Recent Advances in Anti-HCV, Anti-HBV and Anti-flavivirus Agents

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: 15 November 2024 | Viewed by 11044

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Guest Editor
Division of Pharmaceutical Chemistry, Department of Pharmacy, Panepistimiopolis Zografou, 15771 Athens, Greece
Interests: medicinal chemistry; antiviral agents; anticancer agents; trypanocidal agents; anti-HBV drugs; anti-HCV drugs; anti-influenza A agents; anti-flavivirus agents
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Special Issue Information

Dear Colleagues,

Since the beginning of human civilization, viral infections have been part of human life and still represent one of the heaviest burdens for humans and society, with a huge devastating socioeconomic impact. The global burden of viral hepatitis remains substantial despite advances in antiviral therapy and effective vaccines. Mortality related to hepatitis B virus and hepatitis C virus infections is among the top four global infectious diseases, together with human immunodeficiency virus infection, malaria, and tuberculosis. According to the World Health Organization (WHO), for viral-infection-related diseases such as hepatitis B, the achievement of a suitable treatment still has a long way to go. On the other hand, the flaviviruses, Dengue (DENV), Yellow fever (YFV), Zika (ZIKV) and West Nile (WNV) are high-priority targets for drug discovery as they are re-emerging global pathogens with no clinically approved specific therapy (according to the WHO). WNV and YFV are among the most dangerous flaviviruses, having mortality rates up to 30%. Moreover, the emergence of drug resistance that threatens the efficacy of successful therapies used today against HCV makes the discovery and development of antiviral agents an unmet global need. Urged by this global crisis, the field has been involved in an unprecedented endeavour to enhance established antiviral strategies and develop novel and innovative approaches for new classes of antiviral agents targeting different and critical for the virus life cycle pathways, including viral and host factors and new antiviral modalities.

In this Special Issue entitled: “Recent Advances in Anti-HCV, Anti-HBV and Anti-flavivirus Agents”, we are inviting the submission of original research articles, letters, and/or reviews from academia, research institutes, not-for-profit organizations, or industries working over the identification, synthesis, and evaluation of direct-acting anti-HCV, anti-HBV, and anti-flavivirus agents or host-targeting agents which inhibit viral replication or pathogenesis (HCV, HBV, and flaviviruses). Furthermore, papers on mechanistic studies of new small organic molecules, metal complexes, and natural products, as well as studies on drug resistance, in silico designs of anti-HCV, anti-HBV, and anti-Flavivirus agents, or HCV, HBV, and flavivirus target validation studies are also welcome for submissions.

Dr. Grigoris Zoidis 
Guest Editor

Manuscript Submission Information

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Keywords

  • medicinal chemistry of anti-HCV, anti-HBV and anti-flavivirus agents
  • synthesis
  • structure–activity relationships (SARs)
  • antiviral drug discovery
  • HBV
  • HCV
  • dengue virus (DENV)
  • yellow fever virus (YFV)
  • West Nile virus (WNV)
  • Zika virus (ZIKV)
  • mechanism of action
  • drug targets
  • in silico studies

Published Papers (7 papers)

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Research

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11 pages, 497 KiB  
Article
Reduction of the Risk of Hepatocellular Carcinoma over Time Using Direct-Acting Antivirals: A Propensity Score Analysis of a Real-Life Cohort (PITER HCV)
by Maria Giovanna Quaranta, Luisa Cavalletto, Francesco Paolo Russo, Vincenza Calvaruso, Luigina Ferrigno, Alberto Zanetto, Benedetta Mattioli, Roberta D’Ambrosio, Valentina Panetta, Giuseppina Brancaccio, Giovanni Raimondo, Maurizia Rossana Brunetto, Anna Linda Zignego, Carmine Coppola, Andrea Iannone, Elisa Biliotti, Elena Rosselli Del Turco, Marco Massari, Anna Licata, Francesco Barbaro, Marcello Persico, Filomena Morisco, Maurizio Pompili, Federica Cerini, Massimo Puoti, Teresa Santantonio, Antonio Craxì, Loreta A. Kondili, Liliana Chemello and on behalf of PITER Collaborating Investigatorsadd Show full author list remove Hide full author list
Viruses 2024, 16(5), 682; https://doi.org/10.3390/v16050682 - 26 Apr 2024
Viewed by 781
Abstract
The treatment of hepatitis C virus (HCV) with direct-acting antivirals (DAA) leads to high sustained virological response (SVR) rates, but hepatocellular carcinoma (HCC) risk persists in people with advanced liver disease even after SVR. We weighted the HCC risk in people with cirrhosis [...] Read more.
The treatment of hepatitis C virus (HCV) with direct-acting antivirals (DAA) leads to high sustained virological response (SVR) rates, but hepatocellular carcinoma (HCC) risk persists in people with advanced liver disease even after SVR. We weighted the HCC risk in people with cirrhosis achieving HCV eradication through DAA treatment and compared it with untreated participants in the multicenter prospective Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. Propensity matching with inverse probability weighting was used to compare DAA-treated and untreated HCV-infected participants with liver cirrhosis. Kaplan–Meier analysis and competing risk regression analysis were performed. Within the first 36 months, 30 de novo HCC cases occurred in the untreated group (n = 307), with a weighted incidence rate of 0.34% (95%CI: 0.23–0.52%), compared to 63 cases among SVR patients (n = 1111), with an incidence rate of 0.20% (95%CI: 0.16–0.26%). The 12-, 24-, and 36-month HCC weighted cumulative incidence rates were 6.7%, 8.4%, and 10.0% in untreated cases and 2.3%, 4.5%, and 7.0% in the SVR group. Considering death or liver transplantation as competing events, the untreated group showed a 64% higher risk of HCC incidence compared to SVR patients (SubHR 1.64, 95%CI: 1.02–2.62). Other variables independently associated with the HCC occurrence were male sex, increasing age, current alcohol use, HCV genotype 3, platelet count ≤ 120,000/µL, and albumin ≤ 3.5 g/dL. In real-life practice, the high efficacy of DAA in achieving SVR is translated into high effectiveness in reducing the HCC incidence risk. Full article
(This article belongs to the Special Issue Recent Advances in Anti-HCV, Anti-HBV and Anti-flavivirus Agents)
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14 pages, 1635 KiB  
Article
Peripheral Neuropathy in Patients with Hepatitis C Infection—Reversibility after HCV Eradication: A Single Center Study
by Theodoros Androutsakos, Ioanna Tsantzali, Dimitrios S. Karagiannakis, Pagona Flevari, Despoina Iakovou, Abraham Pouliakis, Stylianos Kykalos, Stylianos Doris and Vasileia Xyla
Viruses 2024, 16(4), 522; https://doi.org/10.3390/v16040522 - 28 Mar 2024
Viewed by 768
Abstract
Chronic hepatitis C virus (HCV) infection is characterized by a variety of extra-hepatic manifestations; peripheral neuropathy (PN) is one of the most common, especially when mixed cryoglobulinemia (MCG) is present. The prevalence and risk factors of HCV-related PN in the absence of MCG [...] Read more.
Chronic hepatitis C virus (HCV) infection is characterized by a variety of extra-hepatic manifestations; peripheral neuropathy (PN) is one of the most common, especially when mixed cryoglobulinemia (MCG) is present. The prevalence and risk factors of HCV-related PN in the absence of MCG are largely unknown. We conducted a prospective, single-center study, examining the prevalence and reversibility of HCV-associated neuropathy in the absence of MCG. Nerve fiber density in the epidermis was evaluated through skin biopsy and electroneurography (ENG) before HCV-treatment initiation and 1 year post sustained virological remission (SVR). Forty HCV-infected individuals (nine HIV co-infected) with no other neuron-harming factors were included; four other HCV mono- and three HIV co-infected individuals were excluded due to presence of diabetes, B12 insufficiency, or neurotoxic drugs. Twelve consecutive controls with no neuron-harming conditions were also recruited; eight more were excluded due to meeting exclusion criteria. Four patients had ENG signs of polyneuropathy (two with HCV mono- and two with HIV co-infection), while seven more (five with HCV mono- and two with HIV co-infection) had signs of mono-neuropathy, leading to PN prevalences of 22.5% and 44% for mono- and co-infection, respectively (p value 0.179). The two patients with HCV mono-infection and polyneuropathy and the one with ulnar nerve damage showed ENG improvement 1 year post SVR. Regarding intraepidermal nerve density, HCV infection, irrespective of HIV co-infection, was correlated with a lower intraepidermal neuron density that improved 1 year post SVR (p value 0.0002 for HCV and 0.0326 for HCV/HIV co-infected patients). PN is common in HCV infection; successful eradication of HCV leads to PN improvement. Full article
(This article belongs to the Special Issue Recent Advances in Anti-HCV, Anti-HBV and Anti-flavivirus Agents)
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18 pages, 2719 KiB  
Article
Retreatment with HBV siRNA Results in Additional Reduction in HBV Antigenemia and Immune Stimulation in the AAV-HBV Mouse Model
by Ellen Van Gulck, Nádia Conceição-Neto, Liese Aerts, Wim Pierson, Lore Verschueren, Mara Vleeschouwer, Vinod Krishna, Isabel Nájera and Frederik Pauwels
Viruses 2024, 16(3), 347; https://doi.org/10.3390/v16030347 - 23 Feb 2024
Cited by 1 | Viewed by 1072
Abstract
Background and Aims: Treatment with siRNAs that target HBV has demonstrated robust declines in HBV antigens. This effect is also observed in the AAV-HBV mouse model, which was used to investigate if two cycles of GalNAc-HBV-siRNA treatment could induce deeper declines in HBsAg [...] Read more.
Background and Aims: Treatment with siRNAs that target HBV has demonstrated robust declines in HBV antigens. This effect is also observed in the AAV-HBV mouse model, which was used to investigate if two cycles of GalNAc-HBV-siRNA treatment could induce deeper declines in HBsAg levels or prevent rebound, and to provide insights into the liver immune microenvironment. Methods: C57Bl/6 mice were transduced with one of two different titers of AAV-HBV for 28 days, resulting in stable levels of HBsAg of about 103 or 105 IU/mL. Mice were treated for 12 weeks (four doses q3wk) per cycle with 3 mg/kg of siRNA-targeting HBV or an irrelevant sequence either once (single treatment) or twice (retreatment) with an 8-week treatment pause in between. Blood was collected to evaluate viral parameters. Nine weeks after the last treatment, liver samples were collected to perform phenotyping, bulk RNA-sequencing, and immunohistochemistry. Results: Independent of HBsAg baseline levels, treatment with HBV-siRNA induced a rapid decline in HBsAg levels, which then plateaued before gradually rebounding 12 weeks after treatment stopped. A second cycle of HBV-siRNA treatment induced a further decline in HBsAg levels in serum and the liver, reaching undetectable levels and preventing rebound when baseline levels were 103 IU/mL. This was accompanied with a significant increase in inflammatory macrophages in the liver and significant upregulation of regulatory T-cells and T-cells expressing immune checkpoint receptors. Conclusions: Retreatment induced an additional decline in HBsAg levels, reaching undetectable levels when baseline HBsAg levels were 3log10 or less. This correlated with T-cell activation and upregulation of Trem2. Full article
(This article belongs to the Special Issue Recent Advances in Anti-HCV, Anti-HBV and Anti-flavivirus Agents)
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Review

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26 pages, 3936 KiB  
Review
Current Advances in Japanese Encephalitis Virus Drug Development
by Jiao Guo, Yunqi Mi, Yan Guo, Yang Bai, Meihua Wang, Wei Wang and Yang Wang
Viruses 2024, 16(2), 202; https://doi.org/10.3390/v16020202 - 28 Jan 2024
Viewed by 1660
Abstract
Japanese encephalitis virus (JEV) belongs to the Flaviviridae family and is a representative mosquito-borne flavivirus responsible for acute encephalitis and meningitis in humans. Despite the availability of vaccines, JEV remains a major public health threat with the potential to spread globally. According to [...] Read more.
Japanese encephalitis virus (JEV) belongs to the Flaviviridae family and is a representative mosquito-borne flavivirus responsible for acute encephalitis and meningitis in humans. Despite the availability of vaccines, JEV remains a major public health threat with the potential to spread globally. According to the World Health Organization (WHO), there are an estimated 69,000 cases of JE each year, and this figure is probably an underestimate. The majority of JE victims are children in endemic areas, and almost half of the surviving patients have motor or cognitive sequelae. Thus, the absence of a clinically approved drug for the treatment of JE defines an urgent medical need. Recently, several promising and potential drug candidates were reported through drug repurposing studies, high-throughput drug library screening, and de novo design. This review focuses on the historical aspects of JEV, the biology of JEV replication, targets for therapeutic strategies, a target product profile, and drug development initiatives. Full article
(This article belongs to the Special Issue Recent Advances in Anti-HCV, Anti-HBV and Anti-flavivirus Agents)
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25 pages, 1509 KiB  
Review
Gene-Editing and RNA Interference in Treating Hepatitis B: A Review
by Nadiia Kasianchuk, Krystyna Dobrowolska, Sofiia Harkava, Andreea Bretcan, Dorota Zarębska-Michaluk, Jerzy Jaroszewicz, Robert Flisiak and Piotr Rzymski
Viruses 2023, 15(12), 2395; https://doi.org/10.3390/v15122395 - 8 Dec 2023
Cited by 3 | Viewed by 2032
Abstract
The hepatitis B virus (HBV) continues to cause substantial health and economic burdens, and its target of elimination may not be reached in 2030 without further efforts in diagnostics, non-pharmaceutical prevention measures, vaccination, and treatment. Current therapeutic options in chronic HBV, based on [...] Read more.
The hepatitis B virus (HBV) continues to cause substantial health and economic burdens, and its target of elimination may not be reached in 2030 without further efforts in diagnostics, non-pharmaceutical prevention measures, vaccination, and treatment. Current therapeutic options in chronic HBV, based on interferons and/or nucleos(t)ide analogs, suppress the virus replication but do not eliminate the pathogen and suffer from several constraints. This paper reviews the progress on biotechnological approaches in functional and definitive HBV treatments, including gene-editing tools, i.e., zinc-finger proteins, transcription activator-like effector nucleases, and CRISPR/Cas9, as well as therapeutics based on RNA interference. The advantages and challenges of these approaches are also discussed. Although the safety and efficacy of gene-editing tools in HBV therapies are yet to be demonstrated, they show promise for the revitalization of a much-needed advance in the field and offer viral eradication. Particular hopes are related to CRISPR/Cas9; however, therapeutics employing this system are yet to enter the clinical testing phases. In contrast, a number of candidates based on RNA interference, intending to confer a functional cure, have already been introduced to human studies. However, larger and longer trials are required to assess their efficacy and safety. Considering that prevention is always superior to treatment, it is essential to pursue global efforts in HBV vaccination. Full article
(This article belongs to the Special Issue Recent Advances in Anti-HCV, Anti-HBV and Anti-flavivirus Agents)
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28 pages, 7531 KiB  
Review
Recent Advances in the Development of Sulfamoyl-Based Hepatitis B Virus Nucleocapsid Assembly Modulators
by Sandesha Nayak, Jayaraj Gowda, Syed Azeem Abbas, Hyejin Kim and Soo Bong Han
Viruses 2023, 15(12), 2367; https://doi.org/10.3390/v15122367 - 30 Nov 2023
Viewed by 1803
Abstract
Hepatitis B virus (HBV) is the primary contributor to severe liver ailments, encompassing conditions such as cirrhosis and hepatocellular carcinoma. Globally, 257 million people are affected by HBV annually and 887,000 deaths are attributed to it, representing a substantial health burden. Regrettably, none [...] Read more.
Hepatitis B virus (HBV) is the primary contributor to severe liver ailments, encompassing conditions such as cirrhosis and hepatocellular carcinoma. Globally, 257 million people are affected by HBV annually and 887,000 deaths are attributed to it, representing a substantial health burden. Regrettably, none of the existing therapies for chronic hepatitis B (CHB) have achieved satisfactory clinical cure rates. This issue stems from the existence of covalently closed circular DNA (cccDNA), which is difficult to eliminate from the nucleus of infected hepatocytes. HBV genetic material is composed of partially double-stranded DNA that forms complexes with viral polymerase inside an icosahedral capsid composed of a dimeric core protein. The HBV core protein, consisting of 183 to 185 amino acids, plays integral roles in multiple essential functions within the HBV replication process. In this review, we describe the effects of sulfamoyl-based carboxamide capsid assembly modulators (CAMs) on capsid assembly, which can suppress HBV replication and disrupt the production of new cccDNA. We present research on classical, first-generation sulfamoyl benzocarboxamide CAMs, elucidating their structural composition and antiviral efficacy. Additionally, we explore newly identified sulfamoyl-based CAMs, including sulfamoyl bicyclic carboxamides, sulfamoyl aromatic heterocyclic carboxamides, sulfamoyl aliphatic heterocyclic carboxamides, cyclic sulfonamides, and non-carboxamide sulfomoyl-based CAMs. We believe that certain molecules derived from sulfamoyl groups have the potential to be developed into essential components of a well-suited combination therapy, ultimately yielding superior clinical efficacy outcomes in the future. Full article
(This article belongs to the Special Issue Recent Advances in Anti-HCV, Anti-HBV and Anti-flavivirus Agents)
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33 pages, 7159 KiB  
Review
Hepatitis B Virus Epsilon (ε) RNA Element: Dynamic Regulator of Viral Replication and Attractive Therapeutic Target
by Lukasz T. Olenginski, Solomon K. Attionu, Erica N. Henninger, Regan M. LeBlanc, Andrew P. Longhini and Theodore K. Dayie
Viruses 2023, 15(9), 1913; https://doi.org/10.3390/v15091913 - 12 Sep 2023
Viewed by 2036
Abstract
Hepatitis B virus (HBV) chronically infects millions of people worldwide, which underscores the importance of discovering and designing novel anti-HBV therapeutics to complement current treatment strategies. An underexploited but attractive therapeutic target is ε, a cis-acting regulatory stem-loop RNA situated within the [...] Read more.
Hepatitis B virus (HBV) chronically infects millions of people worldwide, which underscores the importance of discovering and designing novel anti-HBV therapeutics to complement current treatment strategies. An underexploited but attractive therapeutic target is ε, a cis-acting regulatory stem-loop RNA situated within the HBV pregenomic RNA (pgRNA). The binding of ε to the viral polymerase protein (P) is pivotal, as it triggers the packaging of pgRNA and P, as well as the reverse transcription of the viral genome. Consequently, small molecules capable of disrupting this interaction hold the potential to inhibit the early stages of HBV replication. The rational design of such ligands necessitates high-resolution structural information for the ε–P complex or its individual components. While these data are currently unavailable for P, our recent structural elucidation of ε through solution nuclear magnetic resonance spectroscopy marks a significant advancement in this area. In this review, we provide a brief overview of HBV replication and some of the therapeutic strategies to combat chronic HBV infection. These descriptions are intended to contextualize our recent experimental efforts to characterize ε and identify ε-targeting ligands, with the ultimate goal of developing novel anti-HBV therapeutics. Full article
(This article belongs to the Special Issue Recent Advances in Anti-HCV, Anti-HBV and Anti-flavivirus Agents)
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