Search Results (91)

SARS-CoV-2, the causative agent of COVID-19, has led to over seven million deaths worldwide prior to May 2025. Despite widespread vaccination programs, COVID-19 remains a persistent global health challenge, underscoring the urgent need for new therapeutic approaches. Orientin is a flavonoid with reported antiviral activity, though its potential against SARS-CoV-2 remains poorly explored. This study aimed to investigate whether Orientin interacts with the viral Spike protein and impacts viral replication. Molecular docking simulations using DockThor were employed to predict the binding affinity between Orientin and the receptor-binding domain (RBD) of the Spike protein. Fluorescence spectroscopy assays were performed to assess direct interactions between Orientin and the trimeric form of the Spike protein. Additionally, cytotoxicity and viral replication assays were carried out in Vero cells to evaluate Orientin’s antiviral effects. Docking results indicated that Orientin likely binds to key RBD residues involved in ACE2 receptor recognition. Spectroscopic analyses showed a decrease in intrinsic tryptophan fluorescence, suggesting direct interaction. Orientin demonstrated no cytotoxicity in Vero cells and exhibited moderate inhibition of viral replication. These findings suggest that Orientin interacts with critical regions of the Spike protein and may act as a moderate in vitro inhibitor of SARS-CoV-2, warranting further investigation into its therapeutic potential. Full article

Background/Objectives: COVID-19 was responsible for millions of deaths worldwide. This study aimed to identify substances with in vitro and in vivo effects against the SARS-CoV-2 virus. Methods: Compounds PQM-243 and PQM-249, two terpene-N-acyl-aryl-hydrazone analogues, were evaluated in vitro against SARS-CoV-2 to a antiviral activity and inhibitory effect against angiotensin converting enzyme 2 (ACE2). A possible inhibitory effect affecting the interaction between the receptor-binding domain (RBD) protein and/or ACE2 was evaluated using LUMMIT kit. A SARS-CoV-2-induced pulmonary pneumonia model was developed to evaluate the effects of the compounds after 3 days of treatment. Results: Compounds PQM-243 and PQM-249 exhibited IC₅₀ values of 0.0648 ± 0.041 µM and 0.2860 ± 0.057 µM against SARS-CoV-2 with a selective index of >1543.21 and 349.65, respectively, and IC₅₀ values of 12.1 nM and 13.3 nM, respectively, against ACE2. All concentrations used significantly reduced interactions between ACE2 and RBD. Computational studies suggest that these new compounds are potent direct anti-SARS-CoV-2 agents, capable of reducing both virus viability and its invasive ability in the host cells by reducing the interaction between RBD and ACE2. It was also demonstrated that even when administered by the oral route, both compounds reduced SARS-CoV-2-induced lung inflammation. Our data suggests that both compounds can act as potent direct anti-SARS-CoV-2 agents, reducing both viral viability and host cell entry. In addition, they exhibited a significant multi-target-directed pharmacological profile, also reducing SARS-CoV-2-induced lung inflammation when administered orally. Conclusions: Overall, these findings support further investigation of PQM-243 and PQM-249 as promising antiviral and anti-inflammatory multi-target prototypes for the development of innovative drug candidates targeting SARS-CoV-2 and other virus-related respiratory diseases. Full article

New York State and New York City (NYC) developed hepatitis C (HCV) elimination plans to reduce premature deaths and new infections. NYC Health + Hospitals (NYC H + H), the municipal healthcare system for NYC serving over a million individuals annually, designed electronic health record (EHR) tools that collaboratively facilitated screening, linkage, and tracking of patients diagnosed with HCV through to cure. This study reviews the impact of this group of EHR tools by comparing data on HCV testing, linkage, and cure for 12 months before tools were released and a second 12-month period coinciding with the release of tools. Indicators related to HCV screening, diagnoses, treatment initiation, and cure were assessed. All indicators reviewed improved following the implementation of EHR tools. The proportion of individuals screened increased from 34% pre-intervention to 46% during the implementation phase; the number of individuals on direct-acting antivirals increased by 11%; and the number of individuals reaching cure increased by 37%. Efforts to collaboratively develop custom interlinking EHR tools to establish a systematic process proved impactful. Integrating the needs and functions of different care settings and the structure of the local epidemic allowed for the successful development and implementation of impactful resources. Full article

The global elimination of hepatitis C virus (HCV) has been prioritized by the World Health Organization (WHO) as a key public health target, with a deadline set for 2030. This initiative aims to significantly reduce both new infection rates and HCV-associated mortality. A major breakthrough in achieving this goal has been the development of direct-acting antiviral agents (DAAs), which offer cure rates exceeding 95%, along with excellent safety and tolerability. Nevertheless, transmission via parenteral routes continues to be the dominant pathway, particularly among high-risk groups, such as individuals who inject drugs, incarcerated populations, those exposed to unsafe medical practices, and healthcare professionals. Identifying, monitoring, and delivering tailored interventions to these groups is crucial to interrupt ongoing transmission and to reduce the burden of chronic liver disease. On a global scale, several nations have demonstrated measurable progress toward HCV elimination, with some nearing the targets set by WHO. These achievements have largely resulted from context-adapted policies that enhanced diagnostic and therapeutic access while emphasizing outreach to vulnerable communities. This review synthesizes current advancements in HCV prevention and control and proposes strategic frameworks to expedite global elimination efforts. Full article

Since the onset of the COVID-19 pandemic, remarkable progress has been made in the development of antiviral therapies for SARS-CoV-2. Several direct-acting antivirals, such as remdesivir, molnupiravir, and nirmatrelvir/ritonavir, offer clinical benefits. These agents have significantly contributed to reducing the viral loads and duration of the illness, as well as the disease’s severity and mortality. However, despite these advances, important limitations remain. The continued emergence of resistant SARS-CoV-2 variants highlights the urgent need for adaptable and durable therapeutic strategies. Therefore, this review aims to provide an updated overview of the main antiviral strategies that are used and the discovery of new drugs against SARS-CoV-2, as well as the therapeutic limitations that have shaped clinical management in recent years. The major challenges include resistance associated with viral mutations, limited treatment windows, and unequal access to treatment. Moreover, there is an ongoing need to identify novel compounds with broad-spectrum activity, improved pharmacokinetics, and suitable safety profiles. Combination treatment regimens represent a promising strategy to increase the efficacy of treating COVID-19 while minimizing the potential for resistance. Ideally, these interventions should be safe, affordable, and easy to administer, which would ensure broad global access and equitable treatment and enable control of COVID-19 cases and preparedness for future threats. Full article

Background: Remdesivir (RDV) is a broad-spectrum antiviral prodrug, which is rapidly metabolized in vivo within cells to the pharmacologically active triphosphate metabolite, GS-443902. On the other hand, the dephosphorylated metabolite GS-441524 is the main form detected in plasma. RDV acts against RNA viruses, and it was the first antiviral drug to receive EMA and FDA approval for treating COVID-19. Nevertheless, its intracellular pharmacokinetics in real life are poorly explored, particularly due to technical challenges. Methods: The aim of this study was to validate an HPLC-MS/MS method for the direct quantification of GS-443902 in peripheral blood mononuclear cells (PBMCs) with a chromatographic separation of 15 min. Results: The method was validated following EMA and FDA guidelines in terms of sensitivity, specificity, accuracy, precision, matrix effect, recovery, carryover, and stability, and then applied to PBMC isolates from a small cohort of patients with severe COVID-19 who received RDV. Conclusions: This work represents the first method for the direct quantification of GS-443902 in PBMCs, with possible future application to intracellular pharmacokinetic studies in different scenarios, such as new oral prodrugs or drug–drug interaction studies. Full article

Respiratory viruses can cause life-threatening conditions such as sepsis and acute respiratory distress syndrome. However, vaccines and effective antivirals are available for only a limited number of infections. The majority of approved antivirals are direct-acting agents, which target viral proteins essential for infection. Unfortunately, mutations have already emerged that confer resistance to these antivirals. In addition, there is an urgent need for broad-spectrum antivirals to address the unpredictable emergence of new viruses with pandemic potential. One promising strategy involves modulating the innate immune response and cellular signaling. Imiquimod, a Toll-like receptor 7 (TLR7) agonist, has shown efficacy in murine models of influenza and respiratory syncytial virus (RSV). Additionally, it demonstrates antiviral activity against herpes simplex virus type 1 (HSV-1) and RSV independent of the TLR7/nuclear factor kappa B (NF-κB) pathway, with protein kinase A (PKA) as a crucial downstream effector. In this study, we demonstrate that imiquimod exhibits concentration-dependent antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and canine coronavirus (CCoV) in epithelial cells, underscoring its broad-spectrum action against coronaviruses. Moreover, its anti-coronavirus effect appears to be independent of the TLR/NF-κB and PKA/exchange protein directly activated by cyclic adenosine monophosphate (EPAC) pathways and may instead be linked to the activation of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. The ability of imiquimod to inhibit coronavirus replication via the MEK/ERK pathway, coupled with its immunomodulatory properties, highlights its potential as a broad-spectrum antiviral. Full article

The COVID-19 pandemic, driven by the high transmissibility and immune evasion caused by SARS-CoV-2 and its variants (e.g., Alpha, Delta, Omicron), has led to massive casualties worldwide. As of November 2024, the International Committee on Taxonomy of Viruses (ICTV) has identified 14,690 viral species across 3522 genera. The increasing infectious and resistance to FDA and EMA-approved antivirals, such as 300-fold efficacy reduction in Nirmatrelvir against the SARS-CoV-2 3CLpro, highlight the need for mutation-stable antivirals, likewise targeting the essential host proteins like kinases, heat shock proteins, lipid metabolism proteins, immunological pathway proteins, etc. Unlike direct-acting antivirals, HDAs reduce the risk of resistance by targeting conserved host proteins essential for viral replication. The proposal for repurposing current FDA-approved drugs for host-directed antiviral (HDA) approach is not new, such as the Ouabain, a sodium-potassium ATPase inhibitor for herpes simplex virus (HSV) and Verapamil, a calcium channel blocker for influenza A virus (IAV), to name a few. Given the colossal potential of the mutation-stable HDA approach to exterminate the virus infection, it has been increasingly studied on SARS-CoV-2. This review aims to unravel the interaction between viruses and human hosts and their successfully proposed host-directed antiviral approach to provide insight into an alternative treatment to the rampant mutation in SARS-CoV-2. The benefits, limitations, and potential of host protein-targeted antiviral therapies and their prospects are also covered in this review. Full article

Approximately 95% of patients with chronic hepatitis C achieve viral eradication through direct-acting antiviral (DAA) treatment. Ensuing clinical benefits include halting liver fibrosis, thereby reducing the need for liver transplantation, and decreasing both liver-related and overall mortality. It is well established that, although ameliorated, the risk of developing hepatocellular carcinoma (HCC) persists, particularly among patients with pre-treatment advanced fibrosis/cirrhosis. Current guidelines recommend indefinite HCC surveillance in these patients. However, a recent Markov model evaluation shows that HCC surveillance is cost-effective only for patients with cirrhosis but not so for those with F3 fibrosis, a finding which points out the need to better define the risk of HCC in hepatitis C patients after cure and further characterize pre- and post-treatment factors that might affect the incidence of HCC in this setting. We reviewed the literature analyzing this aspect. Here we summarize the main findings: male gender and older age are independent predictors of increased risk of post-cure HCC development. Moreover, non-invasive tests for hepatic fibrosis, namely FIB4, APRI, and liver stiffness, measured before and after treatment and their post-therapy change, contribute to better stratifying the risk of HCC occurrence. Furthermore, low serum albumin, as well as an AFP above 7 ng/mL prior to and after DAA therapy, also constitute independent predictors of HCC development. Considering these findings, we propose to classify patients with HCV viral eradication and advanced fibrosis/cirrhosis into groups of low, medium, or high risk of HCC and to adopt adequate surveillance strategies for each group, including protocols for abbreviated magnetic resonance imaging (MRI) for those at the highest risk. Full article

While direct-acting antivirals (DAAs) are available for the treatment of chronic Hepatitis C virus (HCV) patients in Nepal, knowledge of the circulating genotypes/subtypes and drug target gene mutations of HCV is currently unavailable. Here, we describe HCV genotypes/subtypes and identify antiviral target gene mutations in patients at a tertiary care hospital using genome data. A cross-sectional study was conducted from December 2019 to February 2024, where PCR followed by whole genome sequencing was performed to identify HCV genotypes/subtypes and drug target gene mutations. Among all the patients who tested positive for anti-HCV, 70.6% (149/211) were HCV RNA positive, while 68.2% (30/44) were genotype/subtype 3a, followed by 1a (18.2%, 8/44) and others (13.6%, 6/44), including new subtypes 3g and 3i from Nepal. Subtype 3a was also the dominant subtype (≥70%) among intravenous drug users and sexual routes of transmission. We found 70.5% of the samples with resistant mutations in the NS3/4A region, 22.7% in NS5A, and 45.5% in NS5B. Resistant mutations against sofosbuvir, pibrentasvir, velpatasvir, daclatasvir, and dasabuvir were found at 25%, 18%, 16%, 16%, and 2%, respectively, mostly on subtype 3a. The predominant HCV genotype/subtype in our patient group was 3a, and resistance mutations against direct-acting antivirals were found in most untreated patients. Full article

Background: Since the discovery of successful direct-acting antiviral (DAA) treatment, kidneys from hepatitis C virus (HCV) RNA-positive donors represent a new opportunity to expand the organ donor pool for HCV-negative recipients. Case presentation: In this paper, we describe a unique case of transplantation of an HCV genotype 3a-infected kidney into an HCV-negative recipient who was highly sensitized, with a virtual panel-reactive antibody level of 99.96%. Prior to the kidney transplantation, the recipient received DAA treatment with glecaprevir/pibrentasvir as a viable prophylactic strategy. Post-transplant, the recipient received a triple-combination DAA regimen with glecaprevir/pibrentasvir/sofosbuvir, which continued for 12 weeks. Subsequently, viral load was undetectable at 12 and 24 weeks after treatment, with no significant adverse events associated with DAA therapy. A 12-month post-transplantation biopsy revealed mixed rejection requiring treatment. The 19-month follow-up showed a favorable outcome regarding the function of the kidney allograft and the recipient’s quality of life. HCV-positive transplantation allowed our recipient to receive a kidney from an immunologically compatible donor without donor-specific antibodies and the need for desensitization strategies. Conclusions: Each transplant center should decide on the selection of candidates for kidney transplantation from HCV RNA-positive donors to HCV-negative recipients, the availability and choice of DAA treatment, and post-transplant follow-up. Our case emphasizes the need for early DAA treatment based on viral load and HCV genotyping, as well as for careful post-transplant surveillance including protocol biopsies. Full article

Hepatitis C virus (HCV) infects both pediatric and adult populations and is an important cause of chronic liver disease worldwide. There are differences in the screening and management of HCV between pediatric and adult patients, which have been highlighted in this review. Direct-acting antiviral agents (DAA) have made the cure of HCV possible, and fortunately, these medications are approved down to three years of age. However, treatment in the pediatric population has its own set of challenges. The World Health Organization (WHO) has made a pledge to eliminate HCV as a public health threat by 2030. Despite this, HCV continues to remain a global health burden, leading to cirrhosis as well as hepatocellular carcinoma, and is a reason for liver transplantation in the adult population. Although rare, these complications can also affect the pediatric population. A variety of new technologies t have become available in the current era and can advance our understanding of HCV are discussed. Artificial intelligence, machine learning, liver organoids, and liver-on-chip are some examples of techniques that have the potential to contribute to our understanding of the disease and treatment process in HCV. Despite efforts over several decades, a successful vaccine against HCV has yet to be developed. This would be an important tool to help in worldwide efforts to eliminate the virus. Full article

The Hepatitis C Virus (HCV) is a significant public health challenge in European countries. Historically, healthcare-related procedures were the primary source of HCV infection in Europe. However, with the implementation of blood safety programs, injection drug use has become the main transmission route. The infection’s distribution and genotype prevalence vary widely across the continent. Even with the availability of highly effective direct-acting antiviral (DAA) therapies, HCV infection is far from being controlled. A significant proportion of patients remain undiagnosed, contributing to the ongoing transmission of the virus. Additionally, several barriers hinder the widespread use of DAAs, including high treatment costs, stigma, poor linkage to care, and considerable geographical variations in prevalence and transmission routes. The World Health Organization has set ambitious targets to reduce liver-related deaths, decrease new viral hepatitis infections, and ensure that 90% of infected individuals are diagnosed by 2030. However, most European countries face challenges, highlighting the need for screening programs, funding mechanisms, and public health strategies to effectively control HCV infection in Europe. Full article

This study is a secondary analysis of a randomized clinical trial (October 2013–April 2017) involving 150 People Who Inject Drugs (PWIDs) with hepatitis C virus (HCV) seen in opioid agonist treatment programs in the Bronx, New York, and investigates the impact of distrust in the healthcare system on adherence to Direct-Acting Antivirals (DAAs) HCV treatment therapy among PWIDs. The distrust was scaled on a 9-item instrument and the adherence to DAA medications was measured using electronic blister packs. This study demonstrated a significant inverse relationship between levels of distrust and medication adherence: 71.8 ± 2.2% (se) vs. 77.9 ± 1.8%, p = 0.024 between participants with higher and lower distrust levels. Despite the absence of significant association of distrust with sociodemographic or substance use characteristics, these findings suggest that building trust within the healthcare system is paramount for improving adherence to DAAs among PWIDs. The results call for a healthcare approach that emphasizes trust-building through patient-centered care, sensitivity training, peer support, and health system reform to effectively address the treatment needs of this marginalized population. Full article

The appearance of new respiratory virus infections in humans with epidemic or pandemic potential has underscored the urgent need for effective broad-spectrum antivirals (BSAs). Bioactive compounds derived from plants may provide a natural source of new BSA candidates. Here, we investigated the novel phytocomplex formulation SP4™ as a candidate direct-acting BSA against major current human respiratory viruses, including coronaviruses and influenza viruses. SP4™ inhibited the in vitro replication of SARS-CoV-2, hCoV-OC43, hCoV-229E, Influenza A and B viruses, and respiratory syncytial virus in the low-microgram range. Using hCoV-OC43 as a representative respiratory virus, most of the antiviral activity of SP4™ was observed to stem primarily from its dimeric A-type proanthocyanidin (PAC-A) component. Further investigations of the mechanistic mode of action showed SP4™ and its PAC-A-rich fraction to prevent hCoV-OC43 from attaching to target cells and exert virucidal activity. This occurred through their interaction with the spike protein of hCoV-OC43 and SARS-CoV-2, thereby interfering with spike functions and leading to the loss of virion infectivity. Overall, these findings support the further development of SP4™ as a candidate BSA of a natural origin for the prevention of human respiratory virus infections. Full article