Antiviral Therapeutics Research Articles

P-2367. Qualitative Analysis of Barriers to Outpatient Antiviral Treatment for COVID-19 and Influenza Patients Observed by Infectious Disease Specialists in North America, 2024

Abstract Background Antiviral medications for COVID-19 and influenza can mitigate disease severity in high-risk outpatients if taken early in the course of illness yet are underutilized. We sought to understand barriers to providers prescribing these medications. Table Thematic summary from infectious disease specialists outlining barriers to outpatient antiviral treatment for COVID-19 and influenza patients, United States, 2024 Methods We conducted an on-line survey regarding knowledge, attitudes, and practices of prescribing antiviral treatment for outpatients with COVID-19 and influenza. Respondents were asked about perceived barriers among providers treating COVID-19 and influenza outpatients in their institutions. Questions were structured using a Likert scale and were analyzed using a thematic analysis approach in Microsoft Excel. Results Of 1,898 infectious disease specialists across the United States and Canada who received the survey between 1/10/24 to 2/5/24, 565 (30%) responded, of whom 93% were infectious disease physicians and 7% were healthcare professionals. Surveyed physicians worked in university (45%), non-university teaching (24%), community (20%), city/county (4%), outpatient (0.4%), and veteran affairs hospital settings (6%) and 144 (25%) provided free text responses. The primary barrier to prescribing antivirals was provider skepticism (47%), due to patient symptoms deemed too mild for treatment and needing more evidence about effectiveness. This was followed by perceptions of limited accessibility (31%) related to high cost, limited hospital access, and difficulty administering some medications. Pharmacologic limitations (18%) were concerns about drug interactions, side effects, and incomplete medical history. Other barriers were timeliness of treatment within a short therapeutic window (15%) and patient skepticism (13%). Additional free text responses described successful hospital protocols and suggestions for encouraging antiviral prescribing. Conclusion These themes demonstrate a need for better education of providers about antiviral risks and benefits as well as improved access and coverage of life-saving medications. Infectious disease specialists provided useful insights which can help to shape clinical recommendations, future research for antiviral therapeutics, and public health messaging for improved patient care. Disclosures Philip M. Polgreen, MD, Eli Lily: Advisor/Consultant|Pfizer: Grant/Research Support

A Novel HTNV Budding Inhibitor Interferes the Interaction Between Viral Glycoprotein and Host ESCRT Accessory Protein ALIX.

Virus budding is a critical step in the replication cycle of enveloped viruses, closely linked to viral spread, disease progression, and clinical outcomes. The budding of many enveloped RNA viruses is facilitated by the hijacking of the host endosomal sorting complex required for transport (ESCRT) proteins through viral late domains. These late domains are essential for progeny virus production and are highly conserved, making the interaction between late domains and host ESCRT proteins a potential target for the development of antiviral therapeutics. In this study, we elucidated the functional role of the conserved YRTL motif within the glycoprotein Gn cytoplasmic tail of Orthohantavirus hantanense (Hantaan virus, HTNV), demonstrating that HTNV production is regulated by the interaction between YRTL and the ESCRT accessory protein ALIX (ALG-2 interacting protein X). Through virtual molecule docking screening, followed by in vitro and in vivo assays, we discovered a novel compound, AN-329, which disrupts the YRTL-ALIX interaction and effectively inhibits infectious HTNV production, as well as Crimean-Congo hemorrhagic fever virus (CCHFV) and Rift Valley fever virus (RVFV) VLP release. This makes AN-329 a promising therapeutic candidate for reducing viral dissemination. Given that YRTL is conserved across many hantaviruses, our findings may serve as a prototype for the development of broad-spectrum antiviral drugs.

Target-specific peptides for BK virus agnoprotein identified through phage display screening: advancing antiviral therapeutics

BK virus is implicated in polyomavirus-associated nephropathy (PVAN) and hemorrhagic cystitis, particularly in kidney transplant recipients, affecting the functionality of the transplanted kidney and posing a risk of graft loss. Despite these challenges, specific antiviral drugs targeting BK virus remain elusive. Agnoprotein, a small, positively charged protein encoded by the BK virus late gene, functions in the assembly, maturation, and release of the virus. Consequently, agnoprotein emerges as a promising target for potential anti-BK virus drugs. Utilizing phage display technology, we conducted screening to identify specific binding peptides against the agnoprotein. The primary objective of screening binding peptides is to utilize them to disrupt the virus’s life cycle, impeding its replication and transmission, thereby achieving antiviral effects. In the current experimental study, a combination of phage 7 peptide libraries and 12 peptide libraries was employed for screening purposes. Following four rounds of screening, seven positive phages demonstrating the ability to bind Agnoprotein were successfully isolated. Following ELISA validation, it was observed that the optical density (OD) values for Agnoprotein binding of the seven positive clones significantly exceeded three times the value of the negative control (NC). Subsequent analysis identified one 7-peptide and six 12-peptides within the binding peptides. Moreover, OD values of dodecapeptide phage clones bound to agnoprotein were generally higher than those of heptapeptide phage clones.In conclusion, our study demonstrates the successful identification of specific binding peptides against agnoprotein, a crucial component in the BK virus life cycle.

Harnessing antiviral RNAi therapeutics for pandemic viruses: SARS-CoV-2 and HIV.

Using the knowledge from decades of research into RNA-based therapies, the COVID-19 pandemic response saw the rapid design, testing and production of the first ever mRNA vaccines approved for human use in the clinic. This breakthrough has been a significant milestone for RNA therapeutics and vaccines, driving an exponential growth of research into the field. The development of novel RNA therapeutics targeting high-threat pathogens, that pose a substantial risk to global health, could transform the future of health delivery. In this review, we provide a detailed overview of the two RNA interference (RNAi) pathways and how antiviral RNAi therapies can be used to treat acute or chronic diseases caused by the pandemic viruses SARS-CoV-2 and HIV, respectively. We also provide insights into short-interfering RNA (siRNA) delivery systems, with a focus on how lipid nanoparticles can be functionalized to achieve targeted delivery to specific sites of disease. This review will provide the current developments of SARS-CoV-2 and HIV targeted siRNAs, highlighting strategies to advance the progression of antiviral siRNA along the clinical development pathway.

Design, Synthesis, and Unprecedented Interactions of Covalent Dipeptide-Based Inhibitors of SARS-CoV-2 Main Protease and Its Variants Displaying Potent Antiviral Activity.

The main protease (Mpro) of SARS-CoV-2 is a key drug target for the development of antiviral therapeutics. Here, we designed and synthesized a series of small-molecule peptidomimetics with various cysteine-reactive electrophiles. Several compounds were identified as potent SARS-CoV-2 Mpro inhibitors, including compounds 8n (IC50 = 0.0752 μM), 8p (IC50 = 0.0887 μM), 8r (IC50 = 0.0199 μM), 10a (IC50 = 0.0376 μM), 10c (IC50 = 0.0177 μM), and 10f (IC50 = 0.0130 μM). Most of them additionally inhibited cathepsin L and were also active against SARS-CoV-1 and MERS-CoV Mpro. In Calu-3 cells, several inhibitors, including 8r, 10a, and 10c, displayed high antiviral activity in the nanomolar range without showing cellular toxicity. The cocrystal structure of SARS-CoV-2 Mpro in complex with 8p revealed covalent binding to the enzyme's catalytic residue Cys145 and showed specific, unprecedented interactions within the substrate binding pocket. Compounds 10c and especially 8n were effective against a panel of naturally occurring nirmatrelvir-resistant mutants, particularly E166V, and showed metabolic stability and additional favorable pharmacokinetic properties, making it a suitable candidate for further preclinical development.

Hsa-miR-548d-3p: a potential microRNA to target nucleocapsid and/or capsid genes in multiple members of the Flaviviridae family.

Flaviviridae comprise a group of enveloped, positive-stranded RNA viruses that are mainly transmitted through either mosquitoes or tick bites and/or contaminated blood, blood products, or other body secretions. These viruses cause diseases ranging from mild to severe and are considered important human pathogens. MicroRNAs (miRNAs) are non-coding molecules involved in growth, development, cell proliferation, protein synthesis, apoptosis, and pathogenesis. These small molecules are even being used as gene suppressors in antiviral therapeutics, inhibiting viral replication. In the current study, we used bioinformatic tools to predict a possible miRNA sequence that could be complementary to the nucleocapsid (NP) and/or capsid (CP) gene of the Flaviviridae family and provide an inhibitory solution. Bioinformatics is a field of science that includes tremendous computational analysis, logarithms, and sequence alignments. To predict the right alignments between miRNA and viral mRNA genomes, we used computational databases such as miRBase, NCBI, and Basic Alignment Search Tool-nucleotides (BLAST-n). Of the 2,600 mature miRNAs, hsa-miR-548d-3p revealed complementary sequences with the flavivirus capsid gene and bovine viral diarrhea virus (BVDV) capsid gene and was selected as a possible candidate to inhibit flaviviruses. Although more detailed in vitro and in vivo studies are required to test the possible inhibitory effects of hsa-miR-548d-3p against flaviviruses, this computational study may be the first step to study further, developing a novel therapeutic for lethal viruses within the Flaviviridae family using suggested candidate miRNAs.

Proteomic Analysis of Differentially Expressed Proteins in A549 Cells Infected with H9N2 Avian Influenza Virus.

Influenza A viruses (IAVs) are highly contagious pathogens that cause zoonotic disease with limited availability of antiviral therapies, presenting ongoing challenges to both public health and the livestock industry. Unveiling host proteins that are crucial to the IAV life cycle can help clarify mechanisms of viral replication and identify potential targets for developing alternative host-directed therapies. Using a four-dimensional (4D), label-free methodology coupled with bioinformatics analysis, we analyzed the expression patterns of cellular proteins that changed following H9N2 virus infection. Compared to the control group, the H9N2 infected group displayed 732 differentially expressed proteins (DEPs), with 298 proteins showing upregulation and 434 proteins showing downregulation. Gene Ontology (GO) functional analysis showed that DEPs were catalog in 11 biological processes, three cellular components, and eight molecular functions. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that DEPs were involved in processes including cytokine signaling pathways induced by virus infection and protein digestion and absorption. Proteins including TP53, DDX58, and STAT3 were among the top hub proteins in the protein-protein interaction (PPI) analysis, suggesting that these signaling cascades could be essential for the propagation of IAVs. Furthermore, the host protein SNAPIN was chosen to ascertain the accuracy of expression changes identified through a proteomic analysis. The results indicated that SNAPIN was downregulated following infection with IAVs both in vitro and in vivo, which is consistent with the proteomics results, suggesting that SNAPIN may serve as a key regulatory factor in the viral life cycle of IAVs. Our research delineates an extensive interaction map of IAV infection within the A549 cells, facilitating the discovery of pivotal proteins that contribute to the virus's propagation, potentially offering target candidates to screen for antiviral therapeutics.

Structural Analysis of Inhibitor Binding to Enterovirus-D68 3C Protease.

Enterovirus-D68 (EV68) continues to present as a global health issue causing respiratory illness and outbreaks associated with long-lasting neurological disease, with no antivirals or specific treatment options. The development of antiviral therapeutics, such as small-molecule inhibitors that target conserved proteins like the enteroviral 3C protease, remains to be achieved. While various 3C inhibitors have been investigated, their design does not consider the potential emergence of drug resistance mutations. For other antivirals where resistance has been a challenge, we have demonstrated that the likelihood of resistance can be minimized by designing inhibitors that leverage the evolutionary constraints of the target. Here, we characterize a series of 3C inhibitors against EV68-3C protease through enzyme inhibition, protein crystallography, and structural analysis. We have determined and analyzed three high-resolution inhibitor-bound crystal structures of EV68-3C protease, which revealed possible sites of resistance mutations, a key structural water molecule conserved during ligand binding, and the conformational flexibility of the catalytic histidine H40. This structural analysis combined with enzymatic assays provides insights for the rational design of inhibitors that are robust against resistance toward developing antiviral treatments for EV68 infections.

Emerging Roles of TRIM56 in Antiviral Innate Immunity.

The tripartite-motif protein 56 (TRIM56) is a RING-type E3 ubiquitin ligase whose functions were recently beginning to be unveiled. While the physiological role(s) of TRIM56 remains unclear, emerging evidence suggests this protein participates in host innate defense mechanisms that guard against viral infections. Interestingly, TRIM56 has been shown to pose a barrier to viruses of distinct families by utilizing its different domains. Apart from exerting direct, restrictive effects on viral propagation, TRIM56 is implicated in regulating innate immune signaling pathways that orchestrate type I interferon response or autophagy, through which it indirectly impacts viral fitness. Remarkably, depending on viral infection settings, TRIM56 either operates in a canonical, E3 ligase-dependent fashion or adopts an enzymatically independent, non-canonical mechanism to bolster innate immune signaling. Moreover, the recent revelation that TRIM56 is an RNA-binding protein sheds new light on its antiviral mechanisms against RNA viruses. This review summarizes recent advances in the emerging roles of TRIM56 in innate antiviral immunity. We focus on its direct virus-restricting effects and its influence on innate immune signaling through two critical pathways: the endolysosome-initiated, double-stranded RNA-sensing TLR3-TRIF pathway and the cytosolic DNA-sensing, cGAS-STING pathway. We discuss the underpinning mechanisms of action and the questions that remain. Further studies understanding the complexity of TRIM56 involvement in innate immunity will add to critical knowledge that could be leveraged for developing antiviral therapeutics.

Biocatalytic synthesis of ribonucleoside analogues using nucleoside transglycosylase-2.

Ribonucleosides are essential building blocks used extensively in antiviral and oligonucleotide therapeutics. A major challenge in the further development of nucleoside analogues for therapeutic applications is access to scalable and environmentally sustainable synthetic strategies. This study uses the type II nucleoside 2'-deoxyribosyltransferase from Lactobacillus leichmannii (LlNDT-2) to prepare a suite of ribonucleoside analogues using naturally-occurring uridine and cytidine sugar donors. Crystal structure and mutational analyses are used to define the substrate tolerance of the nucleobase exchange and the 2'-substituent of the nucleoside sugar donor. Nucleobase profiling identified acceptance of both purine and pyrimidine nucleobases. Finally, the scalability of the approach is showcased, enabling the preparation of ribonucleosides on millimolar scales. This biocatalytic strategy opens up opportunities to establish chemoenzymatic routes to prepare nucleoside analogues incorporating 2' modifications that are of therapeutic importance.

Structure-based discovery of dual-target inhibitors of the helicase from bagaza virus.

Bagaza virus (BAGV) is a mosquito-borne flavivirus and has caused significant avian death in many regions, and also garnered recognition as a significant human pathogen causing diseases like encephalitis. The genome of BAGV encodes ten proteins including three structural proteins and seven nonstructural proteins. The C-terminus of the BAGV NS3 helicase serves as a helicase during BAGV replication, aiding in ATP hydrolysis and unwinding of double-stranded RNA. Here we determined the crystal structure of BAGV helicase and revealed the NTP and RNA binding pockets in the helicase which may be used for exploiting antiviral therapeutics. Using structure-based virtual screening, we discovered 20 compounds targeting both NTP and RNA binding pockets of the helicase. Molecular docking, mutation analysis, isothermal calorimetry (ITC) and the ATPase activity assay demonstrated that epigallocatechin-3-gallate (EGCG), and other top three screened compounds (Quercitrin, Citicoline sodium, Isochlorogenic acid C), showed binding affinities for both the NTP binding site and the RNA binding site of BAGV helicase, and inhibited the ATPase activity of the helicase. Taken together, our discovery of dual-target inhibitors provides a viable strategy for advancing innovative therapies against BAGV, as well as other flaviviruses.

MFSD6 is an entry receptor for respiratory enterovirus D68.

Enterovirus D68 (EV-D68) is a leading non-polio enterovirus that causes severe respiratory diseases and poliomyelitis-like illness in children. Viral entry represents a potential multifaceted target for antiviral intervention; however, there are no approved inhibitors to block EV-D68. Here, we identify the functionally undescribed membrane protein major facilitator superfamily-domain-containing protein 6 (MFSD6) as an EV-D68 entry factor amenable to therapeutic intervention. Specifically, MFSD6 expression is crucial for EV-D68 replication. MFSD6 binds to EV-D68 particles and is necessary for virus attachment to cells. The second extracellular domain of the MFSD6 molecule is involved in the recognition of EV-D68. On the basis of these findings, we engineered a recombinant protein complex comprising the MFSD6 ectodomain fused to Fc (MFSD6-Fc(CH3)), which potently inhibited EV-D68 uptake. MFSD6-Fc(CH3) effectively blocked EV-D68 infection invitro and prevented lethality in newborn mice. In conclusion, our study not only identifies MFSD6 as an EV-D68 entry factor but also reveals a potential antiviral target and therapeutic agent.

Advancements in Antiviral Therapeutics: A Comprehensive Review of Hepatitis C Virus and Novel Flavone Leads

This review explores the fundamental characteristics and implications of viruses, focusing on their classification, structure, and the specific case of Hepatitis C Virus (HCV). Viruses, nonliving biological entities reliant on host cells for replication, have been historically pivotal in understanding infectious diseases. The classification of viruses has evolved significantly, leading to a hierarchical system that categorizes them by order, family, genus, and species based on genomic characteristics and structural features. HCV, a member of the Flaviviridae family, presents a significant global health concern, affecting over 150 million people and causing approximately 500,000 deaths annually. The virus is characterized by its enveloped structure and single-stranded RNA genome, which encodes a polyprotein that is cleaved into functional proteins essential for viral replication and assembly. The epidemiology of HCV reveals regional prevalence variations, with higher rates observed in developing countries. Notably, the virus exhibits considerable genetic diversity, categorized into seven genotypes, each demonstrating different responses to treatment. The natural history of HCV infection is complex, often remaining asymptomatic for extended periods, which complicates diagnosis and treatment initiation. Chronic infections can lead to severe complications, including liver fibrosis, cirrhosis, and hepatocellular carcinoma. Understanding the mechanisms of HCV entry, replication, and immune evasion is crucial for developing effective antiviral therapies and preventive measures. This review aims to provide a comprehensive overview of the current knowledge surrounding HCV, highlighting the need for ongoing research to better understand its biology and to improve therapeutic strategies against this pervasive virus.

Withaferin A inhibits Chikungunya virus nsP2 protease and shows antiviral activity in the cell culture and mouse model of virus infection.

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus causing fever, myalgia, and debilitating joint swelling and pain, which in many patients becomes chronic. The frequent epidemics of CHIKV across the world pose a significant public health burden necessitating the development of effective antiviral therapeutics. A cellular imaging-based high-content screening of natural compounds identified withaferin A (WFA), a steroidal lactone isolated from the plant Withania somnifera, as a potent antiviral against CHIKV. In the ERMS cells, WFA inhibited CHIKV replication early during the life cycle by binding the CHIKV non-structural protein nsP2 and inhibiting its protease activity. This inhibited the viral polyprotein processing and the minus-sense viral RNA synthesis. WFA mounted the nsP2 protease inhibitory activity through its oxidising property as the reducing agents N-acetylcysteine and Glutathione-monoethyl ester effectively reversed the WFA-mediated protease inhibition in vitro and abolished the WFA-mediated antiviral activity in cultured cells. WFA inhibited CHIKV replication in the C57BL/6 mouse model of chikungunya disease, resulting in significantly lower viremia. Importantly, CHIKV-infected mice showed significant joint swelling which was not seen in WFA-treated mice. These data demonstrate the potential of WFA as a novel CHIKV antiviral.

Golden Therapeutic Approach to Combat Viral Diseases Using Gold Nanomaterials.

Gold nanoparticles (AuNPs), due to their unique properties and surface modification abilities, have become a promising carrier for a range of biomedical applications. AuNPs have intrinsic antiviral characteristics because of their capacity to enhance drug distribution by making antiviral medications more stable and soluble, which assures that higher quantities reach the intended site. Through surface changes, AuNPs can bind directly to viral particles or infected cells, increasing therapeutic efficiency and reducing side effects. AuNPs efficiently damage cell membranes and hinder viral reproduction within a host cell. Furthermore, because of their large surface area-to-volume ratio, which enables many functional groups to connect, improving interaction with virus particles and ceasing their multiplication. By altering dimensions and morphology or conjugating it with additional antiviral drugs, AuNPs can array their synergistic antiviral activity. Thus, the development of AuNP conjugated therapy presents a promising avenue to address the demand for novel anti-viral therapeutics against infections resistant to several drugs.

Construction, structural modification, and bioactivity evaluation of pentacyclic triterpenoid privileged scaffolds in active natural products.

Pentacyclic triterpenoids, as important representatives of natural products, have garnered widespread attention due to their diverse biological activities, including anti-inflammatory, antiviral, and antitumor effects. Oleanolic acid (OA), betulinic acid (BA), ursolic acid (UA), triptolide, and glycyrrhetinic acid (GA) are typical examples of pentacyclic triterpenoids. Despite their significant biological activities, their poor water solubility and low bioavailability have limited further development and application. In recent years, researchers have developed a series of derivatives with enhanced biological activities and improved drug properties through structural modifications of these compounds, particularly achieving notable progress in the field of antitumor therapy. This review summarizes recent advances in the structural modification of pentacyclic triterpenoids and explores their promising applications in the development of antitumor, antiviral, and other therapeutic agents.

Identification of viral protease-dependent cleavage sites within the human astrovirus polyprotein.

Infection by human astrovirus (HAstV), a small, positive-strand RNA virus, is a major cause of gastroenteritis and has been implicated in an increasing number of severe, sometimes fatal, neurological diseases since 2008. Currently, there are no vaccines or antiviral treatments available to treat HAstV infection. An attractive target for antiviral therapeutics is the viral protease due to its essential functions throughout infection. However, the molecular mechanisms of the HAstV protease, nonstructural protein 1a/3 (nsp1a/3), are poorly understood. In fact, the specific residues within the cleavage junctions that are targeted by nsp1a/3 during polyprotein processing have yet to be experimentally identified. To identify the junctions between viral proteins, we performed mass spectrometry and site-directed mutagenesis using epitope-tagged viral polyprotein expression plasmids. Using these strategies, we identified a consensus motif that is found throughout the polyprotein near previously proposed junctions. We found that cleavage occurs after a hydrophobic residue - X - Gln motif. Further mutagenesis of surrounding sequence identified the importance of basic residues following the motif for efficient processing. Cleavage at each junction was determined to be essential for the production of progeny virions. However, abolishing nsp1a/4-VPg cleavage allowed efficient replication, suggesting that VPg can function in an intermediate form. Overall, our results identify a conserved cleavage motif that is recognized by the nsp1a/3 protease within the viral polyprotein, and cleavage at this motif was found to be essential for the recovery of progeny virions. These findings will be instrumental in further understanding the basic functions of HAstV polyprotein processing during infection.IMPORTANCEHuman astroviruses (HAstVs) are a leading cause of non-bacterial gastroenteritis in children, elderly individuals, and immunocompromised patients. However, infection by divergent strains of HAstV is now recognized as a causative agent of severe neurological diseases, which can have fatal outcomes. Despite the global prevalence of HAstV, we currently have a limited understanding of the biology of these viruses. Translation of the viral genome leads to the production of polyproteins that are processed by viral and host proteases into functional proteins. In this study, we identified a conserved recognition sequence targeted by the viral protease for cleavage. Importantly, these findings elucidate the N- and C-termini of the nonstructural proteins within the HAstV polyprotein, offering valuable information for future studies on the function of individual viral proteins. Similar to other positive-sense RNA viruses, the necessity of proteolytic processing for the HAstV polyprotein highlights the viral protease as a promising target for antiviral development.

Advances in the Development of Non-Structural Protein 1 (NsP1) Inhibitors for the Treatment of Chikungunya Virus Infection.

Chikungunya is a re-emerging viral infection of worldwide concern, and new antiviral therapeutics are necessary to combat this disease. Inhibitors of the non-structural protein 1 (NsP1), which shows Methyltransferase (MTase) activity and plays a crucial in the Chikungunya virus (ChikV) replication, are exhibiting promising results. This review aimed to describe recent advances in the development of NsP1 inhibitors for the treatment of Chikungunya disease. High-throughput screening of novel ChikV NsP1 inhibitors has been widely performed for the identification of new molecule hits through fluorescence polarization, Western blotting, ELISA-based assay, and capillary electrophoresis assays. Additionally, cell-based assays confirmed that the inhibition of ChikV NsP1 abolishes viral replication. In summary, pyrimidine and pyrimidin-7(6H)-one derivatives, GTP and nucleoside analogs have been demonstrated to show inhibitory activity and are considered promising scaffolds that provide useful knowledge for the research and development of new NsP1 inhibitors as potential treatment of Chikungunya re-emerging disease.

Emerging Therapeutics in the Fight Against EV-D68: A Review of Current Strategies.

Enterovirus-D68 (EV-D68) was first identified in 1962 in pediatric patients with acute respiratory conditions in California, USA (US). From the 1970s to 2005, EV-D68 was underestimated due to limited data and serotyping methods. In 2014, the United States experienced outbreaks of acute flaccid myelitis (AFM) in children EV-D68 positive. WIN-like compounds (pleconaril, pocapavir, and vapendavir) bind to the virus capsid and have been tested against various enteroviruses (EVs) in clinical trials. However, these compounds encountered issues with resistance and adverse effects, which impeded their approval by the Food and Drug Administration (FDA). Presently, the medical field lacks FDA-approved antiviral treatments or vaccines for EV-D68. Ongoing research efforts are dedicated to identifying viable therapeutics to address EV-D68 infections. This review explores the current advancements in antiviral therapies and potential therapeutics to mitigate the significant impact of EV-D68 infection control.

Revolutionizing Antiviral Therapeutics: In silico Approaches for Emerging and Neglected RNA Viruses.

The 21st century has shown us how rapidly the pandemic can evolve and devastate the life of human beings without differentiating between the continents. Even after the global investment of billions of dollars into the healthcare sector, we are still lacking multiple therapeutics against emerging viruses. World Health Organization (WHO) has listed a number of viruses that could take the form of pandemics at anytime, depending upon their mutations. Among those listed, the SARS-CoV, Ebola, Zika, Nipah, and Chikungunya virus (CHIKV) are the most known viruses in terms of their number of outbreaks. The common feature among these viruses is their RNA-based genome. Developing a new therapeutic candidate for these RNA viruses in a short period of time is challenging. In silico drug designing techniques offer a simple solution to these problems by implementing supercomputers and complicated algorithms that can evaluate the inhibition activity of proposed synthetic compounds without actually doing the bioassays. A vast collection of protein crystal structures and the data on binding affinity are useful tools in this process. Taking this into account, we have summarized the in silico based therapeutic advances against SARS-CoV, Ebola, Zika, Nipah, and CHIKV viruses by encapsulating state-of-art research articles into different sections. Specifically, we have shown that computer- aided drug design (CADD) derived synthetic molecules are the pillars of upcoming therapeutic strategies against emerging and neglected viruses.