The hypericin of H. perforatum and the different parts (roots, seeds, aerial) of two types of Echinacea species (Echinacea purpurea and Echinacea angustifolia) were tested for their anti-viral activities to measure the inhibition of viral load using quantitative real-time polymerase chain reaction (qRT-PCR) on cell culture assay. Interestingly, the H. perforatum-Echinacea mixture (1:1 ratio) of H. perforatum and Echinacea was tested as well on SARS-CoV-2 and showed crucial anti-viral activity competing H. perforatum then Echinacea effects as anti-viral treatment. Therefore, the results H. perforatum and Echinacea species, applied in this study showed significant anti-viral and virucidal effects in the following order of potency: H. perforatum, H. perforatum-Echinacea mixture, and Echinacea on SARS-CoV-2 infectious cycle. Additionally, molecular simulation analysis of the compounds with essential proteins (Mpro and RdRp) of the SARS-CoV-2 revealed the most potent bioactive compounds such as Echinacin, Echinacoside, Cyanin, Cyanidin 3-(6''-alonylglucoside, Quercetin-3-O-glucuronide, Proanthocyanidins, Rutin, Kaempferol-3-O-rutinoside, and Quercetin-3-O-xyloside. Thus, based on the outcome of this study, it is demanding the setup of clinical trial with specific therapeutic protocol.

Cancer patients with Covid-19 are exposed to treatment combinations that can potentially result in interactions that adversely affect patient outcomes. This study aimed to identify potential drug-drug interactions between antineoplastic agents and medicines used to treat Covid-19.

We conducted a search for potential interactions between 201 antineoplastic agents and 26 medicines used to treat Covid-19 on the Lexicomp^® and Micromedex^® databases. The following data were extracted: interaction severity ("major" and "contraindicated") and interaction effects (pharmacokinetic and pharmacodynamic). We also sought to identify the therapeutic indication of the antineoplastic drugs involved in the potential drug-drug interactions.

A total of 388 "major" or "contraindicated" drug-drug interactions were detected. Eight drugs or combinations (baricitinib, lopinavir/ritonavir, atazanavir, darunavir, azithromycin, chloroquine, hydroxychloroquine, and sirolimus) accounted for 91.5% of these interactions. The class of antineoplastic agents with the greatest potential for interaction was tyrosine kinase inhibitors (accounting for 46.4% of all interactions). The findings show that atazanavir, baricitinib, and lopinavir/ritonavir can affect the treatment of all common types of cancer. The most common pharmacokinetic effect of the potential drug-drug interactions was increased plasma concentration of the antineoplastic medicine (39.4%).

Covid-19 is a recent disease and pharmacological interventions are undergoing constant modification. This study identified a considerable number of potential drug-drug interactions. In view of the vulnerability of patients with cancer, it is vital that health professionals carefully assess the risks and benefits of drug combinations.

The emergence of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected many countries throughout the world. As urgency is a necessity, most efforts have focused on identifying small molecule drugs that can be repurposed for use as anti-SARS-CoV-2 agents. Although several drug candidates have been identified using in silico method and in vitro studies, most of these drugs require the support of in vivo data before they can be considered for clinical trials. Several drugs are considered promising therapeutic agents for COVID-19. In addition to the direct-acting antiviral drugs, supportive therapies including traditional Chinese medicine, immunotherapies, immunomodulators, and nutritional therapy could contribute a major role in treating COVID-19 patients. Some of these drugs have already been included in the treatment guidelines, recommendations, and standard operating procedures. In this article, we comprehensively review the approved and potential therapeutic drugs, immune cells-based therapies, immunomodulatory agents/drugs, herbs and plant metabolites, nutritional and dietary for COVID-19.

The COVID-19 outbreak triggered a serious and potentially lethal pandemic, resulting in massive health and economic losses worldwide. The most common clinical manifestations of COVID-19 patients are pneumonia and acute respiratory distress syndrome, with a variety of complications. Multiple organ failure and damage, ultimately leading to patient death, are possible as a result of medication combinations, and this is exemplified by DILI. We hope to summarize DILI caused by the antiviral drugs favipiravir, remdesivir, lopinavir/ritonavir, and hydroxychloroquine in COVID-19 patients in this review. The incidence of liver injury in the treatment of COVID-19 patients was searched on PubMed to investigate DILI cases. The cumulative prevalence of acute liver injury was 23.7% (16.1%-33.1%). We discuss the frequency of these events, potential mechanisms, and new insights into surveillance strategies. Furthermore, we also describe medication recommendations aimed at preserving DILI caused by treatment in COVID-19 patients.

Several human diseases are caused by viruses, including cancer, Type I diabetes, Alzheimer's disease, and hepatocellular carcinoma. In the past, people have suffered greatly from viral diseases such as polio, mumps, measles, dengue fever, SARS, MERS, AIDS, chikungunya fever, encephalitis, and influenza. Recently, COVID-19 has become a pandemic in most parts of the world. Although vaccines are available to fight the infection, their safety and clinical trial data are still questionable. Social distancing, isolation, the use of sanitizer, and personal productive strategies have been implemented to prevent the spread of the virus. Moreover, the search for a potential therapeutic molecule is ongoing. Based on experiences with outbreaks of SARS and MERS, many research studies reveal the potential of medicinal herbs/plants or chemical compounds extracted from them to counteract the effects of these viral diseases. COVID-19's current status includes a decrease in infection rates as a result of large-scale vaccination program implementation by several countries. But it is still very close and needs to boost people's natural immunity in a cost-effective way through phytomedicines because many underdeveloped countries do not have their own vaccination facilities. In this article, phytomedicines as plant parts or plant-derived metabolites that can affect the entry of a virus or its infectiousness inside hosts are described. Finally, it is concluded that the therapeutic potential of medicinal plants must be analyzed and evaluated entirely in the control of COVID-19 in cases of uncontrollable SARS infection.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a substantial number of deaths around the world, making it a serious and pressing public health hazard. Phytochemicals could thus provide a rich source of potent and safer anti-SARS-CoV-2 drugs. The absence of approved treatments or vaccinations continues to be an issue, forcing the creation of new medicines. Computer-aided drug design has helped to speed up the drug research and development process by decreasing costs and time. Natural compounds like terpenoids, alkaloids, polyphenols, and flavonoid derivatives have a perfect impact against viral replication and facilitate future studies in novel drug discovery. This would be more effective if collaboration took place between governments, researchers, clinicians, and traditional medicine practitioners' safe and effective therapeutic research. Through a computational approach, this study aims to contribute to the development of effective treatment methods by examining the mechanisms relating to the binding and subsequent inhibition of SARS-CoV-2 ribonucleic acid (RNA)-dependent RNA polymerase (RdRp). The in silico method has also been employed to determine the most effective drug among the mentioned compound and their aquatic, nonaquatic, and pharmacokinetics' data have been analyzed. The highest binding energy has been reported -11.4 kcal/mol against SARS-CoV-2 main protease (7MBG) in L05. Besides, all the ligands are non-carcinogenic, excluding L04, and have good water solubility and no AMES toxicity. The discovery of preclinical drug candidate molecules and the structural elucidation of pharmacological therapeutic targets have expedited both structure-based and ligand-based drug design. This review article will assist physicians and researchers in realizing the enormous potential of computer-aided drug design in the design and discovery of therapeutic molecules, and hence in the treatment of deadly diseases.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the ongoing pandemic named COVID-19 which causes a serious emergency on public health hazards of international concern. In the face of a critical medical emergency, repositioning of drugs is one of the most authentic options to design an adequate treatment for infected patients immediately. In this strategy, Remdesivir (Veklury), Hydroxychloroquine appears to be the drug of choice and garnered unprecedented attention as potential therapeutic agents against the pandemic realized worldwide due to SARS-CoV-2 infection. These are the breathtaking instances of possible repositioning of drugs, whose pharmacokinetics and optimal dosage are familiar. In this review, we provide an overview of these medications, their synthesis, and the possible mechanism of action against SARS-CoV-2.

During the last two years following the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, development of potent antiviral drugs and vaccines has been a global health priority. In this context, the understanding of virus pathophysiology, the identification of associated therapeutic targets, and the screening of potential effective compounds have been indispensable advancements. It was therefore of primary importance to develop experimental models that recapitulate the aspects of the human disease in the best way possible. This article reviews the information concerning available SARS-CoV-2 preclinical models during that time, including cell-based approaches and animal models. We discuss their evolution, their advantages, and drawbacks, as well as their relevance to drug effectiveness evaluation.