Antiviral Research Articles

Genetic variation on dolutegravir pharmacokinetics and relation to safety and efficacy outcomes: a systematic review.

Dolutegravir (DTG) is an antiviral agent used for the treatment of HIV, however, there is uncertainty over the influence of genetic variation on DTG exposure, and whether it has clinical implications for the efficacy or toxicity in different populations. This systematic review aims to create an overview of the impact of pharmacogenomics (PGx) on DTG exposure, efficacy, and toxicity. Publications up to 14 November 2023 were searched and articles were selected on the following criteria: original research articles providing data on people with HIV, data on PGx and either PK or PD or both PD and PGx. 711 records were identified, and after screening 10 articles were included. Commonly analyzed genes across the articles were UGT1A1, ABCB1, ABCG2, and NR1I2. The most reported variant associated with PD variability was in SLC22A2, with carriers at higher risk of neuropsychiatric adverse events. This review concludes that while PGx testing may help explain some variability in DTG pharmacokinetics when combined with therapeutic drug monitoring (TDM), current evidence is insufficient to support its routine clinical use. The role of PGx research for DTG remains relevant, especially in specific patient populations where interindividual PK variations are still unexplained.

Impact of oral early antiviral therapies for mild–moderate COVID-19 in the outpatient’s setting during Omicron era: a pharmacoeconomic analysis

BackgroundMolnupiravir (MOL) and nirmatrelvir/ritonavir (NIR) decreased mortality and hospital admissions in high-risk patients with mild to moderate COVID-19. Nevertheless, there is a lack of data about the pharmacoeconomic impact of these antivirals in the Omicron era. We conducted a pharmacoeconomic analysis assessing the medical costs of the use of these antivirals compared to those occurred in people who refused the treatment.MethodsThe study included the first 50 patients vaccinated against SARS-CoV-2 of each month who experienced mild to moderate COVID-19 and were consecutively treated with oral antivirals at Padua University Hospital between February 1, 2022, and June 30, 2022. In addition, all consecutive patients who met the criteria for antiviral therapy during this period but opted not to receive treatment were included as control group. The two groups were compared in terms of costs associated with emergency department visits and hospitalizations, which were identified as the primary outcomes of the study.ResultsNine-hundred-sixty-one patients were analysed, mean age was 67.72 ± 15.19 years and 49% were males. The most prevalent comorbidities were cardiovascular disease (57%), obesity (18) and diabetes mellitus (18%). Two-hundred-fifty-one (26%) patients were treated with MOL (group A), 252/961 (26%) were treated with NIR (group B) and 458/961 (48%) refused antiviral therapy (group C). While a generally more favourable outcomes was observed in the early treated group, no statistically significance differences between hospitalization or emergency department visits were found between group A and C and between group B and C. Total direct medical costs were statistically significantly higher both comparing group A (671.42 ± 460€) vs. group C and comparing group B (1008.42 ± 1562€) vs. group C (446.58 ± 4977€). The main cost driver associated with the increased cost was the antiviral therapy. The average hospitalization cost was 19,334.3 ± 27,030€ for group C, 8956.2 ± 7412€ for group B and 10,267.2€ for group A.ConclusionsIn the context of the Omicron variant during the COVID-19 pandemic, the use of early oral antiviral agents in vaccinated individuals was found to be more expensive compared to avoid treatment, primarily due to the high costs associated with it. To enhance the efficiency in resource allocation, it is essential to pursue policies aimed at reducing drug costs, along with conducting further pharmaco-economic studies.

Natural Compounds and Their Analogs as Antivirals Against Dengue Virus: A Review.

Dengue virus (DENV) continues to pose a significant global health challenge, causing diseases such as dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. While efforts in vaccine development and antiviral drug discovery are ongoing, effective therapeutic options remain limited. In this review, we highlight natural compounds and the analogs that demonstrated antiviral activity against DENV in invitro and invivo studies. Specifically, these studies examine alkaloids, phenolic acids, phenols, flavonoids, terpenoids, and glycosides which have shown potential in inhibiting DENV entry, replication, and reducing the cytokine storm. By focusing on these bioactive compounds and the analogs, a comprehensive overview of their promising roles is provided to advance therapeutic strategies for combating DENV infection.

Rapid Deployment of Antiviral Drugs Using Single-Virus Tracking and Machine Learning.

The outbreak of emerging acute viral diseases urgently requires the acceleration of specialized antiviral drug development, thus widely adopting phenotypic screening as a strategy for drug repurposing in antiviral research. However, traditional phenotypic screening methods typically require several days of experimental cycles and lack visual confirmation of a drug's ability to inhibit viral infection. Here, we report a robust method that utilizes quantum-dot-based single-virus tracking and machine learning to generate unique single-virus infection fingerprint data from viral trajectories and detect the dynamic changes in viral movement following drug administration. Our findings demonstrated that this approach can successfully identify viral infection patterns at various infection phases and predict antiviral drug efficacy through machine learning within 90 min. This method provides valuable support for assessing the efficacy of antiviral drugs and offers promising applications for responding to future outbreaks of emerging viruses.

Human Defensins: Structure, Function, and Potential as Therapeutic Antimicrobial Agents with Highlights Against SARS CoV-2.

The human defensins are a group of cationic antimicrobial peptides that range in size from 2 to 5kDa and share a common structural motif of six disulphide-linked cysteines. Several naturally occurring human α- and β-defensins have been identified over the past two decades. They have a wide variety of antimicrobial effects, and their potential to avoid the development of resistance to antimicrobial treatment makes them attractive as therapeutic agents. Human defensins have recently been the focus of medical and molecular biology studies due to their promising application in medicine and the pharmaceutical industry. This work aims to provide a comprehensive summary of the current developments of human defensins, including their identification, categorization, molecular features, expression, modes of action, and potential application in medical settings. Current obstacles and future opportunities for using human defensins are also covered. Furthermore, we shed light on the potential of this class as an antiviral agent, particularly against SARS CoV-2, by providing an in silico-based investigation of their plausible mechanisms of action.

High-throughput screening of dual-target inhibitors for SARS-CoV-2 main protease and papain-like protease from Chebulae Fructus: in silico prediction and experimental verification

BackgroundThe unavoidable propagation of the coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has underscored the urgent requirement for efficacious therapeutic agents. The dried fruit of Terminalia chebula Retz., namely Chebulae Fructus, is widely used for treating bacterial and viral infectious diseases, which was witnessed to perform anti-SARS-CoV-2 activity in recommended Chinese patent medicine.AimSARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro) present essential effects on SARS-CoV-2 replication and transcription, considering as the attractive targets for therapeutic intervention. In this study, we focused on the dual-target to obtain broad-spectrum antiviral candidates from Chebulae Fructus.MethodsThe identified compounds from Chebulae Fructus were used to build a library in a previous study, which were evaluated by molecular docking to screen potential antiviral agents. The SARS-CoV-2 Mpro and PLpro were expressed in E. coli cells and purified. Fluorescence resonance energy transfer (FRET) and surface plasmon resonance (SPR) were utilized to verify the affinity with dual targets. SARS-CoV-2 wild-type, Omicron BA.5 and Omicron EG.5 variants were employed to validate their antiviral activities in vitro. Molecular dynamics simulation was conducted via Gromacs 2022 software in 500 ns to unveil the conformation stability.ResultsTargeting on Mpro and PLpro, eight compounds were screened as the potential dual-target inhibitors in molecular docking. In FRET and SPR assays, 1,2,3,4,6-penta-O-galloyl-β-D-glucose (PGG) and 1,2,3,6-tetra-O-galloyl-β-D-glucose (TGG) showed good inhibitory activities with IC50 values ranging from 1.33 to 27.37 μM, and affinity with KD values ranging from 0.442 to 0.776 μM. Satisfactorily, both PGG and TGG display antiviral activity in vitro with EC50 values ranging from 3.20 to 37.29 μM, suggesting as the promising candidates against SARS-CoV-2. In molecular dynamics simulation study, the complexes of Mpro-PGG, Mpro-TGG, PLpro-PGG, and PLpro-TGG exhibited stability over 500 ns period, unveiling the potential interactions.ConclusionPGG and TGG are the promising dual-target inhibitors of SARS-CoV-2, which may avoid drug resistance and have a good development prospect. The outcomes of this study provide an effective strategy to systematically explore the antiviral bioactive compounds from Chebulae Fructus.

A Machine Learning Model to Predict De Novo Hepatocellular Carcinoma Beyond Year 5 of Antiviral Therapy in Patients With Chronic Hepatitis B.

This study aims to develop and validate a machine learning (ML) model predicting hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients after the first 5 years of entecavir (ETV) or tenofovir (TFV) therapy. CHB patients treated with ETV/TFV for > 5 years and not diagnosed with HCC during the first 5 years of therapy were selected from two hospitals. We used 36 variables, including baseline characteristics (age, sex, cirrhosis, and type of antiviral agent) and laboratory values (at baseline, at 5 years, and changes between 5 years) for model development. Five machine learning algorithms were applied to the training dataset and internally validated using a test dataset. External validation was performed. In years 5-15, a total of 279/5908 (4.7%) and 25/562 (4.5%) patients developed HCC in the derivation and external validation cohorts, respectively. In the training dataset (n = 4726), logistic regression showed the highest area under the receiver operating curve (AUC) of 0.803 and a balanced accuracy of 0.735, outperforming other ML algorithms. An ensemble model combining logistic regression and random forest performed best (AUC, 0.811 and balanced accuracy, 0.754). The results from the test dataset (n = 1182) verified the good performance of the ensemble model (AUC, 0.784 and balanced accuracy, 0.712). External validation confirmed the predictive accuracy of our ensemble model (AUC, 0.862 and balanced accuracy, 0.771). A web-based calculator was developed (http://ai-wm.khu.ac.kr/HCC/). The proposed ML model excellently predicted HCC risk beyond year 5 of ETV/TFV therapy and, therefore, could facilitate individualised HCC surveillance based on risk stratification.

Metformin in Antiviral Therapy: Evidence and Perspectives

Metformin, a widely used antidiabetic medication, has emerged as a promising broad-spectrum antiviral agent due to its ability to modulate cellular pathways essential for viral replication. By activating AMPK, metformin depletes cellular energy reserves that viruses rely on, effectively limiting the replication of pathogens such as influenza, HIV, SARS-CoV-2, HBV, and HCV. Its role in inhibiting the mTOR pathway, crucial for viral protein synthesis and reactivation, is particularly significant in managing infections caused by HIV, CMV, and EBV. Furthermore, metformin reduces oxidative stress and reactive oxygen species (ROS), which are critical for replicating arboviruses such as Zika and dengue. The drug also regulates immune responses, cellular differentiation, and inflammation, disrupting the life cycle of HPV and potentially other viruses. These diverse mechanisms suppress viral replication, enhance immune system functionality, and contribute to better clinical outcomes. This multifaceted approach highlights metformin’s potential as an adjunctive therapy in treating a wide range of viral infections.

A Randomized, Blinded, Vehicle-Controlled Dose-Ranging Study to Evaluate and Characterize Remdesivir Efficacy Against Ebola Virus in Rhesus Macaques

Ebola virus (EBOV) causes severe disease in humans, with mortality as high as 90%. The small-molecule antiviral drug remdesivir (RDV) has demonstrated a survival benefit in EBOV-exposed rhesus macaques. Here, we characterize the efficacy of multiple intravenous RDV dosing regimens on survival of rhesus macaques 42 days after intramuscular EBOV exposure. Thirty rhesus macaques underwent surgical implantation of telemetry devices for the fine-scale monitoring of body temperature and activity, as well as central venous catheters, to enable treatment administration and blood collection. Treatment, consisting of a loading dose of RDV followed by once-daily maintenance doses for 11 days, was initiated 4 days after virus exposure when all animals were exhibiting disease signs consistent with incipient EBOV disease as well as quantifiable levels of EBOV RNA in plasma. In the RDV treatment groups receiving loading/maintenance doses of 5/2.5 mg/kg, 10/5 mg/kg, and 20/10 mg/kg, a total of 6 of 8 (75%), 7 of 8 (87.5%), and 5 of 7 (71.4%) animals survived, respectively. In the vehicle control group, one of seven animals (14.3%) survived. The improved survival rate compared to the control group was statistically significant only for the 10/5 mg/kg RDV treatment group. This treatment regimen also resulted in a significantly lower systemic viral load compared to the vehicle control after a single RDV treatment. All three RDV regimens produced a significantly lower systemic viral load after two treatments. For most animals, RDV treatment, regardless of dose, resulted in the amelioration of many of the clinical–pathological changes associated with EBOV disease in this model.

Development of a reporter feline herpesvirus-1 for antiviral screening assays

Feline herpesvirus type 1 (FHV-1), a member of the Herpesviridae family, is one of the most important pathogens that causes upper respiratory tract disease in felines. Following infection, FHV-1 can spread retrogradely to the trigeminal ganglia, establishing a life-long latency. Although vaccines are available for routine feline vaccination, FHV-1 is still an agent that poses a serious threat to feline health. There are currently no specific drugs for the treatment of FHV-1. To facilitate the screening of antiviral drugs, we constructed a reporter FHV-1 virus, which expresses a secreted Gaussia luciferase (GLuc) and a bright green fluorescent protein, mNeonGreen. The reporter virus shows slower growth than does the wild-type FHV-1. The expression of the two reporter genes, Gluc and mNeonGreen, was consistent with viral propagation and remained stable during continuous passage in CRFK cells, even after twenty rounds. In addition, the known inhibitor ganciclovir was used to confirm the characteristics of the reporter virus for drug screening. We found that the reporter FHV-1 is suitable for antiviral screening assays. Overall, our work provides a useful tool for screening drugs to combat FHV-1.

History and Therapeutic Benefits of Honey: From Ancient Traditions to Modern Medicine

The history of honey spans millennia, with humans and honeybees intertwined in a remarkable journey dating back to ancient times. From the primitive collection of wild honey by early ancestors to the sophisticated practices of beekeeping and honey production today, honey has played diverse roles in various cultures and civilizations. Its significance transcends mere sustenance, extending into religious rituals, traditional medicine, and culinary delights. Across civilizations, honey has been revered for its delectable taste and myriad health benefits, including its therapeutic properties in wound care, its role in traditional medicinal practices such as Ayurveda, and its potential as an anti-bacterial, antiviral, anti-fungal, anti-inflammatory, and anti-cancer agent. Moreover, honey's versatility extends to oral health, stomach disorders, and wound and burn treatment, making it a valuable natural resource with immense cultural, medicinal, and culinary significance.

Effectiveness of riamilovir in preventing respiratory viral infection among young people from organized collectives

Aim. To evaluate the efficacy of the antiviral drug riamilovir (trade name – «Triazavirin®») for the prevention of SARS-CoV-2 infection (COVID-19) and other acute respiratory viral infections in young people from organized groups. Materials and methods. The study involved 386 individuals aged 18–22 years: 199 received riamilovir at a daily dose of 250 mg for 15 days, while 187 did not receive prophylactic drugs. For 30 days, disease occurrence was monitored among volunteers. In case of illness, the duration, severity of clinical manifestations, complications, and pathogen elimination dynamics were assessed via PCR from nasopharyngeal and oropharyngeal swabs. Results. During riamilovir administration, a statistically significant reduction in cases of acute respiratory viral infections of non-coronavirus etiology was observed, with no COVID-19 cases reported, confirmed by the absence of SARS-CoV-2 RNA in this group. The shortest duration of acute respiratory viral infections was noted in patients taking the prophylactic drug. Conclusion. Riamilovir (trade name – «Triazavirin®») showed statistically significant prophylactic efficacy during its administration in an organized group. Its use decreased the frequency of detection of viral pathogens and resulted in milder acute respiratory disease, likely due to reduced viral load in individuals.

Introduction about Global infectious disease and use of nanotechnology

Infectious diseases, including COVID-19, malaria, tuberculosis, and sexually transmitted diseases (STDs), pose significant threats to global health. Nanotechnology has emerged as a promising tool in the diagnosis, treatment, and prevention of these diseases. This review highlights the applications of nanotechnology in combating infectious diseases. Nanoparticles, such as metallic nanoparticles, liposomes, and quantum dots, have been employed in the detection and treatment of infectious diseases. Nanotechnology-based drug delivery systems have improved the efficacy and reduced the toxicity of antiviral and antibacterial drugs. Additionally, nanotechnology has enabled the development of point-of-care diagnostics and vaccines for infectious diseases. This review provides an overview of the current state of nanotechnology in infectious disease management and highlights its potential to revolutionize the field. By leveraging the unique properties of nanoparticles, nanotechnology can provide innovative solutions for the diagnosis, treatment, and prevention of infectious diseases, ultimately improving global health outcomes. Keywords: Nanotechnology, Infectious diseases, COVID-19, Malaria, Tuberculosis, HIV/AIDS

Treatment of Hepatitis C Virus Infections Among Patients of Ukrainian Origin During the Influx of War Refugees to Poland

Background: The wave of wartime migration from Ukraine has raised a number of concerns about infectious diseases, the prevalence of which is higher in Ukraine than in host countries, with hepatitis C virus (HCV) infection being one of them. Our analysis aimed to assess the percentage of HCV-infected Ukrainian refugees under care in Polish centers providing antiviral diagnosis and therapy, to evaluate their characteristics and the effectiveness of treatment with direct-acting antiviral drugs (DAAs). Methods: The analysis included patients of Polish and Ukrainian nationality treated for HCV infection between 2022 and 2024 in Polish hepatology centers. Data were collected retrospectively and completed online. Results: In the population of 3911 patients with chronic hepatitis C treated with DAAs in 16 Polish centers in 2022–2024, there were 429 war refugees from Ukraine, accounting for 11% of the total treated. The Ukrainian population was significantly younger (45.7 vs. 51 years, p < 0.001) and had a higher percentage of women (50.3% vs. 45.3%, p = 0.048) compared to Polish patients. Patients of Ukrainian origin had less advanced liver disease and were significantly less likely to have comorbidities and the need for comedications. Coinfection with human immunodeficiency virus was significantly more common in Ukrainians than in Polish patients, 16.1% vs. 5.9% (p < 0.001). The distribution of HCV genotypes (GTs) also differed; although GT1b predominated in both populations, its frequency was significantly higher in the Polish population (62.3% vs. 44.5%, p < 0.001), while the second most common GT3 was significantly more common in Ukrainian patients (30.5% vs. 16.2%, p < 0.001). Conclusions: Documented differences in patient characteristics did not affect the effectiveness of antiviral therapy, which exceeded 97% in both populations, but there was a higher rate of those lost to follow-up among Ukrainian patients.

Optimization of antiviral dosing in Herpesviridae encephalitis: a promising approach to improve outcome?

Despite established antiviral therapy for herpes simplex (HSV), varicella zoster (VZV) and cytomegalovirus (CMV) encephalitis, outcome remains poor. To assess pharmacokinetic (PK) and -dynamic (PD) data of antiviral drugs in the central nervous system (CNS) to optimize treatment of Herpesviridae encephalitis. PUBMED search 1950 to September 2024, terms 1. "encephalitis" and ("HSV" or "VZV" or "CMV") or 2. cerebrospinal and ["(val)acyclovir" or "(val)ganciclovir" or "foscarnet" or "cidofovir"]. Antivirals against herpes viruses apparently act in a time-dependent manner. To suppress viral replication, drug concentration in the extracellular space at the site of the infection should be kept above the concentrations active in cell cultures for 24h per day. Most data reflect delayed drug entry into lumbar cerebrospinal fluid (CSF). Ratios of the areas of the concentration/time curves (AUC) in CSF and serum (AUCCSF/AUCS) of acyclovir, ganciclovir and foscarnet are 0.15-0.3 in the absence of meningeal inflammation and increase in severe meningoencephalitis. Elimination half-lives (t1/2β) are longer in CSF than in plasma. CSF concentrations are rough approximations of drug concentrations in the cerebral extracellular fluid (ECF). Lumbar CSF concentrations usually are higher than ventricular or cisternal CSF concentrations tending to overestimate cerebral ECF concentrations. Provided the availability of adequate measurements in individual CNS compartments - antiviral concentrations and efficacy may be predicted by future PK/PD modeling. Probenecid holds potential to reduce efflux of antiviral drugs from the CNS. The long t1/2β of antiviral drugs in CSF suggest relatively uniform steady state CSF levels at dosing intervals ≤12h and accumulation after repeated dosing. Probenecid is of unproven utility. To rapidly attain effective concentrations in the infected tissue, physiologically based pharmacokinetic (PBPK) and PK/PD modeling may be helpful. Until reliable PK/PD data are available, doubling the first dose should be considered.

Late-Stage Functionalization of Guanine-Based Nucleosides, Nucleotides, and Oligonucleotide: Synthesis and Derivatization of Tricyclic Nucleoside Analogues.

We report here the synthesis of tricyclic nucleoside analogues via acid-catalyzed cyclization of guanine with 1,1,3,3-tetramethoxypropane. The method enables the use of hydroxyl-unprotected antiviral drugs (acyclovir, ganciclovir, and penciclovir), guanosines, oligonucleotide, and triazole-linked nucleoside dimers as substrates. Nucleoside trimer and tetramer were synthesized by derivatization reactions.

An explainable deep learning platform for molecular discovery.

Deep learning approaches have been increasingly applied to the discovery of novel chemical compounds. These predictive approaches can accurately model compounds and increase true discovery rates, but they are typically black box in nature and do not generate specific chemical insights. Explainable deep learning aims to 'open up' the black box by providing generalizable and human-understandable reasoning for model predictions. These explanations can augment molecular discovery by identifying structural classes of compounds with desired activity in lieu of lone compounds. Additionally, these explanations can guide hypothesis generation and make searching large chemical spaces more efficient. Here we present an explainable deep learning platform that enables vast chemical spaces to be mined and the chemical substructures underlying predicted activity to be identified. The platform relies on Chemprop, a software package implementing graph neural networks as a deep learning model architecture. In contrast to similar approaches, graph neural networks have been shown to be state of the art for molecular property prediction. Focusing on discovering structural classes of antibiotics, this protocol provides guidelines for experimental data generation, model implementation and model explainability and evaluation. This protocol does not require coding proficiency or specialized hardware, and it can be executed in as little as 1-2 weeks, starting from data generation and ending in the testing of model predictions. The platform can be broadly applied to discover structural classes of other small molecules, including anticancer, antiviral and senolytic drugs, as well as to discover structural classes of inorganic molecules with desired physical and chemical properties.

Dysfunction and regulatory interplay of T and B cells in chronic hepatitis B: immunotherapy and emerging antiviral strategies

In the context of chronic hepatitis B virus (HBV) infection, the continuous replication of HBV within host hepatocytes is a characteristic feature. Rather than directly causing hepatocyte destruction, this replication leads to immune dysfunction and establishes a state of T-B immune tolerance. Successful clearance of the HBV virus is dependent on the close collaboration between humoral and cellular immunity. Humoral immunity, mediated by B-cell subpopulations, and cellular immunity, dominated by T-cell subpopulations show varying degrees of dysfunction during chronic hepatitis B (CHB). Notably, not all T- and B-cells produce positive immune responses. This review examine the most recent developments in the mutual regulation of T-B cells during chronic HBV infection. Our focus is on the prevailing immunotherapeutic strategies, such as T cell engineering, HBV-related vaccines, PD-1 inhibitors, and Toll-like receptor agonists. While nucleos(t)ide analogues (NUCs) and interferons have notable limitations, including inadequate viral suppression, drug resistance, and adverse reactions, several HBV entry inhibitors have shown promising clinical efficacy. To overcome the challenges posed by NUCs or monotherapy, the combination of immunotherapy and novel antiviral agents presents a promising avenue for future CHB treatment and potential cure.

Evaluating the Efficacy and Safety of Baricitinib in Reducing COVID-19 Mortality: A Comprehensive Review of Clinical Evidence and Pharmacological Strategies

Introduction: COVID-19 manifests with symptoms ranging from mild to severe, including respiratory and cardiovascular complications. Severe cases are often marked by a cytokine storm, causing pulmonary damage and multi-organ dysfunction. Current treatments lack a specific antiviral, though several pharmacological options, including immunomodulatory and antiviral drugs, are under investigation. Purpose: The purpose of this article is to provide an evaluation of the efficacy and safety of baricitinib, a JAK inhibitor, combined with standard care for hospitalized adults with COVID-19. By reviewing recent literature, it aims to assess baricitinib's effectiveness in improving patient outcomes. Material and methods: A systematic review of clinical trials and case studies was conducted to analyze baricitinib’s impact on COVID-19 mortality. Data includes treatment-emergent adverse events and patient outcomes in moderate to severe cases. Discussion: Baricitinib has demonstrated potential in managing hyperinflammation in severe COVID-19 by inhibiting multiple proinflammatory cytokines and enhancing immune response. Clinical trials show that baricitinib, particularly in combination with corticosteroids, reduces mortality and serious infections compared to standard care alone. Due to potential adverse events, continuous monitoring of hematological and lipid levels is essential. These findings highlight baricitinib's dual role as an immunomodulatory and antiviral agent, suggesting its importance in treating severe COVID-19. Future research should focus on optimizing treatment regimens and further exploring the long-term implications of baricitinib therapy.

Phthalimide derivatives as a new class of papain-like protease inhibitors in SARS-CoV-2.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) papain-like cysteine protease (PLpro) represents one of only two essential cysteine proteases involved in the regulation of viral replication. It, therefore, qualifies as a promising therapeutic target for the development of antiviral agents. We identified a previously synthesized protease inhibitor, resulting from an earlier project, as a PLpro inhibitor and crafted a structure-activity relationship around the hit, leading to the more potent inhibitors ZHAWOC6941 (17h) and ZHAWOC25153 (17o) displaying IC50 values of 8 and 7 µM, respectively. The two compounds represent a new class of PLpro inhibitors and, with single-digit micromolar IC50 values, are comparable to inhibitors found in the literature.