Treatment Options For COVID-19 Research Articles

In-silico Identification of Dexamethasone-similar Compounds Against SARS-Cov-2 Spike Protein: A Drug Repurposing Approach

Abstract: To identify potential drug candidates for the treatment of COVID-19 using a computational method. The recent pandemic of COVID-19 is observed as not less than a natural calamity of humankind and raised serious concerns for its immediate management. The continued spread of coronavirus disease across the globe poses a significant threat to human health. Out of this, the application of Dexamethasone has been correlated with reduced mortality in COVID-19 cases. This study sheds new light on the pharmacological potential of Dexamethasone and similar compounds in mitigating SARSCoV2 infection. : In this study, we explored Dexamethasone-similar compounds, which can modulate the binding of SARS-CoV-2 spike protein to the host and TH17 programming in the host using a computer-aided drug repurposing method. The docking studies indicate that Desoximetasone can bind to the spike proteins of SARS-CoV-2, which are crucial for viral attachment and entry into host cells. By competing with these spike proteins, Desoximetasone may interfere with the virus's ability to attach to and enter host cells, potentially inhibiting viral replication and spread. The results from molecular dynamic simulation analysis further support this notion by demonstrating that Desoximetasone has a strong interaction with the binding sites of the spike protein. Experimental validation through in vitro studies and clinical trials is needed to evaluate its potential as a treatment option for COVID-19. Together, these findings revealed the underlying mechanism of how Desoximetasone can influence the fate of the virus in the host and advocated its anti-viral potential.

Development of a highly stable, active small interfering RNA with broad activity against SARS-CoV viruses

Treatment options for COVID-19 remain limited. Here, we report the optimization of an siRNA targeting the highly conserved leader region of SARS-CoV-2. The siRNA was rendered nuclease resistant by the introduction of modified nucleotides without loss of activity. Importantly, the siRNA also retained its inhibitory activity against the emerged omicron sublineage variant BA.2, which occurred after the siRNA was designed and is resistant to other antiviral agents such as antibodies. In addition, we show that a second highly active siRNA designed against the viral 5′-UTR can be applied as a rescue molecule, to minimize the spread of escape mutations. We therefore consider our siRNA-based molecules to be promising broadly active candidates for the treatment of current and future SARS-CoV-2 variants.

Myths about COVID-19 among Sindh Population: A Survey based Study.

Background: The COVID-19 pandemic has presented unprecedented challenges globally, with misinformation significantly impacting public health responses. The rapid spread of myths and misconceptions, particularly through social media, has necessitated a deeper understanding of the factors influencing public perception and behavior towards COVID-19 preventive measures, transmission, and treatment options. Objective: This study aimed to quantify the prevalence of COVID-19 related myths among the Sindh population, explore associations with sociodemographic characteristics, and assess the impact of misinformation on public health practices. Methods: Employing a cross-sectional survey design, we recruited 400 participants using convenience sampling. The survey comprised two parts: demographic information and a structured questionnaire assessing beliefs about COVID-19. Questions were designed to capture myths related to transmission, prevention, treatment, and vaccination. Responses were analyzed using SPSS software version 25, employing descriptive statistics, t-tests, and ANOVA to identify significant associations between demographic factors and susceptibility to myths. Ethical approval was obtained from the Research Ethics Committee of Liaquat University of Medical & Health Sciences. Results: The study found that 60% of participants harbored high levels of myths about COVID-19. Misconceptions were significantly associated with age, education, occupation, and marital status. Notably, 85% of respondents reported social media as their primary information source. Misconceptions included the efficacy of disinfecting groceries (62%), the risk posed by non-vegetarian food (12%), and misinformation about COVID-19 transmission through mosquitoes (5%). Additionally, there was a widespread belief in ineffective preventive measures and treatments, such as the use of home remedies (55%) and the misconception that vaccines cause COVID-19 (7%). Conclusion: The high prevalence of COVID-19 myths among the Sindh population highlights the critical role of social media in spreading misinformation. The study underscores the need for targeted interventions to address misinformation and enhance the public's ability to discern reliable information, particularly on digital platforms.

Niclosamide: A career builder

My contribution to honoring Professor Kinam Park celebrates and resonates with his scholarly career in drug delivery, his commitment to encouraging the next generation(s), and his efforts to keep us focused on clinically effective formulations. To do this I take as my example, niclosamide, a small molecule protonophore that, uniquely, can “target” all cell membranes, both plasma and organelle. As such, it acts upstream of many cell pathways and so has the potential to affect many of the essential events that a cell, and particularly a diseased cell or other entities like a virus, use to stay alive and prosper. Literature shows that it has so far been discovered to positively influence (at least): cancer, bacterial and viral infection, metabolic diseases such as Type II diabetes, NASH and NAFLD, artery constriction, endometriosis, neuropathic pain, rheumatoid arthritis, sclerodermatous graft-versus-host disease, systemic sclerosis, Parkinson's, and COPD. With such a fundamental action and broad-spectrum activity, I believe that studying niclosamide in all its manifestations, discovering if and to what extent it can contribute positively to disease control (and also where it can't), formulating it as effective therapeutics, and testing them in preclinical and clinical trials is a career builder for our next generation(s).The article is divided into two parts: Part I introduces niclosamide and other proton shunts mainly in cancer and viral infections and reviews an exponentially growing literature with some concepts and physicochemical properties that lead to its proton shunt mechanism. Part II focuses on repurposing by reformulation of niclosamide. I give two examples of “carrier-free formulations”, — one for cancer (as a prodrug therapeutic of niclosamide stearate for i.v. and other administration routes, exemplified by our recent work on Osteosarcoma in mice and canine patients), and the other as a niclosamide solution formulation (that could provide the basis for a preventative nasal spray and early treatment option for COVID19 and other respiratory virus infections).My goal is to excite and enthuse, encourage, and motivate all involved in the drug development and testing process in academia, institutes, and industry, to learn more about this interesting molecule and others like it. To enable such endeavors, I give many proposed ideas throughout the document, that have been stimulated and inspired by gaps in the literature, urgent needs in disease, and new studies arising from our own work. The hope is that, by reading through this document and studying the suggested topics and references, the drug delivery and development community will continue our lineage and benefit from our legacy to achieve niclosamide's potential as an effective contributor to the treatment and control of many diseases and conditions.

Prebiotic inulin ameliorates SARS-CoV-2 infection in hamsters by modulating the gut microbiome

Current treatment options for COVID-19 are limited, with many antivirals and immunomodulators restricted to the most severe cases and preventative care limited to vaccination. As the SARS-CoV-2 virus and its increasing variants threaten to become a permanent fixture of our lives, this new reality necessitates the development of cost-effective and accessible treatment options for COVID-19. Studies have shown that there are correlations between the gut microbiome and severity of COVID-19, especially with regards to production of physiologically beneficial short-chain fatty acids (SCFAs) by gut microbes. In this study, we used a Syrian hamster model to study how dietary consumption of the prebiotic inulin affected morbidity and mortality resulting from SARS-CoV-2 infection. After two weeks of observation, we discovered that inulin supplementation attenuated morbid weight loss and increased survival rate in hamster subjects. An analysis of microbiome community structure showed significant alterations in 15 genera. Notably, there were also small increases in fecal DCA and a significant increase in serum DCA, perhaps highlighting a role for this secondary bile acid in conferring protection against SARS-CoV-2. In light of these results, inulin and other prebiotics are promising targets for future investigation as preventative treatment options for COVID-19.

Therapeutic and prophylactic effects of quercetin in the treatment of Covid-19: a systematic review

Background: With the COVID-19 pandemic, the need for pharmacological and clinical studies in the search for substances with anti-inflammatory action became evident. To perform a systematic review of randomized controlled trials that evaluated the efficacy and safety of quercetin as a treatment and prevention option for COVID-19 in humans relative to an active comparator, placebo, or standard care alone. Methods: The search for studies was carried out in the following databases: Medline via PubMed, LILACS, Science Direct, Web of Science, and Scopus via Capes periodicals with the descriptors: “Quercetin” AND ''COVID-19” AND “randomized controlled trial”. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. Protocol registration number in the PROSPERO database: CRD42022359842, available: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022359842.Results: 455 articles were found, and after reading the titles, abstracts, and full text, only 8 randomized clinical trials were included. According to the Cochrane RoB 2 tool, most included studies have some concerns about the risk of bias. The use of quercetin in the treatment and prevention of COVID-19 contributed to the rapid evolution of patients compared to standard treatment and protected them against the development of COVID-19 compared to placebo. No adverse events were reported. Conclusion: It is inferred that drug supplementation with quercetin can help in the treatment and prevention of COVID-19, reducing recovery time, laboratory parameters and symptom manifestation, when compared to standard treatment. Thus, further research is needed to confirm the relationship between quercetin in the immune system and the development of COVID-19 in its most severe form. A systematic review carried out with randomized clinical trials for quercetin in COVID-19 is not yet available in the indexes, and this work is unprecedented.

Role of Ivermectin and Colchicine in Treatment of COVID-19: A Randomized Controlled Clinical Trial

Objective: To assess the effectiveness of ivermectin and colchicine as treatment options for COVID-19. Patients and methods: A three-arm randomized controlled clinical trial was conducted in triage clinic of family medicine department at Ain Shams University Hospitals on participants who had been diagnosed as COVID-19 patients with moderate severity. Patients aged <18 years or >65 years with any co-morbidities, pregnant or lactating female and with mild or severe COVID-19 confirmed cases were excluded. Randomization was done by using sealed envelopes for intervention or control. Patients are followed up to improvement of patient’s symptoms with no development of new symptoms over one month. Results: A total of 120 patients with COVID-19 were enrolled in the study, 40 patients in each arm. Their mean age was 40.16(SD 10.74) years. Out of them, 44 (36.6%) were male, 76(63.4%) were female. Mean duration of symptoms was 9.58 (SD 2.206), 9.9 (SD 2.07), and 9.53 (SD 2.37) in the ivermectin, colchicine and control groups, respectively. Most patients (67.5%, 70% and 72.5%) cured with residual symptoms with no difference in between the ivermectin, colchicine and control groups, respectively (P>0.05). Conclusion: Ivermectin and colchicine have no beneficial effect over the standard care in treatment of COVID-19.

Antimicrobial consumption in an acute NHS Trust during the COVID-19 pandemic: intervention time series analysis.

To determine the impact of the COVID-19 pandemic on antimicrobial consumption and trends of therapeutic drugs for COVID-19 treatments, including corticosteroids, remdesivir and monoclonal antibodies (tocilizumab) from April 2017 to September 2022 in a secondary care NHS Trust in England. A retrospective intervention time series analysis was conducted for April 2017 to September 2022 at the Mid Yorkshire Teaching NHS Trust. Data were retrieved from the pharmacy dispensing system as defined daily doses (DDDs) monthly and reported per 1000 occupied bed days (OBDs). Antimicrobial consumption and COVID-19 treatment options were measured. DDDs were calculated according to the classification of antimicrobials for systemic use (J01) and for other drugs classification. Trends for antimicrobial consumption and other therapeutic drugs for treating COVID-19 were also determined in each wave in England. During the pandemic: total antibiotic consumption decreased from 826.4 to 728.2 DDDs per 1000 OBDs (P = 0.0067); piperacillin/tazobactam use increased (P < 0.0001) and ciprofloxacin use decreased (P < 0.0001); there were no changes in Access, Watch, Reserve antibiotic use, and the proportion of antifungal consumption was consistent throughout the study. The use of total antibiotics (P = 0.024), levofloxacin (P = 0.0007), piperacillin/tazobactam (P = 0.0015) and co-amoxiclav (P = 0.0198) increased during wave one. Consumption of COVID-19 treatment drugs was highest during wave two, with 624.3 DDDs per 1000 OBDs for dexamethasone (P = 0.4441), 6.8 DDDs per 1000 OBDs for remdesivir (P < 0.0001) and 35.01 DDDs per 1000 OBDs for tocilizumab (P = 0.2544). This study determined the consumption of antimicrobials trends before and during the pandemic. The individual wave antimicrobial consumption indicates maximum consumption in the first wave, advocating for antimicrobial stewardship and preparedness for future pandemics.

De Novo Potent Peptide Nucleic Acid Antisense Oligomer Inhibitors Targeting SARS-CoV-2 RNA-Dependent RNA Polymerase via Structure-Guided Drug Design.

Global reports of novel SARS-CoV-2 variants and recurrence cases continue despite substantial vaccination campaigns, raising severe concerns about COVID-19. While repurposed drugs offer some treatment options for COVID-19, notably, nucleoside inhibitors like Remdesivir stand out as curative therapies for COVID-19 that are approved by the US Food and Drug Administration (FDA). The emergence of highly contagious SARS-CoV-2 variants underscores the imperative for antiviral drugs adaptable to evolving viral mutations. RNA-dependent RNA polymerase (RdRp) plays a key role in viral genome replication. Currently, inhibiting viral RdRp function remains a pivotal strategy to tackle the notorious virus. Peptide nucleic acid (PNA) therapy shows promise by effectively targeting specific genome regions, reducing viral replication, and inhibiting infection. In our study, we designed PNA antisense oligomers conjugated with cell-penetrating peptides (CPP) aiming to evaluate their antiviral effects against RdRp target using structure-guided drug design, which involves molecular docking simulations, drug likeliness and pharmacokinetic evaluations, molecular dynamics simulations, and computing binding free energy. The in silico analysis predicts that chemically modified PNAs might act as antisense molecules in order to disrupt ribosome assembly at RdRp's translation start site, and their chemically stable and neutral backbone might enhance sequence-specific RNA binding interaction. Notably, our findings demonstrate that PNA-peptide conjugates might be the most promising inhibitors of SARS-CoV-2 RdRp, with superior binding free energy compared to Remdesivir in the current COVID-19 medication. Specifically, PNA-CPP-1 could bind simultaneously to the active site residues of RdRp protein and sequence-specific RdRp-RNA target in order to control viral replication.

Inhibition of SARS-CoV-2 infection and replication by Petasites hybridus CO2-extract (Ze 339)

BackgroundThe intensified search for low-threshold herbal anti-viral drugs would be of great advantage in prevention of early stages of infection. Since the SARS-CoV-2 Omicron variant has prevailed in western countries, the course has only been mild, but there are still no widely available drugs that can alleviate or shorten disease progression and counteract the development of Long-COVID. This study aimed to investigate the antiviral effects of a CO2-extract from Petasites hybridus (Ze 339). MethodsWe analyzed the infection and replication rate of SARS-CoV-2 in primary normal human bronchial epithelial cells (NHBEs) using a GFP-expressing version of the wild-type SARS-CoV-2 virus and live cell imaging. Upon infection with a clinical isolate of the Omicron variant, viral RNA content was quantified, and plaque assays were performed. In addition, the human transcriptome was analyzed after 4- and 24-hours post infection using whole genome microarrays. ResultsZe 339 had a protective effect on primary airway epithelial cells during SARS-CoV-2 infection and impeded SARS-CoV-2 infection and replication in NHBE. Notably, Ze 339 inhibited the expression of infection-induced IFNA10 by 8.6-fold (p < 0.05) and additionally reduced a wide range of other interferons (IFNA6, IFNA7, IFNA8, IFNA21, IFNE, IFNW1). ConclusionThereby, Ze 339 attenuated epithelial infection by SARS-CoV-2 and modeled the IFN response. In conclusion, this study highlights Ze 339 as a potential treatment option for COVID-19 that limits infection-associated cell intrinsic immune responses.

What did we learn about tocilizumab use against COVID-19? A single-center observational study from an intensive care unit in Serbia.

Selection of effective and safe therapy for management of patients with coronavirus disease is challenging. Tocilizumab (TZB) has emerged as a potential treatment option for COVID-19. Several aspects regarding Tocilizumab treatment remain uncertain, such as the optimal timing for its administration and the safety profile, including the potential risk of infections. The aim of the study is to present the clinical characteristics of patients with COVID-19 following the application of Tocilizumab. This is a retrospective analysis of 121 patients with severe forms of COVID-19 previously treated with Tocilizumab was conducted. All patients were admitted to intensive care units (ICUs). Of 121 patients, the majority were men 72 (59.5%) with a median age at presentation of 65 ± 13 years. Only 9 (7.43%) patients were without comorbidities, while the other 112 (92.55%) had two or more comorbidities. Almost all of the 120 patients (99.2%) needed oxygen therapy, such as nasal cannulas in 110 (90.9%) patients, high flow nasal catheter (HFNC) in 4 (3.3%) patients, and continuous positive airway pressure (CPAP) in 5 (4.1%) patients while 1 patient was intubated at the time of hospital admission. The average time from Tocilizumab application to admission to the ICU was 3 days. During clinical deterioration, almost half 57 (47.1%) of the patients were intubated, and 52 (82.5%) of these intubated patients (p < 0.001) had lethal outcomes. The most significant predictors for a lethal outcome according to multivariate analysis were diabetes mellitus (p < 0.001) followed by a subsequent elevation in C-reactive protein levels (CRP; p < 0.002) and ferritin (p < 0.013) after Tocilizumab application. Bloodstream infections were found in 20 (16.5%) patients, most frequently with Gram-negative pathogens like Acinetobacter spp. as in 12 (18.6%) patients, Klebsiella spp. in 6 (8%) patients, and Pseudomonas spp. in 2 (3.2%) patients. Urine culture isolates were found in 9 (7.43%) patients, with Candida spp. being most frequently isolated in 7 (5.8%) patients, followed by Klebsiella spp. and Pseudomonas spp. in 1 patient each (0.8%). Significantly lower survival was seen in patients with proven infection. The benefit of tocilizumab was not found in our study. The high mortality rate among intubated patients after Tocilizumab use suggests appropriate patient selection and monitoring and emphasizes the risk of superinfections. Diabetes mellitus, increased levels of CRP, and ferritin were identified as the most significant predictors of poor outcomes in contrast to increased levels of IL-6.

Dual anti-viral treatment for persistent COVID-19 in immunocompromised hemato-oncological patients is associated with a favorable prognosis and minor side effects

In hemato-oncological patients, COVID-19 can present as a persistent infection with ongoing symptoms and viral replication over a prolonged period of time. Data are scarce on the preferred treatment options for these patients. We describe our experience with a five-day course of dual anti-viral treatment with remdesivir and nirmatrelvir/ritonavir for hemato-oncological immunocompromised patients with persistent COVID-19. Fifteen patients with a history of lymphoma, CLL, and MM were included. Eight were male, median age was 74. All patients had an immediate clinical and virological response. In 73 % of patients, PCR for SARS-CoV-2 became negative at the end of treatment and the rest had an increase in PCR cycle threshold (CT) values, with a median increase of 6 cycles. After a follow-up of three months, 60 % of patients remained in full clinical and virological remission. None required invasive mechanical ventilation or died. The side effects we observed, neutropenia, lactatemia and elevated transaminases, were mild and almost all transient in nature. We conclude that dual anti-viral treatment appears to be a valid treatment option for persistent COVID-19.

The Role of Gut Microbiome Supplementation in COVID-19 Management.

COVID-19, which is caused by the RNA virus, SARS-CoV-2, mainly affects the respiratory system and has a varied clinical presentation. However, several studies have shown that COVID-19 can also affect the gastrointestinal (GI) system. Patients can experience various GI symptoms, such as vomiting and diarrhea, and the virus has been detected in the stool samples of patients hospitalized with COVID-19. There have also been rare reports of COVID-19 presenting with isolated GI symptoms and lack of respiratory symptoms, and the virus has also been detected for prolonged periods in the fecal samples of COVID-19 patients. Major alterations in the gut microbiome in the form of depletion of beneficial organisms and an abundance of pathogenic organisms have been reported in the fecal samples of hospitalized COVID-19 patients. Although the US FDA has approved several drugs to manage COVID-19, their efficacy remains modest. So, there is a constant ongoing effort to investigate novel treatment options for COVID-19. Health supplements like probiotics, prebiotics, postbiotics, and synbiotics have been popularly known for their various health benefits. In this review, we have summarized the current literature, which shows the potential benefit of these health supplements to mitigate and/or prevent the clinical presentation of COVID-19.

Assessment of the available therapeutic approaches for severe COVID-19: a meta-analysis of randomized controlled trials

The study aimed to evaluate severe COVID-19 treatment approaches. We conducted a meta-analysis of randomized controlled trials (RTCs) with standard of care (SoC) as a control group and/or placebo. Database searching was performed separately for severe COVID-19 treatment such as anakinra, remdesivir, baricitinib, ivermectin, ritonavir, tocilizumab, sarilumab, sotrovimab, casirivimab/imdevimab. The results are presented as Risk Ratio (RR), 95% Confidence Interval (CI), and heterogeneity (I2). We obtained the most statistically significant outcomes favorable tocilizumab compared to SoC for death incidents RR 0.87 [95% CI 0.80, 0.95], overall effect p = 0.002, heterogeneity p = 0.85, I2 = 0%, need for mechanical ventilation RR 0.78 [95% CI 0.68, 0.89], overall effect p = 0.0004, heterogeneity p = 0.55, I2 = 0%, and number of patients discharged from hospital. RR 1.13 [95% CI 1.07, 1.20], overall effect p < 0.00001, heterogeneity p = 0.009, I2 = 85%. This meta-analysis has revealed that a considerable amount of research characterized by a very diverse methodology is available. Despite the limited data that met the criteria for inclusion in the meta-analysis, we showed that the available treatment options for severe COVID-19 are effective.

Prevalence of SARS-CoV-2 Omicron Sublineages and Spike Protein Mutations Conferring Resistance against Monoclonal Antibodies in a Swedish Cohort during 2022-2023.

Monoclonal antibodies (mAbs) are an important treatment option for COVID-19 caused by SARS-CoV-2, especially in immunosuppressed patients. However, this treatment option can become ineffective due to mutations in the SARS-CoV-2 genome, mainly in the receptor binding domain (RBD) of the spike (S) protein. In the present study, 7950 SARS-CoV-2 positive samples from the Uppsala and Örebro regions of central Sweden, collected between March 2022 and May 2023, were whole-genome sequenced using amplicon-based sequencing methods on Oxford Nanopore GridION, Illumina MiSeq, Illumina HiSeq, or MGI DNBSEQ-G400 instruments. Pango lineages were determined and all single nucleotide polymorphism (SNP) mutations that occurred in these samples were identified. We found that the dominant sublineages changed over time, and mutations conferring resistance to currently available mAbs became common. Notable ones are R346T and K444T mutations in the RBD that confer significant resistance against tixagevimab and cilgavimab mAbs. Further, mutations conferring a high-fold resistance to bebtelovimab, such as the K444T and V445P mutations, were also observed in the samples. This study highlights that resistance mutations have over time rendered currently available mAbs ineffective against SARS-CoV-2 in most patients. Therefore, there is a need for continued surveillance of resistance mutations and the development of new mAbs that target more conserved regions of the RBD.

Safety Evaluation and Population Pharmacokinetics of Camostat Mesylate and Its Major Metabolites Using a Phase I Study.

Camostat mesylate is expected to be promising as a treatment option for COVID-19, in addition to other indications for which it is currently used. Furthermore, in vitro experiments have confirmed the potential of camostat and its metabolites to be effective against COVID-19. Therefore, clinical trials were conducted to evaluate the safety and pharmacokinetic characteristics of camostat after single-dose administration. Additionally, we aim to predict the pharmacokinetics of repeated dosing through modeling and simulation based on clinical trials. Clinical trials were conducted on healthy Korean adults, and an analysis was carried out of the metabolites of camostat, GBPA, and GBA. Pharmacokinetic modeling and simulation were performed using Monolix. There were no safety issues (AEs, physical examinations, clinical laboratory tests, vital sign measurements, and ECG) during the clinical trial. The pharmacokinetic characteristics at various doses were identified. It was confirmed that AUC last and Cmax increased in proportion to dose in both GBPA and GBA, and linearity was also confirmed in log-transformed power model regression. Additionally, the accumulation index was predicted (1.12 and 1.08 for GBPA and GBA). The pharmacokinetics of camostat for various dose administrations and indications can be predicted prior to clinical trials using the developed camostat model. Furthermore, it can be used for various indications by connecting it with pharmacodynamic information.

MULGA, a unified multi-view graph autoencoder-based approach for identifying drug-protein interaction and drug repositioning.

Identifying drug-protein interactions (DPIs) is a critical step in drug repositioning, which allows reuse of approved drugs that may be effective for treating a different disease and thereby alleviates the challenges of new drug development. Despite the fact that a great variety of computational approaches for DPI prediction have been proposed, key challenges, such as extendable and unbiased similarity calculation, heterogeneous information utilization and reliable negative sample selection, remain to be addressed. To address these issues, we propose a novel, unified multi-view graph autoencoder framework, termed MULGA, for both DPI and drug repositioning predictions. MULGA is featured by: (i) a multi-view learning technique to effectively learn authentic drug affinity and target affinity matrices; (ii) a graph autoencoder to infer missing DPI interactions; and (iii) a new "guilty-by-association"-based negative sampling approach for selecting highly reliable non-DPIs. Benchmark experiments demonstrate that MULGA outperforms state-of-the-art methods in DPI prediction and the ablation studies verify the effectiveness of each proposed component. Importantly, we highlight the top drugs shortlisted by MULGA that target the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SAR-CoV-2), offering additional insights into and potentially useful treatment option for COVID-19. Together with the availability of datasets and source codes, we envision that MULGA can be explored as a useful tool for DPI prediction and drug repositioning. MULGA is publicly available for academic purposes at https://github.com/jianiM/MULGA/. Supplementary data are available at Bioinformatics online.

Multicomponent Synthesis of the SARS-CoV-2 Main Protease Inhibitor Nirmatrelvir.

In the wake of the Covid-19 pandemic, it has become clear that global access to efficacious antiviral drugs will be critical to combat future outbreaks of SARS-CoV-2 or related viruses. The orally available SARS-CoV-2 main protease inhibitor nirmatrelvir has proven an effective treatment option for Covid-19, especially in compromised patients. We report a new synthesis of nirmatrelvir featuring a highly enantioselective biocatalytic desymmetrization (>99% ee) and a highly diastereoselective multicomponent reaction (>25:1 dr) as the key steps. Our route avoids the use of transition metals and peptide coupling reagents, resulting in an overall highly efficient and atom-economic process.

A review of the mechanisms of blood-brain barrier disruption during COVID-19 infection.

Coronaviruses are prevalent in mammals and birds, including humans and bats, and they often spread through airborne droplets. In humans, these droplets then interact with angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), which are the main receptors for the SARS-CoV-2 virus. It can infect several organs, including the brain. The blood-brain barrier (BBB) is designed to maintain the homeostatic neural microenvironment of the brain, which is necessary for healthy neuronal activity, function, and stability. It prevents viruses from entering the brain parenchyma and does not easily allow chemicals to pass into the brain while assisting numerous compounds in exiting the brain. The purpose of this review was to examine how COVID-19 influences the BBB along with the mechanisms that indicate the BBB's deterioration. In addition, the cellular mechanism through which SARS-CoV-2 causes BBB destruction by binding to ACE2 was evaluated and addressed. The mechanisms of the immunological reaction that occurs during COVID-19 infection that may contribute to the breakdown of the BBB were also reviewed. It was discovered that the integrity of the tight junction (TJs), basement membrane, and adhesion molecules was damaged during COVID-19 infection, which led to the breakdown of the BBB. Therefore, understanding how the BBB is disrupted by COVID-19 infection will provide an indication of how the SARS-CoV-2 virus is able to reach the central nervous system (CNS). The findings of this research may help in the identification of treatment options for COVID-19 that can control and manage the infection.

Dual combined antiviral treatment with remdesivir and nirmatrelvir/ritonavir in patients with impaired humoral immunity and persistent SARS-CoV-2 infection.

Despite global vaccination efforts, immunocompromized patients remain at high risk for COVID-19-associated morbidity. In particular, patients with impaired humoral immunity have shown a high risk of persistent infection. We report a case series of adult patients with B cell malignancies and/or undergoing B cell targeting therapies with persisting SARS-CoV-2 infection and treated with a combination antiviral therapy of remdesivir and nirmatrelvir/ritonavir, in three Italian tertiary academic hospitals. A total of 14 patients with impaired adaptive humoral immunity and prolonged SARS-CoV-2 infection were treated with the dual antiviral therapy. The median age was 60 (IQR 56-68) years, and 11 were male. Twelve patients had B cell lymphoma, one patient had chronic lymphocytic leukemia and one patient had multiple sclerosis. Thirteen out of 14 patients had received prior B cell-targeting therapies, consisting of anti-CD20 monoclonal antibodies in 11 patients, and chimeric antigen receptor T therapy in 2 patients. The median time between diagnosis and therapy start was 42.0 (IQR 35-46) days. Seven patients had mild, 6 moderate and one severe disease. Nine patients had signs of interstitial pneumonitis on chest computed tomography scans before treatment. The median duration of nirmatrelvir/ritonavir and remdesivir combination therapy was 10days. All patients showed resolution of COVID-19-related symptoms after a median of 6 (IQR 4-11) days and viral clearance after 9 (IQR 5-11) days. Combination therapy with remdesivir and nirmatrelvir/ritonavir is a promising treatment option for persistent COVID-19 in immunocompromized patients with humoral immunity impairment, worthy of prospective comparative trials.