ABSTRACT
La resistencia a los antirretrovirales (ARV) es un problema de salud pública. Con el uso de inhibidores de la integrasa (INSTI) en pediatría, también comienzan a aparecer resistencias. El objetivo de esta comunicación es describir 3 casos con resistencia a los INSTI. Se describen 3 pacientes pediátricos con transmisión vertical del virus de la inmunodeficiencia humana (VIH). Iniciaron ARV de lactantes y preescolares, con mala adherencia al tratamiento, cursaron con diferentes planes secundarios a comorbilidades asociadas y fallas virológicas por resistencia. Los 3 casos clínicos describen la rápida aparición de resistencia frente a la falla virológica y el compromiso de los INSTI. La adherencia debe ser supervisada para detectar precozmente el aumento de la viremia. La falla virológica en un paciente tratado con raltegravir obliga a un rápido cambio de esquema ARV, ya que continuar utilizándolo podría favorecer nuevas mutaciones y resistencia a los INSTI de segunda generación.
Antiretroviral (ARV) drug resistance is a public health issue. Resistance has also been observed in the case of integrase strand transfer inhibitors (INSTIs) used in pediatrics. The objective of this article is to describe 3 cases of INSTI resistance. These are the cases of 3 children with vertically-transmitted human immunodeficiency virus (HIV). They were started on ARVs as infants and preschoolers, with poor treatment adherence, and had different management plans due to associated comorbidities and virological failure due to resistance. In the 3 cases, resistance developed rapidly as a result of virological failure and INSTI involvement. Treatment adherence should be monitored so that any increase in viremia can be detected early. Virological failure in a patient treated with raltegravir forces to a rapid change in ARV therapy because its continued use may favor new mutations and resistance to second-generation INSTIs.
Subject(s)
Humans , Male , Female , Child, Preschool , Child , Adolescent , HIV Infections/drug therapy , HIV-1/genetics , HIV Integrase Inhibitors/therapeutic use , HIV Integrase Inhibitors/pharmacology , Anti-HIV Agents/therapeutic use , Uruguay , Raltegravir Potassium/therapeutic use , Raltegravir Potassium/pharmacology , MutationABSTRACT
Influenza virus causes serious threat to human life and health. Due to the inherent high variability of influenza virus, clinically resistant mutant strains of currently approved anti-influenza virus drugs have emerged. Therefore, it is urgent to develop antiviral drugs with new targets or mechanisms of action. RNA-dependent RNA polymerase is directly responsible for viral RNA transcription and replication, and plays key roles in the viral life cycle, which is considered an important target of anti-influenza drug design. From the point of view of medicinal chemistry, this review summarizes current advances in diverse small-molecule inhibitors targeting influenza virus RNA-dependent RNA polymerase, hoping to provide valuable reference for development of novel antiviral drugs.
ABSTRACT
To address the continuous emergence of drug-resistant strains of viruses and the outbreaks of novel virus infections, developing new antiviral drugs based on novel strategies has become an important and urgent research topic. In recent years, the rapidly developing multi-specific binding strategy has become a focus and been widely applied in antiviral. This review summarizes the recent progress of the multi-specific binding strategy in the antiviral field from the perspective of medicinal chemistry and discusses existing challenges as well as future opportunities for antiviral drug discovery.
ABSTRACT
The COVID-19 outbreak has drawn attention to viral infectious diseases once again, and the development of antiviral drugs for both known and potentially emerging viruses is of great significance. In recent years, peptides and protein drugs are becoming a hot spot in the field of antiviral drug research and development. Phage display technology, as a powerful tool for screening peptides and protein drugs, has been increasingly concerned in the academic and industrial fields. The present review introduced the basic principle of phage display technology, summarized phage display libraries often used in antiviral drug discovery and their applications, discussed the challenges and future direction of antiviral drug research and development based on phage display technology.
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Virus infection is a serious threat to human health and social development. The increase in pandemics caused by emerging and re-emerging viruses highlights the urgent need for broad-spectrum antivirals. In this perspective, we highlight recent case studies and summarize the universal strategies and methodologies in broad-spectrum antiviral drug discovery from common targets, common steps in viral life cycle, universal strategies, and broad-spectrum molecules, hoping to provide valuable guidance for the current and future development of antiviral drugs.
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Over the course of human civilization, viral infections have been a part of human life and still represent one of the heaviest burdens for human and society, with a huge devastating socioeconomic impact. Inorganic and bioinorganic chemistry have made important contributions to medical science and human health in the past half century. In this paper, we selected the representative cases in recent years, and reviewed the research progress of antiviral drug discovery from the perspective of bioinorganic chemistry.
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EIDD-2801 is an orally bioavailable prodrug, which will be applied for emergency use authorization from the U.S. Food and Drug Administration for the treatment of COVID-19. To investigate the optimal parameters, EIDD-2801 was optimized
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The pandemic of coronavirus disease 2019 (COVID-19) is changing the world like never before. This crisis is unlikely contained in the absence of effective therapeutics or vaccine. The papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays essential roles in virus replication and immune evasion, presenting a charming drug target. Given the PLpro proteases of SARS-CoV-2 and SARS-CoV share significant homology, inhibitor developed for SARS-CoV PLpro is a promising starting point of therapeutic development. In this study, we sought to provide structural frameworks for PLpro inhibitor design. We determined the unliganded structure of SARS-CoV-2 PLpro mutant C111S, which shares many structural features of SARS-CoV PLpro. This crystal form has unique packing, high solvent content and reasonable resolution 2.5 Å, hence provides a good possibility for fragment-based screening using crystallographic approach. We characterized the protease activity of PLpro in cleaving synthetic peptide harboring nsp2/nsp3 juncture. We demonstrate that a potent SARS-CoV PLpro inhibitor GRL0617 is highly effective in inhibiting protease activity of SARS-CoV-2 with the IC
ABSTRACT
RNA interference (RNAi) is one of the important mechanisms to regulate gene expression in eukaryotes. One of the original functions of RNAi is to facilitate the antiviral strategy of host. Early studies reveal that invertebrates can use RNAi to resist viruses. However, if this mechanism exists in mammals is still controversial. The latest studies confirm that mammals do have the RNAi-based immunity, and researchers believe that RNAi-based antiviral immunity is a brand-new immunological mechanism that was neglected in the past. It is worthy to note that virus can also use RNAi to enhance its infectivity and immune escape in host cells. This review introduces the research history of RNAi-based antiviral immunity in animals and summarizes the main findings in this field. Last but not least, we indicate a series of unresolved questions about RNAi-based antiviral immunity, and explore the relationship between RNAi-based antiviral immunity and other innate immunological pathways. The virus-mediated RNAi pathway in animal is not only an interesting basic biology question, but also has important guiding roles in the development of antiviral drugs.
Subject(s)
Animals , Antiviral Agents , Immunity, Innate/genetics , Mammals , RNA Interference , RNA, Small Interfering/genetics , RNA, ViralABSTRACT
Since December 2019, a new type of coronavirus pneumonia (coronavirus disease 2019,COVID-19) has been emerging and has attracted widespread attention. Because of its characteristics of rapid spread, wide spread, long incubation period and high infection rate, a few pregnant women are infected. In order to better cooperate with the clinical pharmaceutical care, the pregnancy pharmaceutical care points of antiviral drugs mentioned in COVID-19 diagnosis and treatment guidelines are specially sorted out. It aims to provide clinicians and pharmacists with a quick understanding of the characteristics, usage and dosage and precautions of recommended antiviral drugs at present, so as to ensure the safety and rational use of drugs and improve the treatment effect of patients with new crown pneumonia.
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Since the outbreak of coronavirus disease 2019 (COVID-19), the National Health Commission and the expert group of the army have formulated multiple versions of diagnosis and treatment scheme, and drug therapy regimens have become a research hotspot for scholars. Meanwhile, some clinicians found that acute kidney injury (AKI) was an important risk factor in the death of patients with severe COVID 19. The mechanism of AKI in COVID-19 patients is still unclear and the causes may be related to virus infection or drug toxicity. Drug-related AKI directly affects the clinical treatment options and the patient's long-term prognosis. This article targets interferon-α, lopinavir / ritonavir, ribavirin, chloroquine phosphate, abidol and tocilizumab. This article reviewed potential novel coronavirus pneumonia treatment-related AKI, characteristics of the clinical cases, and mechanisms of renal toxicity, to provide a reference for clinical treatment.
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The outbreak of COVID-19 coronavirus pneumonia in December 2019 has aroused great concern worldwide. At present, the COVID-19 coronavirus pneumonia is highly contagious, rapid and widespread. It has been reported that COVID-19 virus is spread by respiratory droplets and direct contact transmission, and it has various clinical manifestations and recurrent is common. Some patients do not even appear obvious fever and have negative results for throat swab virus culture at the onset of the disease, but the rapid deterioration in their clinical condition usually occurred, which bring difficulties to scientific diagnosis and treatment. At present, western medicine treats most patients with anti-viral drugs, hormones and other drugs, or treats critically ill patients with ECMO oxygenation, important organ function support and other emergency treatments. Traditional Chinese medicine (TCM) based on syndrome differentiation and treatment has obtained curative effects in this outbreak. In order to improve the effects and safety of Chinese and western drug therapy, we applied literature-mining method and network pharmacology, summarized the potential liver injury during the application of western medicine and discussed hepatotoxicity networks and potential pathway targets of ingredients in Chinese patent medicine and Chinese herbal compound. This study not only summarizes essential information regarding potential drug-induced liver injury and biomarkers for pharmacovigilance, but also provides insights for liver protection by TCM or TCM in combination with western medicine in the treatment of novel coronavirus.
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The novel coronavirus pneumonia was first discovered in December 2019. By February 21, 2020, the virus had spread to 27 countries, and the total number of patients were nearly 80 thousands. In order to effectively prevent and control the epidemic, countries around the world are organizing scientific research, especially in screening of therapeutic drugs, researching and developing of vaccine, which is the key point and difficulty of epidemic control. On the basis of a large number of relevantly collected information about drugs and biological products in the academia and the press of various countries, this paper focus on the research status and development of antiviral chemical drugs, Chinese traditional medicines and biological products, aiming to provide reference for relevant departments, units and scientists.
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Chikungunya fever (CHIKF) is an arthropod-borne infection disease caused by Chikungunya virus (CHIKV), which represents a serious health problem worldwide. There is no antiviral drugs treatment for CHIKV infections, neither is there an effective vaccine for prevention of the disease. Herein, we reviewed the recent reported and classical inhibitors of CHIKV, and summarized the medicinal chemistry strategies for discovering CHIKV inhibitors.
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Hepatitis C virus (HCV) infection is one of the global public health issues. Approximately, 130-150 million individuals are chronically infected worldwide and a quarter of these patients are at increased risk of developing liver cirrhosis, hepatocellular carcinoma and even liver failure. A complete eradication of the virus is one of the most important treatment goals for antiviral research. From the point of view of medicinal chemistry, we summarize and discuss current endeavors towards the discovery and development of novel inhibitors with various scaffolds or distinct mechanisms of action.
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The outbreak of the influenza viruses (IFV) caused significant harm to our health and life. Human infections caused by pathogenic avian influenza virus (AIV) have continually brought great panic and death threats to people all over the world. With the in-depth study of the biological characteristics of influenza viruses and the rapid development of drug discovery screening technology, a new generation of anti-influenza drug targets and their inhibitors have been continuously discovered, providing more options for the treatment of influenza. From the point of view of medicinal chemistry, this review summarizes and discusses current endeavours towards the discovery and development of novel inhibitors and also provides examples illustrating new methodologies that contribute to the identification of novel anti-influenza drugs.
ABSTRACT
Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. Although several HCV protease/polymerase inhibitors were recently approved by U.S. FDA, the combination of antivirals targeting multiple processes of HCV lifecycle would optimize anti-HCV therapy and against potential drug-resistance. Viral entry is an essential target step for antiviral development, but FDA-approved HCV entry inhibitor remains exclusive. Here we identify serotonin 2A receptor (5-HTR) is a HCV entry factor amendable to therapeutic intervention by a chemical biology strategy. The silencing of 5-HTR and clinically available 5-HTR antagonist suppress cell culture-derived HCV (HCVcc) in different liver cells and primary human hepatocytes at late endocytosis process. The mechanism is related to regulate the correct plasma membrane localization of claudin 1 (CLDN1). Moreover, phenoxybenzamine (PBZ), an FDA-approved 5-HTR antagonist, inhibits all major HCV genotypes in vitro and displays synergy in combination with clinical used anti-HCV drugs. The impact of PBZ on HCV genotype 2a is documented in immune-competent humanized transgenic mice. Our results not only expand the understanding of HCV entry, but also present a promising target for the invention of HCV entry inhibitor.
ABSTRACT
@#The genome, replication mode and nosogenesis of duck hepatitis B virus are similar to those of human hepatitis B virus. In addition, the natural host of duck hepatitis B virus is readily available, cheap and has a high success rate of infection. Therefore, duck hepatitis B virus-infected models have been widely used for drug screening, pharmacological and pathological studies. For drug screening, the model is easy to obtain with high infection success rate and good stability. In the pharmacological research, the model can maintain high levels of viral DNA replication in the hepatocytes and exhibit significant damaged liver phenotypes which can reflect the pharmacological effects of drugs with different mechanisms. Also in the pathologic mechanisms research, the model has entire virus life cycle and maintains a pool of covalent closed-loop DNA in the hepatocytes, which can help scientific researchers better understand human hepatitis B virus. This article reviews the applications of duck hepatitis B animal model in drug screening, pharmacological and pathological studies, also outlooks the application prospect of this model.
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The medical workers are always facing great challenge when the influenza season comes every year,such as the variation of the virus strain,the occurrence of the high mortality complication and the reduced potence of the influenza vaccine.Meanwhile,the medical institution,as one of the most dangerous settings of the influenza outbreak,and the consequence could be deadly severe once it happened.So the aim of this manuscript is that,to review the knowledge regarding to influenza which is integrated with the newest research progress.On this basis,the manuscript goes into the influenza pandemic preventing strategy of medical institution in particular.
ABSTRACT
Dengue virus ( DENV) threatens the lives of hundreds of millions of people every year. Animal model is an effective tool for virus pathogenesis research and vaccine evaluation. At present, the de-velopment of animal models of DENV infection and disease has been challenging, as epidemic DENV does not naturally infect non-human species. Animal models of dengue virus infection are mainly non-human pri-mate ( NHP) model and mouse model. NHPs have been used to study dengue infection and candidate vac-cines because they can sustain viral replication in relevant cell types and develop a robust immune response, but they do not develop overt disease. However, NHP models are not suitable for early preclinical studies be-cause the cost of using these animals is high. In contrast, mouse models that are established mainly by using wild-type and immunodeficient mice can be more economical for preclinical evaluation of dengue vaccines. Overall, every model has its advantages and disadvantages and is differentially suited for studies of dengue pathogenesis and immunopathogenesis and/or preclinical testing of antiviral drugs.