Structures of Hepatitis B Virus Subviral Particles and Identification of Potential Druggable Pockets for the Discovery of Antiviral Agents.

Structural Overview of Herpesvirus Tegument Proteins

Structure-guided design of a CD81-binding mini-protein that blocks hepatitis C virus entry

Structure-based design of stable recombinant hepatitis C virus E1E2 heterodimers

Hepatitis C virus (HCV) affects 47 million people and causes 239,000 deaths annually, yet no vaccine is on the horizon. Generating a stable native-like mimic of the envelope complex E1E2, the only target for known neutralizing antibodies, is an important aim for HCV vaccine development. Starting from a recombinant E1E2 design that utilizes a leucine zipper for proper folding, we used an iterative structure-based design approach to engineer antigens with at least 100-fold stronger binding to conformational antibodies and increased thermal stability. These new E1E2 designs facilitate production of native-like E1E2 antigens based on strains from different HCV genotypes and enable the generation of a recombinant E1E2 antigen design that lacks the immunogenic leucine zipper. A cryo-EM structure of one of the stabilized E1E2 antigens in complex with neutralizing antibody AT1211 provides atomic-level insights into an atypical epitope on the E2 subunit. Finally, immunogenicity studies in rabbits with adjuvanted E1E2 proteins show that immunogen stabilization alone does do not enhance serum neutralization breadth, but that removing the leucine zipper does increase homologous serum neutralization. The hepatitis C virus E1E2 glycoprotein is the only target of neutralizing antibodies. Here, the authors used structure-based design to generate soluble antigens that resemble the viral E1E2 heterodimer.

Inhibitors of the Influenza Virus Polymerase Basic 2 (PB2): Recent Advances and Future Perspectives.

Influenza, an acute respiratory infectious disease caused by influenza viruses, poses a serious public health threat with high infectivity and virulence. Existing antivirals suffer from numerous limitations, such as the frequent emergence of drug resistance and inconvenient administration, highlighting the urgent need for the development of next-generation anti-influenza agents. As a core component of the RNA-dependent RNA polymerase (RdRp) complex, the PB2 subunit mediates cap binding in the cap-snatching process, a prerequisite for viral mRNA transcription. Owing to its indispensable biological roles, high sequence conservation, and distinct structural differences from host proteins, PB2 serves as an attractive therapeutic target for antiviral drug development. Recently, the approval of onradivir, the first-in-class PB2 inhibitor, has not only validated the scientific rationale and feasibility of drug discovery targeting the PB2 subunit but also underscored the considerable clinical potential of this novel class of agents. In this review, we systematically summarize the research advances in PB2 inhibitors and discuss the challenges and prospects for their broader clinical application, with the aim of providing new insights into the development of novel anti-influenza drugs.

Identification of potential inhibitors of dengue virus ns5 methyltransferase and polymerase domains through virtual screening and molecular dynamics studies

Molecular dynamics simulations showed that the S-adenosylmethionine (SAM)-binding site ligand formed a more stable complex with lower root-mean-square deviation (RMSD) and reduced flexibility, indicating a promising lead candidate for further optimization and experimental validation against dengue virus NS5.

The conserved bridging domain on HCV E1E2 glycoprotein complex is targeted by neutralizing antibodies from diverse lineages.

The bridging domain (BD) region on hepatitis C virus (HCV) E1E2 glycoprotein complex is a conserved, E1-dependent conformational site of vulnerability formed by E2 residues 646-704. Given its importance for rational vaccine design, here, we characterized the genetic, structural, functional, and epitope features of 25 BD-directed nAbs isolated from HCV-infected individuals or immunized macaques. These antibodies derive from diverse B cell lineages but frequently display recurrent CDRH3 motifs and recognize overlapping epitopes spanning antigenic regions AR4 and AR5, with variable engagement of the E2 back layer (BL) region. A crystal structure of the macaque nAb RM3-26 bound to E2 core domain reveals a BL-directed binding mode analogous to the human nAb hcab40. Importantly, BD-directed nAbs achieve broad neutralization with minimal somatic hypermutation at contact residues and act additively with neutralizing face-directed antibodies. Together, these findings underscore BD as a promising target for rational HCV vaccine design.