antiviral therapeutics / Cyclica, Chinese Academy of Medical Sciences - LARVOL DELTA

Molecular Mechanisms of Zika Virus Entry into Host Cells. (PubMed, Viruses) - "Owing to the absence of approved vaccines and targeted antiviral therapeutics, the prevention and management of ZIKV outbreaks remain extremely challenging. Viral entry into host cells marks the very first step of productive ZIKV infection, and mechanistic investigations into this entry process lay an essential theoretical foundation for developing small-molecule agents that block ZIKV cellular entry. This review summarizes recent advances concerning ZIKV host receptor usage, membrane fusion cascades, and entry-targeted inhibitor development; systematically discusses existing inconsistencies and core controversies in cell type-dependent entry pathways, functionally redundant host receptor usage, especially the disputed AXL receptor, and unresolved molecular details of membrane fusion resulting from diverse experimental models and technical limitations; and proposes targeted future research directions to resolve these bottlenecks and clarify the context-dependent ZIKV..."

Journal • Review • Infectious Disease • AXL

Establishment of an ex vivo vascular tissue model to investigate bunyavirus-triggered vascular endothelial injury. (PubMed, mBio) - "This model enables evaluation of antiviral compound efficacy, demonstrating that niclosamide or 4'-fluorouridine significantly inhibits SFTSV and RVFV replication in ex vivo vascular tissues. These findings establish the ex vivo human vascular tissue as a valuable tool for investigating bunyavirus-induced vascular pathogenesis and for evaluating antiviral therapeutics...Using this model, we demonstrate that bunyavirus infection triggers endothelial disruption and that antiviral compounds can suppress viral replication and alleviate infection-associated tissue injury. This model provides a valuable experimental system for studying virus-vascular interactions and can support antiviral development against emerging bunyaviruses."

Journal • Preclinical • Hematological Disorders • Infectious Disease • Respiratory Diseases • Thrombocytopenia

Lethal C57BL/6 mouse model for Yezo virus infection and antiviral therapeutic evaluation. (PubMed, Emerg Microbes Infect) - "Antiviral evaluation demonstrated that both favipiravir and ribavirin significantly suppressed in vivo YEZV replication, improved survival, and reduced hepatic viral burden. Collectively, this model establishes a rigorously validated platform for mechanistic studies of YEZV pathogenesis and the preclinical evaluation of antiviral therapeutics."

Journal • Preclinical • Hematological Disorders • Hepatology • Infectious Disease • Inflammation • Leukopenia • Liver Failure • Thrombocytopenia

Structure prediction and drug screening targeting monkeypox virus polymerase and surface proteins. (PubMed, J Comput Aided Mol Des) - "The global outbreak and ongoing spread of the monkeypox virus (MPXV) have highlighted the urgent need for effective antiviral therapeutics...Three compounds, including cepharanthine, eltrombopag, and simeprevir, exhibited measurable A35R‑associated binding signals with equilibrium dissociation constants (KD) in the micromolar range...However, no antiviral activity has been demonstrated for these compounds; therefore, the three hit compounds warrant further optimization and biological evaluation. Our integrated approach provides a framework for rapid drug screening against emerging viral threats."

Journal • Preclinical • Infectious Disease

Discovery of Novel Druggable Binding Pockets on SARS-CoV-2 PLpro via Fragment Screening and Insights for Structure-Based Inhibitor Design. (PubMed, J Biol Chem) - "Biochemical assays confirmed that 5-fluorouracil exhibits inhibitory activity against PLpro. Collectively, these findings provide a robust structural framework for the rational design of PLpro inhibitors and support the development of novel antiviral therapeutics."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

GTPase domain of porcine Mx1 protein interacts with the N protein of porcine deltacoronavirus to inhibit viral replication. (PubMed, J Gen Virol) - "Collectively, our study elucidates the mechanism by which the pMx1 protein, as a host antiviral factor, inhibits PDCoV infection. These findings provide novel insights into the innate immune defence against coronaviruses and highlight the pMx1 gene as a promising host-derived antiviral factor with potential applications in antiviral therapeutics and genetic improvement strategies for PDCoV control."

Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease • IFNA1 • KEAP1 • MX1 • PRRX1

MMF inhibits poxvirus infection by disrupting IMPDH2 interaction with USP5 and inducing its Rod-and-Ring assemblies. (PubMed, Virol Sin) - "The conserved strategy by which viruses remodel host nucleotide metabolism to secure biosynthetic precursors for replication and spread has emerged as a pivotal target for the development of broad-spectrum antiviral therapeutics...Mycophenolate mofetil (MMF), an inosine 5'-monophosphate dehydrogenase type II (IMPDH2) inhibitor, displayed potent inhibition effects against both VACV and MPXV...Mechanistic studies suggest that MMF inhibits IMPDH2 activity by suppressing ubiquitin-specific protease 5 (USP5)-mediated deubiquitination of IMPDH2 and inducing rod-and-ring (R&R) assembly, leading to reducing dNTP pools and enhancing antiviral effects. In conclusion, our findings demonstrate that MMF is an effective antiviral drug against VACV and MPXV infection and establish a host-directed therapeutic strategy to combat future orthopoxvirus outbreaks."

Journal • Infectious Disease • Targeted Protein Degradation • IMPDH2 • USP5

A novel monoclonal antibody targeting the hemagglutinin-neuraminidase of peste des petits ruminants virus maintains neutralizing activity by blocking viral adsorption and receptor interaction. (PubMed, J Virol) - "The identified epitope represents a promising target for next-generation epitope-based vaccines and entry-targeted antiviral therapeutics. In addition, HN1D4-4D9 may have potential applications in passive immunoprophylaxis, diagnostics, and studies of PPRV pathogenesis."

Journal • Infectious Disease • NECTIN4

A conserved mechanism for stabilization of viral innate immune antagonists via interaction with Elongin BC. (PubMed, Proc Natl Acad Sci U S A) - "NSP1 protein was significantly less stable in infected cells in the absence of Elongin B. Importantly, Elongin BC was required for the stability of additional BC box-containing viral antagonists, including pestiviral N proteases and human adenovirus E4orf6, indicating that Elongin BC functions not only as an adaptor for host protein degradation but also as a broadly exploited stabilizing factor for viral innate immune antagonists. This knowledge of virus co-opting of the host ubiquitin ligase machinery may instruct the development of broad-spectrum antiviral therapeutics."

Journal • Rotavirus Infections • Targeted Protein Degradation

Fe2O3-based nanozyme synergistic with oseltamivir for broad-spectrum inhibition of influenza A virus. (PubMed, Int Immunopharmacol) - "Influenza A virus infection is responsible for seasonal epidemics worldwide, which have a significant impact on public health and economic development. Significantly, γ-Fe2O3-OTV is a broad-spectrum inhibitor against different subtypes of influenza A viruses. This study presents a novel strategy for the application of nanomaterials in antiviral therapeutics."

Journal • Infectious Disease • Inflammation • Influenza • Respiratory Diseases

Molecular mechanism of Tembusu virus nonstructural protein 5 antagonising RNA interference. (PubMed, Vet Res) - "Furthermore, we found that NS5 not only interacts with DEAD-box helicase 3 X-linked (DDX3X), a key protein in the RNAi pathway, but also binds directly to double-stranded RNA (dsRNA). In summary, our findings indicated that TMUV NS5 can act as a VSR in vitro, thereby providing a theoretical foundation for the development of antiviral therapeutics."

Journal • DDX3X

SPCS2 serves as a critical host factor for JEV replication by regulating viral protein stability and virion assembly. (PubMed, Microbiol Spectr) - "Identification of NS2B-interacting host factors is essential for a detailed understanding of the viral life cycle, as well as for the development of antiviral therapeutics...We revealed that SPCS2 plays essential roles in maintaining the stability of the viral proteins prM, E, and NS1, and in the assembly of infectious JEV particles. This study enriches our understanding of the molecular details underlying host factor involvement in the JEV replication life cycle."

Journal

Porcine influenza mAbs to H3, H5, and H7 hemagglutinins recognize H3 egg adapted site and target the HA stem. (PubMed, Discov Immunol) - "Monoclonal antibodies (mAbs) are critical tools for elucidating viral evolution, informing vaccine design, and developing antiviral therapeutics...These findings demonstrate that pigs mount antibody responses closely resembling those observed in humans, including recognition of conserved stem epitopes and adaptive head mutations. Porcine mAbs represent powerful new tools for dissecting influenza immunity, guiding vaccine design, and enhancing pandemic preparedness using a physiologically relevant large-animal model."

Journal • Preclinical • Infectious Disease • Influenza • Respiratory Diseases

Establishment of a reverse genetics system for feline panleukopenia virus and feasibility study of a live vector vaccine. (PubMed, Virus Genes) - "Nevertheless, strategies such as optimizing insertion sites or modifying the viral backbone are required to enhance the stability of exogenous protein expression. This study lays the groundwork for the development of novel FPV-based genetically engineered vaccines and antiviral therapeutics."

Journal • Hematological Disorders

Crystallographic fragment screening discovers novel micromolar active inhibitors and druggable hotspots of SARS-CoV-2 PLpro. (PubMed, Int J Biol Macromol) - "The COVID-19 pandemic has highlighted the need to develop broad-spectrum antiviral therapeutics targeting rapidly evolving coronaviruses...Detailed structural analysis revealed these fragments engage key functional regions including the blocking loop 2 (BL2) and ubiquitin/ISG15 binding interface through extensive hydrogen-bond networks and hydrophobic interactions. Our study reveals novel micromolar active inhibitors and druggable sites of SARS-CoV-2 PLpro by crystallographic fragment screening, provides crucial scaffold and a structural roadmap for developing broad-spectrum antivirals against coronaviruses."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • Targeted Protein Degradation

Elements of Viral Outbreak Preparedness: Lessons, Strategies, and Future Directions. (PubMed, Viruses) - "Here, we explore the key components of viral outbreak preparedness, including surveillance systems, diagnostic capacity, prevention and control measures, non-pharmaceutical interventions, antiviral therapeutics, and research and development...These experiences highlight the importance of early detection, rapid response, and multisectoral collaboration in mitigating the impact of viral outbreaks. By applying best practices and lessons learned from recent events, global health systems can strengthen resilience and improve readiness for future viral threats."

Journal • Review • Infectious Disease • Novel Coronavirus Disease

Indirect ELISA for African swine fever virus serological detection and recombinant porcine reproductive and respiratory syndrome virus-based bivalent vaccine. (PubMed, Int J Biol Macromol) - "To date, no globally recognized, effective vaccines or antiviral therapeutics are available for African swine fever (ASF), making rapid and reliable serological diagnosis a critical component of disease control and prevention strategies...Furthermore, animal experiments demonstrated that rPRRSV-I215L elicited simultaneous antibody responses against both PRRSV N protein and ASFV pI215L in immunized pigs. These findings not only provide a reliable and sensitive serodiagnosis tool for ASFV surveillance but also identify promising live vector vaccine candidate for simultaneous immunoprophylaxis against ASFV and PRRS, offering new avenues for integrated disease control in swine populations."

Journal • Preclinical • Hematological Disorders • Respiratory Diseases

Structure-Based Development of Ultra-Broad-Spectrum 3C-Like Protease Inhibitors. (PubMed, Adv Sci (Weinh)) - "The highly conserved 3C-like protease (3CLpro) in coronaviruses, together with the well-established druggability, makes it an ideal target for broad-spectrum antiviral therapeutics. Here, the inhibitory activity of approved 3CLpro inhibitors, including nirmatrelvir, ensitrelvir, and simnotrelvir, against fifteen 3CLpros is first reported by enzymatic assays...Moreover, it effectively inhibits nirmatrelvir-resistant 3CLpro mutants and demonstrates broad-spectrum antiviral efficacy in cells. These findings suggest an important rule that a small, non-cyclic P2 segment and a P4 segment with a suitable size are preferred by the design of ultra-broad-spectrum 3CLpro inhibitors, and provide a proof-of-concept guide for developing broad-spectrum antivirals as potential pan-CoV therapeutics."

Journal • Infectious Disease • Novel Coronavirus Disease

Structure-guided discovery of a small molecule inhibitor of SARS-CoV-2 main protease with potent in vitro and in vivo antiviral activities. (PubMed, J Virol) - "H135 may serve as a new lead for developing antiviral therapeutics for SARS-CoV-2 infection.IMPORTANCEIn this study, a structure-guided hit-to-lead strategy was employed to develop a nanomolar potent small molecule inhibitor H135 of SARS-CoV-2 Mpro with strong anti-SARS-CoV-2 infection activity in cell cultures and animals. H135 may serve as a new lead for developing antiviral agents targeting the virus's main protease Mpro."

Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Structural insight into RNA encapsidation by the severe fever with thrombocytopenia syndrome virus nucleocapsid protein. (PubMed, mBio) - "This work provides structural insight into RNA encapsidation by SFTSV NP and offers a foundation for the rational design of antiviral therapeutics targeting this essential viral protein.IMPORTANCESevere fever with thrombocytopenia syndrome virus (SFTSV) is a highly pathogenic bunyavirus that causes severe hemorrhagic fever, leukopenia, thrombocytopenia, and multi-organ failure, with a case fatality rate of up to 30%...Structural comparisons and evolutionary conservation analysis of NPs across the family Phenuiviridae uncovered a conserved RNA-binding mode among phenuiviruses, suggesting a shared RNA encapsidation mechanism among related viruses. Our findings provide critical structural insights into SFTSV RNA encapsidation and will aid future efforts to develop antivirals against SFTSV and related pathogenic viruses."

Journal • Hematological Disorders • Leukopenia • Thrombocytopenia

Mechano-Locking Strategy for Broad-Spectrum SARS-CoV-2 Neutralization. (PubMed, Small) - "This stabilization mechanism offers a mutation-resistant approach to neutralization and introduces a new design paradigm for antiviral therapeutics. These findings establish a mechanistically driven framework for developing biomechanically enhanced strategies potentially applicable to a wide range of mechanically activated enveloped viruses."

Journal • Human Immunodeficiency Virus • Infectious Disease • Influenza • Novel Coronavirus Disease • Respiratory Diseases

Single amino acid substitution at position 614 in SARS-CoV-2 Spike Protein alters viral assembly and infectivity. (PubMed, Virus Res) - "However, co-immunoprecipitation analysis indicated that D614 mutations did not hinder the interaction between the S protein and the ACE2 receptor. These findings emphasize the significance of D614 or G614 in S protein expression and virus assembly, providing novel targets and perspectives for the progress of research on spike-based vaccines and antiviral therapeutics."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • ACE2

IncRNA IPAN antagonizes RIG-I/TRIM25-mediated degradation of influenza A virus PB1 to promote viral replication. (PubMed, Biosaf Health) - "Identification of key cellular lncRNAs and elucidation of their molecular mechanisms in IAV replication are expected to expand our understanding of virus-host interactions and develop antiviral therapeutics...These results collectively demonstrated that IAV hijacked host IPAN to protect PB1 from RIG-I/TRIM25-mediated antiviral degradation. Thus, our data reveal a mechanism of RIG-I and TRIM25 against IAV infection by degrading PB1 and highlight how IAV exploits host lncRNAs to evade immune surveillance."

Journal • Infectious Disease • Influenza • Respiratory Diseases

Development and validation of a LC-MS/MS method for the simultaneous determination of simnotrelvir and ritonavir in human serum and bronchoalveolar lavage fluid. (PubMed, BMC Chem) - "At present, it has been put into clinical use, while a simple, accurate and sensitive detection method is urgently needed for the quantification of simnotrelvir/ritonavir in human serum and bronchoalveolar lavage fluid (BALF) to ensure safe and efficacious antiviral therapeutics. The validation results demonstrated that this LC-MS/MS method was robust and reliable. Notably, we can use the urea dilution correction method to calculate the concentrations of simnotrelvir and ritonavir in epithelial lining fluid (ELF), which is of great significance for evaluating the effectiveness and safety of antiviral drug treatment."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Host factor Rab4b promotes the replication of influenza A virus. (PubMed, Biosaf Health) - "In summary, this work provided the first evidence to support the involvement of Rab4b in the IAV replication. Understanding the mechanisms underlying IAV and Rab4b interactions helps elucidate viral infection and pathogenesis and leads to the development of antiviral therapeutics."

Journal • Infectious Disease • Influenza • Respiratory Diseases