Graphene-based materials as nanoplatforms for antiviral therapy and prophylaxis.

INTRODUCTION: The dramatic effects caused by viral diseases have prompted the search for effective therapeutic and preventive agents. In this context, 2D graphene-based nanomaterials (GBNs), have shown great potential for antiviral therapy, enabling the functionalization and/or or decoration with biomolecules, metals and polymers, able to improve their interaction with viral nanoparticles. AREAS COVERED: This review summarize the most recent advances of the antiviral research related to 2D GBNs, based on their antiviral mechanism of action. Their ability to inactivate viruses by inhibiting the entry inside cells, or through drug/gene delivery, or by stimulating host immune response are here discussed. As reported, biological studies performed in vitro and/or in vivo allowed to demonstrate the antiviral activity of the developed GBNs, at different stage of the virus life cycle and the evaluation of their long-term toxicity. Other mechanisms closely related to the physicochemical properties of GBNs are also reported, demonstrating the potential of these materials for antiviral prophylaxis. EXPERT OPINION: GBNs represent valuable tools to fight emerging or reemerging viral infections. However, their translation into the clinic requires standardized scale-up procedures leading to the reliable and reproducible synthesis of these nanomaterials with suitable physicochemical properties, as well as more in-depth pharmacological and toxicological investigations.We believe that multidisciplinary approaches will give valuable solutions to overcome the encountered limitations in the application of GBNs in biomedical and clinical field.

Recent Synthesis of Nucleoside Phosphonate Analogs Using Olefin Cross-metathesis.

Nucleotide analogs known as acyclic and cyclic nucleoside phosphonates (ANPs and CNPs, respectively) have a variety of biological properties, including antibacterial, antiviral, antiparasitic, antineoplastic, and immunomodulatory. A strong reaction that has emerged in the last several decades has fundamentally changed our knowledge of the chemistry of nucleoside phosphonates. In particular, Olefin cross-metathesis (CM) has been a potent and practical synthesis route to produce functionalized olefins from essential alkene precursors. This review describes recent synthesis examples of ANPs and CNPs analogs using the Ru-catalyzed olefin cross-metathesis reactions. Olefin cross-metathesis reactions are performed in the olefinic parts of nucleoside and phosphonate produced by Grubbs, Hoveyda-Grubbs, and Nolan. This review presents a synthetic overview of a few chosen nucleosides with biological significance. Their biological activity results are briefly discussed.

Development of a mutant aerosolized ACE2 that neutralizes SARS-CoV-2 in vivo.

The rapid evolution of SARS-CoV-2 variants highlights the need for new therapies to prevent disease spread. SARS-CoV-2, like SARS-CoV-1, uses the human cell surface protein angiotensin-converting enzyme 2 (ACE2) as its native receptor. Here, we design and characterize a mutant ACE2 that enables rapid affinity purification of a dimeric protein by altering the active site to prevent autoproteolytic digestion of a C-terminal His10 epitope tag. In cultured cells, mutant ACE2 competitively inhibits lentiviral vectors pseudotyped with spikes from multiple SARS-CoV-2 variants and infectious SARS-CoV-2. Moreover, the protein can be nebulized and retains virus-binding properties. We developed a system for the delivery of aerosolized ACE2 to K18-hACE2 mice and demonstrated protection by our modified ACE2 when delivered as a prophylactic agent. These results show proof-of-concept for an aerosolized delivery method to evaluate anti-SARS-CoV-2 agents in vivo and suggest a new tool in the ongoing fight against SARS-CoV-2 and other ACE2-dependent viruses. IMPORTANCE: The rapid evolution of SARS-CoV-2 variants poses a challenge for immune recognition and antibody therapies. However, the virus is constrained by the requirement that it recognizes a human host receptor protein. A recombinant ACE2 could protect against SARS-CoV-2 infection by functioning as a soluble decoy receptor. We designed a mutant version of ACE2 with impaired catalytic activity to enable the purification of the protein using a single affinity purification step. This protein can be nebulized and retains the ability to bind the relevant domains from SARS-CoV-1 and SARS-CoV-2. Moreover, this protein inhibits viral infection against a panel of coronaviruses in cells. Finally, we developed an aerosolized delivery system for animal studies and show the modified ACE2 offers protection in an animal model of COVID-19. These results show proof-of-concept for an aerosolized delivery method to evaluate anti-SARS-CoV-2 agents in vivo and suggest a new tool in the ongoing fight against SARS-CoV-2.

Repurposing anti-cancer porphyrin derivative drugs to target SARS-CoV-2 envelope.

Antiviral medicines to treat COVID-19 are still scarce. Porphyrins and porphyrin derivatives (PDs) usually present broad-spectrum antiviral activity with low risk of resistance development. In fact, some PDs are clinically approved to be used in anti-cancer photodynamic therapy and repurposing clinically approved PDs might be an alternative to treat COVID-19. Here, we characterize the ability of temoporfin, verteporfin, talaporfin and redaporfin to inactivate SARS-CoV-2 infectious particles. PDs light-dependent and -independent effect on SARS-CoV-2 infectivity were evaluated. PDs photoactivation successfully inactivated SARS-CoV-2 with very low concentrations and light dose. However, only temoporfin and verteporfin inactivated SARS-CoV-2 in the dark, being verteporfin the most effective. PDs treatment reduced viral load in infected Caco-2 cells, while not inducing cytotoxicity. Furthermore, light-independent treatment with temoporfin and verteporfin act on early stages of viral infection. Using lipid vehicles as membrane models, we characterized PDs interaction to the viral envelope. Verteporfin presented the lowest IC50 for viral inactivation and the highest partition coefficients (Kp) towards lipid bilayers. Curiously, although temoporfin and redaporfin presented similar Kps, redaporfin did not present light-independent antiviral activity, and only temoporfin and verteporfin caused lipid membrane disorder. In fact, redaporfin is located closer to the bilayer surface, while temoporfin and verteporfin are located closer to the centre. Our results suggest that viral envelope affinity, with penetration and destabilization of the lipid bilayer, seems critical to mediate PDs antiviral activity. Altogether, these findings open new avenues for the off-label application of temoporfin and verteporfin in the systemic treatment of COVID-19.

Hospitalization Endpoint in Clinical Trials of Outpatient Settings: using Anti-SARS-COV-2 Therapy as an Example.

Purpose: In response to the COVID-19 pandemic, the World Health Organization (WHO) developed a set of outcome measures for trials primarily aimed at hospitalised patients. However, a gap exists in defining outcome standards for non-hospitalised patients. Therefore, this study aims to discuss hospitalisation as a primary outcome in outpatient trials and its potential pitfalls, specifically focusing on trials related to anti-SARS-COV-2 therapy. Methods: In this narrative review, researchers thoroughly searched MEDLINE and ClinicalTrials.gov from January 2020 to December 2022, targeting Phase III randomized controlled trials involving outpatients with mild-to-moderate COVID-19. The trials were specifically related to anti-SARS-COV-2 monoclonal antibodies or antiviral agents. The study collected essential data, including the type of intervention, comparator, primary objective, primary endpoint, and the use of estimands in the trial. Results: The search identified 12 trials that evaluated the efficacy of anti-SARS COV-2 therapies in a predefined population. Three studies used hospitalisation and death as primary endpoints in high-risk patients receiving monoclonal antibodies. Nine studies assessed the efficacy of several antiviral agents: four trials used hospitalisation and death as the main endpoints, while others used different measures such as virologic measures using the Reverse Transcription-Polymerase Chain Reaction test (RT-PCR), the eight-point WHO ordinal scale, symptom alleviation by Day 7 and time to clinical response. Conclusion: Choosing hospitalization as an endpoint may provide meaningful data such as the cost-effectiveness ratio of a drug. However, different hospital utilisation patterns and investigator decisions could bias clinical outcomes if no specific criteria are considered. Therefore, investigators should have clear criteria for determining variables that influence this measure.

Exploring current and emerging therapies for porphyrias.

Porphyrias are rare, mostly inherited disorders resulting from altered activity of specific enzymes in the haem synthesis pathway that lead to accumulation of pathway intermediates. Photocutaneous symptoms occur when excess amounts of photoreactive porphyrins circulate in the blood to the skin, whereas increases in potentially neurotoxic porphyrin precursors are associated with neurovisceral symptoms. Current therapies are suboptimal and their mechanisms are not well established. As described here, emerging therapies address underlying disease mechanisms by introducing a gene, RNA or other specific molecule with the potential to cure or slow progression of the disease. Recent progress in nanotechnology and nanoscience, particularly regarding particle design and formulation, is expanding disease targets. More secure and efficient drug delivery systems have extended our toolbox for transferring specific molecules, especially into hepatocytes, and led to proof-of-concept studies in animal models. Repurposing existing drugs as molecular chaperones or haem synthesis inhibitors is also promising. This review summarizes key examples of these emerging therapeutic approaches and their application for hepatic and erythropoietic porphyrias.

Hepatocellular carcinoma after direct-acting antivirals for hepatitis C is associated with KIR-HLA types predicting weak NK cell-mediated immunity.

BACKGROUND AND AIMS: Second-generation direct-acting antivirals (2G DAA) to cure HCV have led to dramatic clinical improvements. HCV-associated hepatocellular carcinoma (HCC), however, remains common. Impaired immune tumor surveillance may play a role in HCC development. Our cohort evaluated the effects of innate immune types and clinical variables on outcomes including HCC. METHODS: Participants underwent full HLA class I/KIR typing and long-term HCV follow-up. RESULTS: A total of 353 HCV+ participants were followed for a mean of 7 years. Cirrhosis: 25% at baseline, developed in 12% during follow-up. 158 participants received 2G DAA therapy. HCC developed without HCV therapy in 20 subjects, 24 HCC after HCV therapy, and 10 of these after 2G DAA. Two predictors of HCC among 2G DAA-treated patients: cirrhosis (OR, 10.0, p = 0.002) and HLA/KIR profiles predicting weak natural killer (NK) cell-mediated immunity (NK cell complementation groups 6, 9, 11, 12, OR of 5.1, p = 0.02). Without 2G DAA therapy: cirrhosis was the main clinical predictor of HCC (OR, 30.8, p < 0.0001), and weak NK-cell-mediated immunity did not predict HCC. CONCLUSION: Cirrhosis is the main risk state predisposing to HCC, but weak NK-cell-mediated immunity may predispose to post-2G DAA HCC more than intermediate or strong NK-cell-mediated immunity.

A novel test and treat program for hepatitis C virus infection utilizing HCV core antigen testing, among police and general population, Islamabad, Pakistan, 2022.

Hepatitis C virus core antigen (HCVcAg) testing can simplify and decrease costs of HCV infection confirmation compared to molecular testing (nucleic acid testing). We piloted HCVcAg testing for the confirmation of active infection. The study was conducted during June through December 2022 among the police and the general population of Islamabad, Pakistan age 18 years and older. Initial screening for HCV antibody was conducted using a rapid diagnostic test (RDT) for all consenting participants. Those who tested positive had venous blood samples tested for HCVcAg, platelets and aspartate aminotransferase (AST). Persons with HCVcAg values ≥3 fmol/L were defined as viremic, and they were offered treatment with direct acting antiviral (DAA) medications, sofosbuvir and daclatasvir. Aspartate aminotransferase to platelet ratio index (APRI) was calculated for each HCV infected person, and those with an APRI score <1.5 received treatment for 12 weeks, while those with APRI ≥ to 1.5 received 24 weeks of treatment. A total of 15,628 persons were screened for anti-HCV using RDT and 643 (4.1%) tested positive. HCVcAg values of ≥3 fmol/L was found in 399/643 (62.1%), and all were offered and accepted treatment. Of those treated, 273/399 (68.4%) returned for a follow-up SVR and HCVcAg was not detected in 261/273, a 95.6% cure rate. The pilot study demonstrated the effectiveness of reaching and treating an urban population using RDT for screening and HCVcAg for confirmation of infection and test of cure.

Hepatitis C Virus Clearance and Diffusing Capacity for Carbon Monoxide in Women With and Without Human Immunodeficiency Virus.

Hepatitis C virus (HCV) infection is associated with extrahepatic effects, including reduced diffusing capacity of the lungs. It is unknown whether clearance of HCV infection is associated with improved diffusing capacity. In this sample of women with and without human immunodeficiency virus, there was no association between HCV clearance and diffusing capacity.

Antiviral treatment for SARS-CoV-2 infection in the current situation: a position paper of the Spanish Society of Emergency Medicine (SEMES). / Posicionamiento de la Sociedad Española de Medicina de Urgencias y Emergencias (SEMES) ante el tratamiento antiviral frente al SARS-CoV-2 en la situación epidemiológica actual.

SUMMARY: COVID-19 continues to pose a significant threat: mortality stands at nearly twice that of influenza, and the incidence rate is growing as the population's vaccination rate decreases, particularly in Spain and other areas of Europe. Given this situation, it is vitally important know whether medical protocols are consistent and appropriately implemented by health care staff in the interest of preventing possible inefficiency or inequity. Physicians from hospital emergency departments met to study their hospitals' usual clinical practices for managing SARS-CoV-2 infection and to determine their expert opinions on the use of antiviral agents. The participating physicians then reached consensus on evidencebased recommendations for strategies that would optimize emergency treatment.

RESUMEN: Actualmente, la COVID-19 sigue representando una amenaza significativa, con una mortalidad cercana al doble de la ocasionada por la gripe y con una incidencia variable debido a una disminución en la tasa de vacunación de la población, especialmente en el contexto europeo y español. Ante este panorama, es de vital importancia comprobar que los protocolos médicos están consolidados y son debidamente implementados por los profesionales sanitarios, con la finalidad de evitar posibles ineficiencias o inequidades. A través de reuniones con profesionales de urgencias se han observado las prácticas clínicas habituales en los servicios de urgencias hospitalarios para pacientes con infección por SARS-CoV-2, con la finalidad de comprender la perspectiva de estos profesionales acerca del uso de antivirales y, tras un consenso de expertos basados en la evidencia actual, se han generado estas de recomendaciones para poder enfocar estrategias que optimicen el tratamiento de los pacientes en estos servicios.

A comprehensive review on targeting cluster of differentiation: An attractive strategy for inhibiting viruses through host proteins.

Viral infections continue to pose a significant global public health threat. Targeting host proteins, such as cluster of differentiation (CD) macromolecules, may offer a promising alternative approach to developing antiviral treatments. CDs are cell-surface biological macromolecules mainly expressed on leukocytes that viruses can use to enter cells, thereby evading immune detection and promoting their replication. The manipulation of CDs by viruses may represent an effective and clever means of survival through the prolonged co-evolution of hosts and viruses. Targeting of CDs is anticipated to hinder the invasion of related viruses, modulate the body's immune system, and diminish the incidence of subsequent inflammation. They have become crucial for biomedical diagnosis, and some have been used as valuable tools for resisting viral infections. However, a summary of the structures and functions of CDs involved in viral infection is currently lacking. The development of drugs targeting these biological macromolecules is restricted both in terms of their availability and the number of compounds currently identified. This review provides a comprehensive analysis of the critical role of CD proteins in virus invasion and a list of relevant targeted antiviral agents, which will serve as a valuable reference for future research in this field.

Evaluation of two inoculation routes of an adenovirus-mediated viral protein inhibitor in a Crimean-Congo hemorrhagic fever mouse model.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne nairovirus with a wide geographic spread that can cause severe and lethal disease. No specific medical countermeasures are approved to combat this illness. The CCHFV L protein contains an ovarian tumor (OTU) domain with a cysteine protease thought to modulate cellular immune responses by removing ubiquitin and ISG15 post-translational modifications from host and viral proteins. Viral deubiquitinases like CCHFV OTU are attractive drug targets, as blocking their activity may enhance cellular immune responses to infection, and potentially inhibit viral replication itself. We previously demonstrated that the engineered ubiquitin variant CC4 is a potent inhibitor of CCHFV replication in vitro. A major challenge of the therapeutic use of small protein inhibitors such as CC4 is their requirement for intracellular delivery, e.g., by viral vectors. In this study, we examined the feasibility of in vivo CC4 delivery by a replication-deficient recombinant adenovirus (Ad-CC4) in a lethal CCHFV mouse model. Since the liver is a primary target of CCHFV infection, we aimed to optimize delivery to this organ by comparing intravenous (tail vein) and intraperitoneal injection of Ad-CC4. While tail vein injection is a traditional route for adenovirus delivery, in our hands intraperitoneal injection resulted in higher and more widespread levels of adenovirus genome in tissues, including, as intended, the liver. However, despite promising in vitro results, neither route of in vivo CC4 treatment resulted in protection from a lethal CCHFV infection.

Natural Product-Derived Phytochemicals for Influenza A Virus (H1N1) Prevention and Treatment.

Influenza A (H1N1) viruses are prone to antigenic mutations and are more variable than other influenza viruses. Therefore, they have caused continuous harm to human public health since the pandemic in 2009 and in recent times. Influenza A (H1N1) can be prevented and treated in various ways, such as direct inhibition of the virus and regulation of human immunity. Among antiviral drugs, the use of natural products in treating influenza has a long history, and natural medicine has been widely considered the focus of development programs for new, safe anti-influenza drugs. In this paper, we focus on influenza A (H1N1) and summarize the natural product-derived phytochemicals for influenza A virus (H1N1) prevention and treatment, including marine natural products, flavonoids, alkaloids, terpenoids and their derivatives, phenols and their derivatives, polysaccharides, and derivatives of natural products for prevention and treatment of influenza A (H1N1) virus. We further discuss the toxicity and antiviral mechanism against influenza A (H1N1) as well as the druggability of natural products. We hope that this review will facilitate the study of the role of natural products against influenza A (H1N1) activity and provide a promising alternative for further anti-influenza A drug development.

The nucleoside analog 4'-fluorouridine suppresses the replication of multiple enteroviruses by targeting 3D polymerase.

Human enteroviruses are the major pathogens causing hand-foot-and-mouth disease in infants and young children throughout the world, and infection with enterovirus is also associated with severe complications, such as aseptic meningitis and myocarditis. However, there are no antiviral drugs available to treat enteroviruses infection at present. In this study, we found that 4'-fluorouridine (4'-FlU), a nucleoside analog with low cytotoxicity, exhibited broad-spectrum activity against infections of multiple enteroviruses with EC50 values at low micromolar levels, including coxsackievirus A10 (CV-A10), CV-A16, CV-A6, CV-A7, CV-B3, enterovirus A71 (EV-A71), EV-A89, EV-D68, and echovirus 6. With further investigation, the results indicated that 4'-FlU directly interacted with the RNA-dependent RNA polymerase of enterovirus, the 3D pol, and impaired the polymerase activity of 3D pol, hence inhibiting viral RNA synthesis and significantly suppressing viral replication. Our findings suggest that 4'-FlU could be promisingly developed as a broad-spectrum direct-acting antiviral agent for anti-enteroviruses therapy.

Global trends in hepatitis C-related hepatocellular carcinoma mortality: A public database analysis (1999-2019).

BACKGROUND: Hepatitis C is the leading cause of chronic liver disease worldwide and it significantly contributes to the burden of hepatocellular carcinoma (HCC). However, there are marked variations in the incidence and mortality rates of HCC across different geographical regions. With the advent of new widely available treatment modalities, such as direct-acting antivirals, it is becoming increasingly imperative to understand the temporal and geographical trends in HCC mortality associated with Hepatitis C. Furthermore, gender disparities in HCC mortality related to Hepatitis C are a crucial, yet underexplored aspect that adds to the disease's global impact. While some studies shed light on gender-specific trends, there is a lack of comprehensive data on global and regional mortality rates, particularly those highlighting gender disparities. This gap in knowledge hinders the development of targeted interventions and resource allocation strategies. AIM: To understand the global and regional trends in Hepatitis C-related HCC mortality rates from 1990 to 2019, along with gender disparities. METHODS: We utilized the Global Burden of Disease database, a comprehensive repository for global health metrics to age-standardized mortality rates due to Hepatitis C-related HCC from 1999 to 2019. Rates were evaluated per 100000 population and assessed by World Bank-defined regions. Temporal trends were determined using Joinpoint software and the Average Annual Percent Change (AAPC) method, and results were reported with 95% confidence intervals (CI). RESULTS: From 1990 to 2019, overall, there was a significant decline in HCC-related mortality rates with an AAPC of -0.80% (95%CI: -0.83 to -0.77). Females demonstrated a marked decrease in mortality with an AAPC of -1.06% (95%CI: -1.09 to -1.03), whereas the male cohort had a lower AAPC of -0.52% (95%CI: -0.55 to -0.48). Regionally, East Asia and the Pacific demonstrated a significant decline with an AAPC of -2.05% (95%CI: -2.10 to -2.00), whereas Europe and Central Asia observed an uptrend with an AAPC of 0.72% (95%CI: 0.69 to 0.74). Latin America and the Caribbean also showed an uptrend with an AAPC of 0.06% (95%CI: 0.02 to 0.11). In the Middle East and North Africa, the AAPC was non-significant at 0.02% (95%CI: -0.09 to 0.12). North America, in contrast, displayed a significant upward trend with an AAPC of 2.63% (95%CI: 2.57 to 2.67). South Asia (AAPC -0.22%, 95%CI: -0.26 to -0.16) and Sub-Saharan Africa (AAPC -0.14%, 95%CI: -0.15 to -0.12) trends significantly declined over the study period. CONCLUSION: Our study reports disparities in Hepatitis C-related HCC mortality between 1999 to 2019, both regionally and between genders. While East Asia and the Pacific regions showed a promising decline in mortality, North America has experienced a concerning rise in mortality. These regional variations highlight the need for healthcare policymakers and practitioners to tailor public health strategies and interventions. The data serves as a call to action, particularly for regions where mortality rates are not improving, emphasizing the necessity for a nuanced, region-specific approach to combat the global challenge of HCC secondary to Hepatitis C.

Do oral antiseptics used in the dental routine have anti-viral efficacy? a systematic review of in vitro studies / Os antissépticos orais utilizados na rotina odontológica têm eficácia anti-viral? Uma revisão sistemática de estudos in vitro / ¿Los antisépticos orales utilizados en la rutina odontológica tienen eficacia antiviral? Una revisión sistemática de estudios in vitro

Introduction: Mouthwashes play an important role in the dental clinic, but their role on viruses requires investigation. Objective:to review in vitro studies to identify the effect of different mouthwashes on the main viruses associated with routine dental care. Methodology:The following databases were searched in September 2023: PubMed, Embase, Scopus and Web of Science databases; the Cochrane Library and the Virtual Health Library (VHL); and grey literature. In vitro studies that used mouthwashes to reduce the viral load were selected. The PICOS strategy was considered to define eligibility criteria: the Population (viruses involved in the etiology of oral infection), the Intervention (oral antiseptics), the appropriate comparator (positive and negative controls), the Outcomes of interest (reduction of viral load) and the Study design (in vitro studies). Results:Considering the eligibility criteria, 19 articles were included in this review. The efficacy of povidone-iodine (PVP-I), chlorhexidine, Listerine®, essential oils, and cetylpyridinium chloride (CPC) rinses were investigated. PVP-I (0.23%) had its effects mainly associated with coronaviruses SARS(Severe Acute Respiratory Syndrome),demonstrating a significant reduction in viral load after 15 seconds of exposure. Chlorhexidine (0.05%; 0.1% and 0.5%) was ineffective against adenovirus, poliovirus, and rhinovirus respiratory viruses. Listerine® demonstrated superior efficacy against HSV-1 and 2 viruses and influenza A, and cetylpyridine chloride also demonstrated virucidal activity against influenza A. Conclusions:The type, concentration, and time of exposure to antiseptics varied between studies. PVP-I and chlorhexidine digluconate were the most studied substances, butin general, PVP-I was more effective in reducing viral titers, especially concerning coronaviruses. Other antiseptics such as CPC, H2O2 and Listerine® have also shown significant reduction in viral load, but this is a limited number of studies (AU).

Introdução: Os enxaguantes bucais desempenham um papel importante na clínica odontológico, porém seu papel sobre os vírus requer investigações. Objetivo: revisar estudos in vitro para identificar o efeito de diferentes colutórios sobre os principais vírus associados ao atendimento odontológico de rotina. Metodologia: As seguintes bases foram pesquisadas até setembro de 2023: PubMed, Embase, Scopus e Web of Science; a Biblioteca Cochrane e a Biblioteca Virtual em Saúde (BVS); e literatura cinzenta. Foram selecionados estudos in vitro que utilizaram bochechos com o objetivo de reduzir a carga viral. A estratégia PICOS foi considerada para a definição dos critérios de elegibilidade: População (vírus envolvidos na etiologia da infecção oral), Intervenção (antissépticos orais), Comparador (controles positivos e negativos), os Desfechos de interesse (redução da carga viral) e o desenho do estudo (estudos in vitro). Resultados: Considerando os critérios de elegibilidade, 19 artigos foram incluídos para esta revisão. A eficácia da povidona-iodo (PVP-I), clorexidina, Listerine®, óleos essenciais e lavagens com cloreto de cetilpiridínio foram investigadas. O PVP-I(0.23%)teve seus efeitos principalmente associados ao coronavírusSARS (Síndrome Respiratória Aguda Severa),demonstrando uma redução significativa da carga viral após 15 segundos de exposição. A clorexidina mostrou-se ineficaz contra vírus respiratórios de adenovírus, poliovírus e rinovírus. Listerine® demonstrou eficácia superior contra vírus HSV-1 e 2 e vírus influenza A, e cloreto de cetilpiridinio também demonstrou atividade virucida contra influenza A.Conclusões:O tipo, concentração e tempo de exposição aos antissépticos variaram entre os estudos. O PVP-I e o digluconato de clorexidina foram as substâncias mais estudadas, mas no geral, o PVP-I foi mais eficaz na redução dos títulos virais, principalmente no que diz respeito aos coronavírus. Outros antissépticos como CPC, H2O2 e Listerine® também mostraram redução significativa da carga viral, mas trata-se de um número limitado de estudos (AU).

Introducción: Los enjuagues bucales son importantesen la clínica dental, sin embargo, su efecto sobre los virus requiere investigaciones. Objetivo: Revisar estudios in vitro para identificar el efecto de enjuagues bucales sobre los principales virus asociados con larutinaodontológica. Metodología: Las siguientes bases de datos fueron investigadas hasta septiembrede 2023: PubMed, Embase, Scopus y Web of Science; Biblioteca Cochrane y Biblioteca Virtual en Salud (BVS); yliteratura gris. Se seleccionaron estudios in vitro que utilizaron enjuagues bucales con el objetivo de reducir la carga viral. Se consideró la estrategia PICOS para definir los criterios de elegibilidad: Población (virus implicados en la etiología de la infección oral), Intervención (antisépticos bucales), Comparador (controles positivos y negativos), Resultados de interés (reducción de la carga viral) y diseño del estudio (in vitro). Resultados: Considerando los criterios de elegibilidad, se incluyeron 19 artículos.Se investigó la eficacia de povidona yodada (PVP-I), clorhexidina, Listerine®,aceites esenciales y enjuagues de cloruro de cetilpiridinio (CPC). PVP-I(0.23%)mostró sus efectos principalmente asociados al coronavirus SARS(Síndrome Respiratorio Agudo Severo), demostrando una reducción significativa de la carga viral después de 15 segundos. Se ha demostrado que la clorhexidina es ineficaz contra losvirus respiratorios adenovirus, poliovirus y rinovirus. Listerine® demostró una eficacia superior contra los virus HSV-1 y 2 y el virus de la influenza A, y el CPCtambién mostró actividad virucida contra la influenza A.Conclusiones: El tipo, la concentración y el tiempo de exposiciónvariaron entre los estudios. PVP-I y digluconato de clorhexidina fueron las sustancias más estudiadas, pero,PVP-I fue más efectiva en la reducción de los títulos virales, especialmente en lo que respecta a los coronavirus. Otros antisépticos como CPC, H2O2 y Listerine® también mostraron una reducción significativa de la carga viral, pero se trata de un número limitado de estudios (AU).

Discovery of C-Linked Nucleoside Analogues with Antiviral Activity against SARS-CoV-2.

The recent COVID-19 pandemic underscored the limitations of currently available direct-acting antiviral treatments against acute respiratory RNA-viral infections and stimulated major research initiatives targeting anticoronavirus agents. Two novel nsp5 protease (MPro) inhibitors have been approved, nirmatrelvir and ensitrelvir, along with two existing nucleos(t)ide analogues repurposed as nsp12 polymerase inhibitors, remdesivir and molnupiravir, but a need still exists for therapies with improved potency and systemic exposure with oral dosing, better metabolic stability, and reduced resistance and toxicity risks. Herein, we summarize our research toward identifying nsp12 inhibitors that led to nucleoside analogues 10e and 10n, which showed favorable pan-coronavirus activity in cell-infection screens, were metabolized to active triphosphate nucleotides in cell-incubation studies, and demonstrated target (nsp12) engagement in biochemical assays.

Effect of Paxlovid in COVID-19 treatment during the periods of SARS-CoV-2 Omicron BA.5 and BN.1 subvariant dominance in the Republic of Korea: a retrospective cohort study.

BACKGROUND: This study was conducted to assess the efficacy of nirmatrelvir/ritonavir treatment in patients with coronavirus disease 2019 (COVID-19), particularly those aged 60 years and older. Using real-world data, the period during which the BN.1 Omicron variant was dominant was compared to the period dominated by the BA.5 variant. METHODS: In this retrospective cohort study, data were collected regarding 2,665,281 patients infected with severe acute respiratory syndrome coronavirus 2 between July 24, 2022, and March 31, 2023. Propensity score matching was utilized to match patients who received nirmatrelvir/ ritonavir in a 1:4 ratio between BN.1 and BA.5 variant groups. Multivariable logistic regression analysis was employed to assess the effects of nirmatrelvir/ritonavir within these groups. RESULTS: Compared to the prior period, the efficacy of nirmatrelvir/ritonavir did not significantly differ during the interval of Omicron BN.1 variant dominance in the Republic of Korea. Among patients treated with nirmatrelvir/ritonavir, a significantly lower risk of mortality was observed in the BN.1 group (odds ratio [OR], 0.698; 95% confidence interval [CI], 0.557-0.875) compared to the BA.5 group. However, this treatment did not significantly reduce the risk of severe or critical illness, including death, for those in the BN.1 group (OR, 0.856; 95% CI, 0.728-1.007). CONCLUSION: Nirmatrelvir/ritonavir has maintained its effectiveness against COVID-19, even with the emergence of the BN.1 Omicron subvariant. Consequently, we strongly recommend the administration of nirmatrelvir/ritonavir to patients exhibiting COVID-19-related symptoms, irrespective of the dominant Omicron variant or their vaccination status, to mitigate disease severity and decrease the risk of mortality.

Systematic review of the impact of protease-inhibitor-based combination antiretroviral therapy on renal transplant outcomes in recipients living with HIV infection.

Advances in human immunodeficiency virus (HIV) treatment, including combination antiretroviral therapy (cART), have transformed HIV into a chronic condition. Kidney diseases cause morbidity and mortality in patients living with HIV (PLWH), though cART has permitted kidney transplants with acceptable post-transplant graft and patient survival. Risk of allograft rejection remains high, which may be related to interactions between cART, specifically protease inhibitors (PI), and immunosuppressants prescribed post-transplant. This systematic review evaluates renal transplant outcomes in PLWH treated with PI- vs non-PI-based cART. A search strategy was generated with terms related to renal transplant, HIV, and cART and run on PubMed, Embase, Scopus, and Cochrane. Studies were evaluated using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines on Covidence by two reviewers and then evaluated for bias. Of 803 studies, 9 were included. Included papers were prospective or retrospective cohort studies or chart reviews of adult patients. Outcome measures included acute graft rejection, graft survival, and patient survival. One study had significant results demonstrating that PI-based therapy was correlated with increased graft rejection rates. Two studies demonstrated significant graft survival benefit to non-PI-based therapy, while one demonstrated significant benefit to PI-based therapy. Two studies found significant patient survival benefit to non-PI-based therapy. For each outcome measure, remaining data suggested improved outcomes with non-PI-based therapies without achieving statistical significance. The results demonstrate superior outcomes in PLWH taking non-PI-based cART, though the paucity of significant results suggests that PLWH who require PI-based cART for virological control may continue their regimen safely post-kidney transplant.

The Inhibition of NS2B/NS3 Protease: A New Therapeutic Opportunity to Treat Dengue and Zika Virus Infection.

In the global pandemic scenario, dengue and zika viruses (DENV and ZIKV, respectively), both mosquito-borne members of the flaviviridae family, represent a serious health problem, and considering the absence of specific antiviral drugs and available vaccines, there is a dire need to identify new targets to treat these types of viral infections. Within this drug discovery process, the protease NS2B/NS3 is considered the primary target for the development of novel anti-flavivirus drugs. The NS2B/NS3 is a serine protease that has a dual function both in the viral replication process and in the elusion of the innate immunity. To date, two main classes of NS2B/NS3 of DENV and ZIKV protease inhibitors have been discovered: those that bind to the orthosteric site and those that act at the allosteric site. Therefore, this perspective article aims to discuss the main features of the use of the most potent NS2B/NS3 inhibitors and their impact at the social level.