Efavirenz Repurposing Challenges: A Novel Nanomicelle-Based Antiviral Therapy Against Mosquito-Borne Flaviviruses DOI Creative Commons
Sara Maldonado,

Pedro Fuentes,

Ezequiel Bernabeu

et al.

Pharmaceutics, Journal Year: 2025, Volume and Issue: 17(2), P. 241 - 241

Published: Feb. 12, 2025

Background/Objective: World Health Organization latest statistics state that 17% of infectious diseases are transmitted by vectors, causing more than 700,000 deaths each year. Particularly, dengue (DENV), Zika (ZIKV) and yellow fever (YFV) viral infections have generated international awareness due to their epidemic proportion risks spread. In this framework, the repositioning strategy Efavirenz (EFV) represents a key clinical feature improve different antiviral therapies. Therefore, development Soluplus®-based nanomicelles (NMs) loaded with EFV (10 mg/mL) for optimized oral pharmacotherapy against ZIKV, DENV YFV was investigated. Methods: EFV-NMs were obtained an acetone diffusion technique. Micellar size in vitro micellar interaction mucin assessed dynamic light scattering. cytocompatibility investigated A549 Vero cells activity evaluated. vivo bioavailability histological studies Wistar rats. Results: encapsulation within Soluplus® NMs increased drug's apparent aqueous solubility up 4803-fold unimodal distribution ~90 nm at 25 37 °C. also pH range 1.2-7.5 its storage physicochemical stability 4 °C confirmed over 2 years. assays dispersions resulted safe nanoformulations. Interestingly, EFV-loaded exhibited significantly higher compared solution all tested flaviviruses. addition, selectivity index (SI) values reveal considerably biological efficacy cell lines infection (SI > 10). Further, drug pharmacokinetics parameters enhanced after administration NMs, being biocompatible not damage gastrointestinal segments. Conclusions: Overall, our nanoformulation highlighted potential as novel delivery platform therapy.

Language: Английский

Dengue virus pathogenesis and host molecular machineries DOI Creative Commons

Saumya Sinha,

Kinjal Singh,

Yogesh Kumar

et al.

Journal of Biomedical Science, Journal Year: 2024, Volume and Issue: 31(1)

Published: April 22, 2024

Abstract Dengue viruses (DENV) are positive-stranded RNA belonging to the Flaviviridae family. DENV is causative agent of dengue, most rapidly spreading viral disease transmitted by mosquitoes. Each year, millions people contract virus through bites from infected female mosquitoes Aedes species. In majority individuals, infection asymptomatic, and immune system successfully manages control replication within a few days. Symptomatic individuals may present with mild fever (Dengue or DF) that not progress more critical termed hemorrhagic (DHF) fatal shock syndrome (DSS). absence universally accepted prophylactic vaccine therapeutic drug, treatment mostly restricted supportive measures. Similar many other induce acute illness, has developed several ways modulate host metabolism create an environment conducive genome dissemination progeny. To search for new options, understanding underlying host-virus regulatory involved in various biological processes life cycle essential. This review aims summarize complex interaction between cellular machinery, comprising mechanisms at molecular levels such as epigenetic modulation genome, transcription genes, translation mRNAs, post-transcriptional regulation transcriptome, post-translational proteins, pathways protein degradation.

Language: Английский

Citations

27
A Comprehensive Review of the Development and Therapeutic Use of Antivirals in Flavivirus Infection DOI Creative Commons
Aarti Tripathi,

Shailendra Chauhan,

Renu Khasa

et al.

Viruses, Journal Year: 2025, Volume and Issue: 17(1), P. 74 - 74

Published: Jan. 8, 2025

Flaviviruses are a diverse group of viruses primarily transmitted through hematophagous insects like mosquitoes and ticks. Significant expansion in the geographic range, prevalence, vectors flavivirus over last 50 years has led to dramatic increase infections that can manifest as hemorrhagic fever or encephalitis, leading prolonged morbidity mortality. Millions every year pose serious threat worldwide public health, encouraging scientists develop better understanding pathophysiology immune evasion mechanisms these for vaccine development antiviral therapy. Extensive research been conducted developing effective antivirals flavivirus. Various approaches have extensively utilized clinical trials development, targeting virus entry, replication, polyprotein synthesis processing, egress pathways exploiting well host proteins. However, date, no licensed drug exists treat diseases caused by viruses. Understanding host-pathogen interaction, immunity, viral evasion, disease pathogenesis is highly warranted foster antivirals. This review provides an detailed summary most recent advances drugs combat diseases.

Language: Английский

Citations

1
Exploiting venom toxins in paratransgenesis to prevent mosquito-borne disease DOI Creative Commons
Stephanie French,

Rachael Da Silva,

Janet Storm

et al.

Parasites & Vectors, Journal Year: 2025, Volume and Issue: 18(1)

Published: Jan. 29, 2025

Language: Английский

Citations

1
The endoplasmic reticulum (ER): a crucial cellular hub in flavivirus infection and potential target site for antiviral interventions DOI Creative Commons
M Verhaegen, Kurt Vermeire

npj Viruses, Journal Year: 2024, Volume and Issue: 2(1)

Published: June 21, 2024

Abstract Dengue virus (DENV) is the most prevalent arthropod-borne flavivirus and imposes a significant healthcare threat worldwide. At present no FDA-approved specific antiviral treatment available, safety of vaccine against DENV still on debate. Following its entry into host cell, takes advantage cellular secretory pathway to produce new infectious particles. The key organelle cell in infections endoplasmic reticulum (ER) which supports various stages throughout entire life cycle flaviviruses. This review delves intricate interplay between flaviviruses ER during their with focus molecular mechanisms underlying viral replication, protein processing virion assembly. Emphasizing significance cycle, we highlight potential targets ER-related steps replication summarize current drugs that are (pre)clinical developmental stage. Insights exploitation by offer promising avenues for development targeted strategies, providing foundation future research therapeutic interventions

Language: Английский

Citations

7
CRISPR Screen Reveals PACT as a Pro-Viral Factor for Dengue Viral Replication DOI Creative Commons
Shwetha Shivaprasad, Wenjie Qiao, Kuo‐Feng Weng

et al.

Viruses, Journal Year: 2024, Volume and Issue: 16(5), P. 725 - 725

Published: May 3, 2024

The dengue virus is a single-stranded, positive-sense RNA that infects ~400 million people worldwide. Currently, there are no approved antivirals available. CRISPR-based screening methods have greatly accelerated the discovery of host factors essential for DENV infection and can be targeted in host-directed antiviral interventions. In present study, we performed focused CRISPR (Clustered Regularly Interspaced Palindromic Repeats) library screen to discover key human Huh7 cells identified Protein Activator Interferon-Induced Kinase (PACT) as novel pro-viral factor DENV. PACT double-stranded RNA-binding protein generally known activate responses virus-infected block viral replication. However, our studies, observed plays role specifically promotes Knockout resulted significant decrease abundances infected cells, which was rescued upon ectopic expression full-length PACT. An analysis global gene changes indicated several ER-associated genes such ERN1, DDIT3, HERPUD1, EIF2AK3 not upregulated DENV-infected knockout compared wildtype cells. Thus, study demonstrates promoting replication, possibly through modulating genes.

Language: Английский

Citations

6
Insight into Preventing Global Dengue Spread: Nanoengineered Niclosamide for Viral Infections DOI Creative Commons
N. Sanoj Rejinold, Geun‐woo Jin, Jin‐Ho Choy

et al.

Nano Letters, Journal Year: 2024, Volume and Issue: 24(46), P. 14541 - 14551

Published: Aug. 28, 2024

Millions of cases dengue virus (DENV) infection yearly from Aedes mosquitoes stress the need for effective antivirals. No current drug effectively combats efficiently. Transient immunity and severe risks highlight broad-spectrum antivirals targeting all serotypes DENV. Niclosamide, an antiparasitic, shows promising antiviral activity against virus, but enhancing its bioavailability is challenging. To overcome this issue enable niclosamide to address global problem, nanoengineered niclosamides can be solution. Not only does it cost issues also with effects offers hope in addressing health crisis associated DENV will play a crucial role combating other arboviruses as well.

Language: Английский

Citations

6
Back-Pocket Optimization of 2-Aminopyrimidine-Based Macrocycles Leads to Potent EPHA2/GAK Kinase Inhibitors DOI

Joshua Gerninghaus,

Rezart Zhubi, Andreas Krämer

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(15), P. 12534 - 12552

Published: July 19, 2024

Macrocyclization of acyclic compounds is a powerful strategy for improving inhibitor potency and selectivity. Here we have optimized 2-aminopyrimidine-based macrocycles to use these as chemical tools the ephrin kinase family. Starting with promiscuous macrocyclic inhibitor,

Language: Английский

Citations

5
Dengue virus infection and neurological manifestations: an update DOI
Si‐Lei Fong, Kum Thong Wong,

Chong-Tin Tan

et al.

Brain, Journal Year: 2023, Volume and Issue: 147(3), P. 830 - 838

Published: Dec. 9, 2023

Abstract Dengue virus is a flavivirus transmitted by the mosquitoes, Aedes aegypti and albopictus. infection all four serotypes (DEN 1 to 4) endemic globally in regions with tropical subtropical climates, an estimated 100–400 million infections annually. Among those hospitalized, mortality about 1%. Neurological involvement has been reported be 5%. The spectrum of neurological manifestations spans both peripheral central nervous systems. These could possibly categorized into directly related dengue infection, i.e. acute chronic encephalitis, indirect complications leading encephalopathy, post-infectious syndrome due immune-mediated reactions, uncertain mechanisms, such as transverse myelitis, cerebellitis myositis. rising trend global incidence calls for attention more explicit definition each manifestation accurate epidemiological data. actual burden essential future planning execution strategies, especially development effective antivirals vaccines against virus. In this article, we discuss recent findings different spectrums provide update on antiviral vaccine their challenges.

Language: Английский

Citations

12
Aminopyrimidine Derivatives as Multiflavivirus Antiviral Compounds Identified from a Consensus Virtual Screening Approach DOI
Mateus Sá Magalhães Serafim, Thales Kronenberger, Rafael E. O. Rocha

et al.

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 9, 2024

Around three billion people are at risk of infection by the dengue virus (DENV) and potentially other flaviviruses. Worldwide outbreaks DENV, Zika (ZIKV), yellow fever (YFV), lack antiviral drugs, limitations on vaccine usage emphasize need for novel research. Here, we propose a consensus virtual screening approach to discover potential protease inhibitors (NS3pro) against different flavivirus. We employed an in silico combination hologram quantitative structure–activity relationship (HQSAR) model molecular docking characterized binding sites followed dynamics (MD) simulations, which filtered data set 7.6 million compounds 2,775 hits. Lastly, MD simulations selected six final NS3pro with stable interactions along simulations. Five had their activity confirmed ZIKV, YFV, DENV-2, DENV-3 (ranging from 4.21 ± 0.14 37.51 0.8 μM), displaying aggregator characteristics enzymatic inhibition ZIKV 28 7 70 μM). Taken together, identified this may contribute design promising candidates treat flavivirus infections.

Language: Английский

Citations

4
Antimicrobial peptides for novel antiviral strategies in the current post‐COVID‐19 pandemic DOI Creative Commons
Maria Rosa Loffredo, Lucia Nencioni, Maria Luisa Mangoni

et al.

Journal of Peptide Science, Journal Year: 2023, Volume and Issue: 30(1)

Published: July 28, 2023

The recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has highlighted how urgent and necessary the discovery of new antiviral compounds is for novel therapeutic approaches. Among various classes molecules with activity, antimicrobial peptides (AMPs) innate immunity are among most promising ones, mainly due to their different mechanisms action against viruses additional biological properties. In this review, main physicochemical characteristics AMPs described, particular interest toward derived from amphibian skin. Living in aquatic terrestrial environments, amphibians one richest sources primary secondary structures. Besides describing activities these underlying mechanism, review aims at emphasizing high potential small development agents that likely reduce selection resistant strains.

Language: Английский

Citations

10