Background: Despite advancements in vaccination, early treatments, and understanding of SARS-CoV-2, its impact remains significant worldwide. Many patients require intensive care due to severe COVID-19. Remdesivir, a key treatment option among viral RNA polymerase inhibitors, lacks comprehensive studies on factors associated with its effectiveness. Methods: We conducted a retrospective study in 2022, analyzing data from 252 hospitalized COVID-19 patients treated with remdesivir. Six machine learning algorithms were compared to predict factors influencing remdesivir's clinical benefits regarding mortality and hospital stay. Results: The extreme gradient boost (XGB) method showed the highest accuracy for both mortality (95.45%) and hospital stay (94.24%). Factors associated with worse outcomes in terms of mortality included limitations in life support, ventilatory support needs, lymphopenia, low albumin and hemoglobin levels, flu and/or coinfection, and cough. For hospital stay, factors included vaccine doses, lung density, pulmonary radiological status, comorbidities, oxygen therapy, troponin, lactate dehydrogenase levels, and asthenia. Conclusions: These findings underscore XGB's effectiveness in accurately categorizing COVID-19 patients undergoing remdesivir treatment.

SARS-CoV-2 burdens healthcare systems worldwide, yet specific drug-based treatments are still unavailable. Understanding the effects of SARS-CoV-2 on host molecular pathways is critical for providing full descriptions and optimizing therapeutic targets. The present study used Nuclear Magnetic Resonance-based metabolic footprinting to characterize the secreted cellular metabolite levels (exometabolomes) of Vero E6 cells in response to SARS-CoV-2 infection and to two candidate drugs (Remdesivir, RDV, and Azithromycin, AZI), either alone or in combination. SARS-CoV-2 infection appears to force VE6 cells to have increased glucose concentrations from extra-cellular medium and altered energetic metabolism. RDV and AZI, either alone or in combination, can modify the glycolic-gluconeogenesis pathway in the host cell, thus impairing the mitochondrial oxidative damage caused by the SARS-CoV-2 in the primary phase. RDV treatment appears to be associated with a metabolic shift toward the TCA cycle. Our findings reveal a metabolic reprogramming produced by studied pharmacological treatments that protects host cells against virus-induced metabolic damage, with an emphasis on the glycolytic-gluconeogenetic pathway. These findings may help researchers better understand the relevant biological mechanisms involved in viral infection, as well as the creation of mechanistic hypotheses for such candidate drugs, thereby opening up new possibilities for SARS-CoV-2 pharmacological therapy.

Epstein-Barr virus (EBV) reactivation in COVID-19 patients has been reported, but studies on its clinical significance are lacking. We herein report the occurrence of infectious mononucleosis (IM) due to EBV reactivation in a 60-year-old man with rheumatoid arthritis being treated with methotrexate and tocilizumab. The patient presented with a fever and tested positive for COVID-19. Laboratory findings revealed an increased atypical lymphocyte count, decreased platelet count, and elevated liver enzyme levels. Flow cytometry showed predominant expansion of reactive T cells. EBV reactivation was confirmed using real-time polymerase chain reaction. The patient was treated with remdesivir, and clinical improvement was observed after 10 days of treatment. Follow-up showed a gradual decrease in the EBV-DNA load with no recurrence of atypical lymphocytes. These findings suggest that COVID-19 in immunocompromised patients may lead to unexpected EBV reactivation and IM, even for patients outside the age at which IM is likely to occur.

SARS-CoV-2 isolates of a given clade may contain low frequency genomes that encode amino acids or deletions which are typical of a different clade.

The Advisory Committee on Immunization Practices (ACIP), a group of medical and public health experts that provides advice to the Centers for Disease Control and Prevention, normally meets 3 times per year to develop US vaccine recommendations. The ACIP met February 28 to 29, 2024, to discuss coronavirus disease (COVID-19) vaccines, chikungunya vaccines, DT vaccine, influenza vaccines, polio vaccines, RSV vaccines, meningococcal vaccines, pneumococcal vaccines and Vaxelis (DTaP, Inactivated Poliovirus, Haemophilus influenzae b Conjugate & Hepatitis B Vaccine). This update summarizes the proceedings of these meetings, with an emphasis on topics that are most relevant to the pediatric population. Major updates for pediatric clinicians include information about changes on influenza vaccine composition, meningococcal vaccination considerations, updated guidance for children with a contraindication to pertussis-containing vaccines, and recommendations of the world's first chikungunya vaccine for certain populations.

SARS-CoV-2 Omicron subvariants with increased transmissibility and immune evasion are spreading globally with alarming persistence. Whether the mutations and evolution of spike (S) Omicron subvariants alter the viral hijacking of human TMPRSS2 for viral entry remains to be elucidated. This is particularly important to investigate because of the large number and diversity of mutations of S Omicron subvariants reported since the emergence of BA.1. Here we report that human TMPRSS2 is a molecular determinant of viral entry for all the Omicron clinical isolates tested in human lung cells, including ancestral Omicron subvariants (BA.1, BA.2, BA.5), contemporary Omicron subvariants (BQ.1.1, XBB.1.5, EG.5.1) and currently circulating Omicron BA.2.86. First, we used a co-transfection assay to demonstrate the endoproteolytic cleavage by TMPRSS2 of spike Omicron subvariants. Second, we found that N-0385, a highly potent TMPRSS2 inhibitor, is a robust entry inhibitor of virus-like particles harbouring the S protein of Omicron subvariants. Third, we show that N-0385 exhibits nanomolar broad-spectrum antiviral activity against live Omicron subvariants in human Calu-3 lung cells and primary patient-derived bronchial epithelial cells. Interestingly, we found that N-0385 is 10-20 times more potent than the repositioned TMPRSS2 inhibitor, camostat, against BA.5, EG.5.1, and BA.2.86. We further found that N-0385 shows broad synergistic activity with clinically approved direct-acting antivirals (DAAs), i.e., remdesivir and nirmatrelvir, against Omicron subvariants, demonstrating the potential therapeutic benefits of a multi-targeted treatment based on N-0385 and DAAs.

Feline infectious peritonitis (FIP) is a multisystemic, generally lethal immuno-inflammatory disease of domestic cats caused by an infection with a genetic variant of feline coronavirus, referred to as the FIP virus (FIPV). We leveraged data from four different antiviral clinical trials performed at the University of California, Davis. Collectively, a total of 60 client-owned domestic cats, each with a confirmed diagnosis of naturally occurring FIP, were treated with a variety of antiviral compounds. The tested therapies included the antiviral compounds GS-441524, remdesivir, molnupiravir and allogeneic feline mesenchymal stem/stroma cell transfusions. Four client-owned cats with FIP did not meet the inclusion criteria for the trials and were not treated with antiviral therapies; these cats were included in the data set as untreated FIP control cats. ELISA and Western blot assays were performed using feline serum/plasma or ascites effusions obtained from a subset of the FIP cats. Normalized tissue/effusion viral loads were determined in 34 cats by a quantitative RT-PCR of nucleic acids isolated from either effusions or abdominal lymph node tissue. Twenty-one cats were PCR "serotyped" (genotyped) and had the S1/S2 region of the coronaviral spike gene amplified, cloned and sequenced from effusions or abdominal lymph node tissue. In total, 3 untreated control cats and 14 (23.3%) of the 60 antiviral-treated cats died or were euthanized during (13) or after the completion of (1) antiviral treatment. Of these 17 cats, 13 had complete necropsies performed (10 cats treated with antivirals and 3 untreated control cats). We found that anticoronaviral serologic responses were persistent and robust throughout the treatment period, primarily the IgG isotype, and focused on the viral structural Nucleocapsid and Membrane proteins. Coronavirus serologic patterns were similar for the effusions and serum/plasma of cats with FIP and in cats entering remission or that died. Viral RNA was readily detectable in the majority of the cats in either abdominal lymph node tissue or ascites effusions, and all of the viral isolates were determined to be serotype I FIPV. Viral nucleic acids in cats treated with antiviral compounds became undetectable in ascites or abdominal lymph node tissue by 11 days post-treatment using a sensitive quantitative RT-PCR assay. The most common pathologic lesions identified in the necropsied cats were hepatitis, abdominal effusion (ascites), serositis, pancreatitis, lymphadenitis, icterus and perivasculitis. In cats treated with antiviral compounds, gross and histological lesions characteristic of FIP persisted for several weeks, while the viral antigen became progressively less detectable.

Due to the molecular mechanisms of action of antidiabetic drugs, they are considered to be effective in the treatment of both COVID-19 and the post-COVID-19 syndromes. The aim of this study was to determine the effect of administering insulin and metformin on the mortality of patients with type 2 diabetes (T2DM) with symptomatic COVID-19 with the use of logistic regression models. The association between death and insulin and metformin was weak and could not be included in the multivariate model. However, the interaction of both drugs with other factors, including remdesivir and low-molecular-weight heparin (metformin), age and hsCRP (insulin), modulated the odds of death. These interactions hint at multifaceted (anti-/pro-) associations of both insulin and metformin with the odds of death, depending on the patient's characteristics. In the multivariate model, RDW-SD, adjusted with low-molecular-weight heparin treatment, age, sex and K[+], was associated with mortality among patients with COVID-19 and T2DM. With a 15% increase in RDW-SD, the risk of death increased by 87.7%. This preliminary study provides the foundations for developing further, more personalized models to assess the risk of death in T2DM patients, as well as for identifying patients at an increased risk of death due to COVID-19.

Plasma collected from people recovered from COVID-19 (COVID-19 convalescent plasma, CCP) was the first antibody-based therapy employed to fight the pandemic. CCP was, however, often employed in combination with other drugs, such as the antiviral remdesivir and glucocorticoids. The possible effect of such interaction has never been investigated systematically. To assess the safety and efficacy of CCP combined with other agents for treatment of patients hospitalized for COVID-19, a systematic literature search using appropriate Medical Subject Heading (MeSH) terms was performed through PubMed, EMBASE, Cochrane central, medRxiv and bioRxiv. The main outcomes considered were mortality and safety of CCP combined with other treatments versus CCP alone. This review was carried out in accordance with Cochrane methodology including risk of bias assessment and grading of the quality of evidence. Measure of treatment effect was the risk ratio (RR) together with 95% confidence intervals (CIs). A total of 11 studies (8 randomized controlled trials [RCTs] and 3 observational) were included in the systematic review, 4 studies with CCP combined with remdesivir and 6 studies with CCP combined with corticosteroids, all involving hospitalized patients. One RCT reported information on both remdesivir and steroids use with CCP. The use of CCP combined with remdesivir was associated with a significantly reduced risk of death (RR 0.74; 95% CI 0.56-0.97; p = 0.03; moderate certainty of evidence), while the use of steroids with CCP did not modify the mortality risk (RR 0.72; 95% CI 0.34-1.51; p = 0.38; very low certainty of evidence). Not enough safety data were retrieved form the systematic literature analysis. The current evidence from the literature suggests a potential beneficial effect on mortality of combined CCP plus remdesivir compared to CCP alone in hospitalized COVID-19 patients. No significant clinical interaction was found between CCP and steroids.

The impact of COVID-19 urges scientists to develop targeted drug delivery to manage Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) viral infections with a fast recovery rate. The aim of the study is to develop Hyaluronic Acid (HA) drug conjugates of viral drugs to target two important enzymes (Mpro and PLpro) of SARS-CoV-2. Three antiviral drugs, namely Dexamethasone (DEX), Favipiravir (FAV), and Remdesivir (REM), were chosen for HA conjugation due to their reactive functional groups. Free forms of drugs (DEX, FAV, REM) and HA drug conjugates (HA-DEX, HA-FAV, HA-REM, HA-RHA, HA-RHE) were validated against Mpro (PDB ID 6LU7) and PLpro (PDB 7LLZ), which play an essential role in the replication and reproduction of the SARS-CoV-2 virus. The results of the present study revealed that HA-drug conjugates possess higher binding affinity and the best docking score towards the Mpro and PLpro target proteins of SARS-CoV-2 than their free forms of drugs. ADMET screening resulted that HA-drug conjugates exhibited better pharmacokinetic profiles than their pure forms of drugs. Further, molecular dynamic simulation studies, essential dynamics and free energy landscape analyses show that HA antiviral drug conjugates possess good trajectories and energy status, with the PLpro target protein (PDB 7LLZ) of SARS-CoV-2 through long-distance (500 ns) simulation screening. The research work recorded the best drug candidate for Cell-Targeted Drug Delivery (CTDD) for SARS-CoV-2-infected cells through hyaluronic acid conjugates of antiviral drugs.Communicated by Ramaswamy H. Sarma.

Novel approach for synthesizing triazine sulfonamide derivatives is accomplished via reacting the sulfaguanidine derivatives with N-cyanodithioiminocarbonate. Further reaction of the novel triazine sulfonamide analogues with various secondary amines and anilines generated various substituted triazine sulfonamide analogues of promising broad-spectrum activities including anti-microbial, anti-tumor, and anti-viral properties. The in vitro anti-proliferative activities of most of the novel compounds were evaluated on the NCI-60 cell line panel. The antifungal and antibacterial activities of the compounds were also estimated. The anti-viral activity against SARS CoV-2 virus was performed using MTT cytotoxicity assay to evaluate the half-maximal cytotoxic concentration (CC50) and inhibitory concentration 50 (IC50) of a representative compound from the novel triazine sulfonamide category. Compound 3a demonstrated potent antiviral activity against SARS-CoV-2 with IC50 = 2.378 µM as compared to the activity of the antiviral drug remdesivir (IC50 = 10.11 µM). Our results indicate that, upon optimization, these new triazine sulfonamides could potentially serve as novel antiviral drugs.

While the majority of COVID-19 cases in South Africa (SA) are mild, patients with severe COVID-19 requiring hospitalisation present with significant morbidity and mortality and place a substantial burden on healthcare services. Given the low vaccine uptake in SA and other low- and middle-income countries in sub-Saharan Africa, the high prevalence of comorbidities and limited healthcare system capacity, evidence-based interventions that reduce the risk of severe disease and death should be considered for implementation. Several antiviral classes have been newly developed or repurposed to treat COVID-19 early after infection to retard progression to severe disease and reduce the risk of death, particularly in the elderly and/or in patients with comorbidities. COVID-19 antivirals such as remdesivir, nirmatrelvir/ ritonavir and molnupiravir are safe and cost-effective and have received either full approval or emergency use authorisation from regulators. Using a proposed test-and-treat strategy, judicious use of antivirals could be impactful.

The COVID-19 pandemic began in 2019 as a result of the advent of a novel coronavirus, SARS-CoV-2. At present, there are a limited number of approved antiviral agents for the treatment of COVID-19. Remdesivir, Molnupiravir, and Paxlovid have been approved by the FDA to treat COVID-19 infections. Research has shown that the main protease enzyme (Mpro) of SARS-CoV-2 plays a crucial role in the enzymatic processing of viral polyproteins. This makes Mpro an interesting therapeutic target for combating infections caused by emerging coronaviruses.

Severe acute respiratory syndrome-2 (SARS-CoV-2) infection in immunocompromised patients presents a challenge, as patients with such conditions may have severe courses. Identifying modalities to shorten the course or lessen the severity of infection could be potentially beneficial. A 76-year-old male with follicular lymphoma on rituximab and lenalidomide presented with COVID-19 pneumonia requiring intensive care unit (ICU) level care for persistent hypoxemia. He was treated with an extended course of remdesivir, as recommended by the Infectious Diseases service, but he maintained a persistently high viral load, necessitating a delay of his cancer treatment until he had recovered from his infection. On hospital day 31, he was given one dose of convalescent plasma with improvement in his SARS-CoV-2 viral load. He was able to be discharged and resumed cancer treatment soon thereafter. Convalescent plasma is a potential therapeutic option for immunocompromised patients with SARS-CoV-2 infection and should be considered early in the hospital course. Additionally, cycle threshold monitoring may be beneficial in certain scenarios: for instance to guide consideration of alternative therapies in patients with severe COVID-19 who have persistent symptoms and viremia while on guideline-directed therapy.

A 26-year-old woman receiving immunosuppressive therapy for polymyositis was infected with COVID-19 (an omicron mutant strain) and presented with fever. On the second day after the onset, she was admitted to our hospital and developed status epilepticus. Brain magnetic resonance imaging on admission revealed abnormal symmetric hyperintensities in the bilateral putamen and around the dorsal horns of the lateral ventricle. Three days after admission, brain computed tomography revealed marked cerebral edema and herniation. The cerebrospinal fluid (CSF) cell count was normal, and the reverse transcription polymerase chain reaction for severe acute respiratory syndrome coronavirus 2 was negative. Interleukin (IL)-2, 6, and 10 levels were within the normal range in both serum and CSF, whereas IL-8 levels in the CSF were markedly higher compared to serum levels. She had fulminant acute encephalopathy, suspected to be in the early stages of acute necrotizing encephalopathy (ANE). Steroid pulse therapy and intravenous infusions of remdesivir were ineffective, and the patient died of sepsis on the 26th day after admission. We demonstrated that ANE may occur even in patients infected with Omicron strains and speculated that the pathogenesis in this case might be associated with intrathecal IL-8 production by microglial activation.

We have previously developed a bacterial artificial chromosome (BAC)-vectored SARS-CoV-2 replicon, namely BAC-CoV2-Rep, which, upon transfection into host cells, serves as a transcription template for SARS-CoV-2 replicon mRNA to initiate replicon replication and produce nanoluciferase (Nluc) reporter from the subgenomic viral mRNA. However, an inherent issue of such DNA-launched replicon system is that the nascent full-length replicon transcript undergoes process by host RNA splicing machinery, which reduces replicon replication and generates spliced mRNA species expressing NLuc reporter independent of replicon replication. To mitigate this problem, we employed Isoginkgetin, a universal eukaryotic host splicing inhibitor, to treat cells transfected with BAC-CoV2-Rep. Isoginkgetin effectively increased the level of full-length replicon transcripts while concurrently reducing the level of Nluc signal derived from spliced replicon mRNA, making the Nluc reporter signal more correlated with replicon replication, as evidenced by treatment with known SARS-CoV-2 replication inhibitors including Remdesivir, GC376, and EIDD-1931. Thus, our study emphasizes that host RNA splicing is a confounding factor for DNA-launched SARS-CoV-2 replicon systems, which can be mitigated by Isoginkgetin treatment.

Carboxylesterases (CES1 and CES2) and arylacetamide deacetylase (AADAC), which are expressed primarily in the liver and/or gastrointestinal tract, hydrolyze drugs containing ester and amide bonds in their chemical structure. These enzymes often catalyze the conversion of prodrugs, including the COVID-19 drugs remdesivir and molnupiravir, to their pharmacologically active forms. Information on the substrate specificity and inhibitory properties of these enzymes, which would be useful for drug development and toxicity avoidance, has accumulated. Recently,in vitroandin vivostudies have shown that these enzymes are involved not only in drug hydrolysis but also in lipid metabolism. CES1 and CES2 are capable of hydrolyzing triacylglycerol, and the deletion of their orthologous genes in mice has been associated with impaired lipid metabolism and hepatic steatosis. Adeno-associated virus-mediated human CES overexpression decreases hepatic triacylglycerol levels and increases fatty acid oxidation in mice. It has also been shown that overexpression of CES enzymes or AADAC in cultured cells suppresses the intracellular accumulation of triacylglycerol. Recent reports indicate that AADAC can be up- or downregulated in tumors of various organs, and its varied expression is associated with poor prognosis in patients with cancer. Thus, CES and AADAC not only determine drug efficacy and toxicity but are also involved in pathophysiology. This review summarizes recent findings on the roles of CES and AADAC in drug metabolism, physiology, and pathology.

Obeldesivir (ODV, GS-5245) is an orally administered prodrug of the parent nucleoside of remdesivir (RDV) and is presently in phase 3 trials for COVID-19 treatment. In this work, we show that ODV and its circulating parent nucleoside metabolite, GS-441524, have similar in vitro antiviral activity against filoviruses, including Marburg virus, Ebola virus, and Sudan virus (SUDV). We also report that once-daily oral ODV treatment of cynomolgus monkeys for 10 days beginning 24 hours after SUDV exposure confers 100% protection against lethal infection. Transcriptomics data show that ODV treatment delayed the onset of inflammation and correlated with antigen presentation and lymphocyte activation. Our results offer promise for the further development of ODV to control outbreaks of filovirus disease more rapidly.