Influenza viruses are a major cause of respiratory illness, with significant public health impact due to their ability to cause pandemics. This dialogue brought together experts including Professors George Fu Gao, Stephen Cusack, Mark von Itzstein, Ervin Fodor, Jonathan Grimes, Aartjan J.W. te Velthuis, and Tao Deng to decode the pressing scientific challenges and future directions in influenza research. They discussed how structural studies of the influenza polymerase have advanced our understanding of viral RNA transcription and replication. These insights are crucial for developing new antiviral drugs, with a particular focus on targeting the polymerase and its interactions with host factors like acidic nuclear phosphoprotein 32 (ANP32). The dialogue also highlighted the potential of artificial intelligence (AI) to assist in designing small-molecule drugs, offering new strategies for combating influenza. Future research will continue to unravel the complexities of the polymerase’s role in replication, aiming to translate these findings into effective therapies and resilient public health strategies.

At the BIOHK2024, held on September 11–14, 2024, the roundtable discussion titled “Time is now: Preparing for the next pandemic,” brought together Professors Jun Liu, George Fu Gao, Kwok-Yung Yuen, Lit Man Leo Poon, and Nan Song. They explored the current state of global readiness for impending viral threats, focusing on the necessity for enhanced surveillance, improved diagnostic technologies, and the development of more efficient vaccines and drugs. The panel underscored the importance of a coordinated global response, the role of vaccination in mitigating pandemic impacts, and the challenges posed by emerging viruses and their variants. They also highlighted the potential of artificial intelligence in disease prediction and basic researches, and also the need for continuous investment in pandemic preparedness to address the gaps exposed by the coronavirus disease 2019 (COVID-19) pandemic. The discussion concluded on a note of cautious optimism, emphasizing the importance of learning from past experiences and the resilience demonstrated by many countries during the recent pandemic.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuously evolving since 2019. Some monoclonal antibodies (mAbs) have been developed and widely used, such as etesevimab (CB6) developed by Eli-Lilly/Junshi. However, the mAb escaped from the variant of concern (VOC) ever since the emergence of Beta VOC, with a complete loss of efficacy against the Omicron subvariants. Here, we developed a broad-spectrum and affinity-mature antibody design (BAADesign) procedure to design CB6, enabling it to bind to the receptor-binding domains (RBDs) of multiple important Omicron subvariants, including the recent variant KP.2. Structural analysis confirmed the desired CB6-RBD interactions. Additionally, identical mutations in the complementarity determining regions (CDR)1 and CDR2 of the CB6 mutants also restored neutralizing potency for some RBD-1 group antibodies. Overall, the enhanced CB6 neutralizing capacity makes it a promising candidate against SARS-CoV-2 infection, and the BAADesign method has implications for the design of other antibodies.

Leptin receptor (LepR) signaling plays an essential role in balancing food intake and energy expenditure. The architecture of LepR signaling assembly is critical for its function. In this study, we determined the structures of three distinct conformations of human leptin–LepR using cryo-electron microscopy at resolutions of 3.88, 3.77, and 3.58 Å. Both 2:2 and 3:3 stoichiometric assemblies were observed, and the complexes exhibited asymmetric open conformations. Leptin undergoes substantial rearrangement of its flexible regions to accommodate binding to LepR. The assembled leptin–LepR complexes connect through a “hand-in-hand” geometry. The open, interlocked 3:3 trimeric assembly results from the engagement of a third leptin–LepR heterodimer with a 2:2 dimer. The asymmetric geometry of LepR is substantially distinct from that of other gp130 cytokine homologs, and that may be due to the twisted and rigid interface between the D3 and D4 domains. These results highlight the distinct engagement of leptin with LepR and provide important insights into the structural plasticity of LepR-signaling assemblies.