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A novel coronavirus [severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2)] outbreak has caused a global coronavirus disease 2019 (COVID-19) pandemic, resulting in tens of thousands of infections and thousands of deaths worldwide. The RNA-dependent RNA polymerase [(RdRp), also named nsp12] is the central component of coronaviral replication and transcription machinery, and it appears to be a primary target for the antiviral drug remdesivir. We report the cryo–electron microscopy structure of COVID-19 virus full-length nsp12 in complex with cofactors nsp7 and nsp8 at 2.9-angstrom resolution. In addition to the conserved architecture of the polymerase core of the viral polymerase family, nsp12 possesses a newly identified β-hairpin domain at its N terminus. A comparative analysis model shows how remdesivir binds to this polymerase. The structure provides a basis for the design of new antiviral therapeutics that target viral RdRp.

Non-structural proteins (nsp) constitute the SARS-CoV-2 replication and transcription complex (RTC) to play a pivotal role in the virus life cycle. Here we determine the atomic structure of a SARS-CoV-2 mini RTC, assembled by viral RNA-dependent RNA polymerase (RdRp, nsp12) with a template-primer RNA, nsp7 and nsp8, and two helicase molecules (nsp13-1 and nsp13-2), by cryo-electron microscopy. Two groups of mini RTCs with different conformations of nsp13-1 are identified. In both of them, nsp13-1 stabilizes overall architecture of the mini RTC by contacting with nsp13-2, which anchors the 5′-extension of RNA template, as well as interacting with nsp7-nsp8-nsp12-RNA. Orientation shifts of nsp13-1 results in its variable interactions with other components in two forms of mini RTC. The mutations on nsp13-1:nsp12 and nsp13-1:nsp13-2 interfaces prohibit the enhancement of helicase activity achieved by mini RTCs. These results provide an insight into how helicase couples with polymerase to facilitate its function in virus replication and transcription. SARS-CoV-2 virus replication and transcription is mediated by the replication and transcription complex (RTC) that is composed of 16 non-structural proteins (nsp). Here, the authors present the cryo-EM structure of a SARS-CoV-2 mini RTC consisting of the viral RNA-dependent RNA polymerase with a template-primer RNA, the RdRp cofactors nsp7 and nsp8 and two nsp13 helicase molecules, and they propose a model for helicase-polymerase coupling during SARS-CoV-2 RTC assembly.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting Mpro. Both exhibited excellent inhibitory activity and potent anti–SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a or 11b, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of Mpro. Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.

The antineoplastic drug carmofur is shown to inhibit the SARS-CoV-2 main protease (Mpro). Here, the X-ray crystal structure of Mpro in complex with carmofur reveals that the carbonyl reactive group of carmofur is covalently bound to catalytic Cys145, whereas its fatty acid tail occupies the hydrophobic S2 subsite. Carmofur inhibits viral replication in cells (EC50 = 24.30 μM) and is a promising lead compound to develop new antiviral treatment for COVID-19.A crystal structure of SARS-CoV-2 with inhibitor carmofur reveals the mechanism of action of this compound and opens the way to develop more potent drugs.

Nirmatrelvir is a specific antiviral drug that targets the main protease (M pro ) of SARS-CoV-2 and has been approved to treat COVID-19 1 , 2 . As an RNA virus characterized by high mutation rates, whether SARS-CoV-2 will develop resistance to nirmatrelvir is a question of concern. Our previous studies have shown that several mutational pathways confer resistance to nirmatrelvir, but some result in a loss of viral replicative fitness, which is then compensated for by additional alterations 3 . The molecular mechanisms for this observed resistance are unknown. Here we combined biochemical and structural methods to demonstrate that alterations at the substrate-binding pocket of M pro can allow SARS-CoV-2 to develop resistance to nirmatrelvir in two distinct ways. Comprehensive studies of the structures of 14 M pro mutants in complex with drugs or substrate revealed that alterations at the S1 and S4 subsites substantially decreased the level of inhibitor binding, whereas alterations at the S2 and S4′ subsites unexpectedly increased protease activity. Both mechanisms contributed to nirmatrelvir resistance, with the latter compensating for the loss in enzymatic activity of the former, which in turn accounted for the restoration of viral replicative fitness, as observed previously 3 . Such a profile was also observed for ensitrelvir, another clinically relevant M pro inhibitor. These results shed light on the mechanisms by which SARS-CoV-2 evolves to develop resistance to the current generation of protease inhibitors and provide the basis for the design of next-generation M pro inhibitors. A biochemical and structural analysis demonstrates that alterations at the substrate-binding pocket of the main protease of SARS-CoV-2 can allow the virus to develop resistance to nirmatrelvir in two distinct ways.

Since 2019, SARS-CoV-2 has evolved rapidly and gained resistance to multiple therapeutics targeting the virus. Development of host-directed antivirals offers broad-spectrum intervention against different variants of concern. Host proteases, TMPRSS2 and CTSL/CTSB cleave the SARS-CoV-2 spike to play a crucial role in the two alternative pathways of viral entry and are characterized as promising pharmacological targets. Here, we identify compounds that show potent inhibition of these proteases and determine their complex structures with their respective targets. Furthermore, we show that applying inhibitors simultaneously that block both entry pathways has a synergistic antiviral effect. Notably, we devise a bispecific compound, 212-148 , exhibiting the dual-inhibition ability of both TMPRSS2 and CTSL/CTSB, and demonstrate antiviral activity against various SARS-CoV-2 variants with different viral entry profiles. Our findings offer an alternative approach for the discovery of SARS-CoV-2 antivirals, as well as application for broad-spectrum treatment of viral pathogenic infections with similar entry pathways. TMPRSS2 and CTSL/CTSB, host proteases that facilitate SARS-CoV-2 entry, are promising drug targets. Here the authors simultaneously inhibit these host proteases and see synergistic antiviral effects, offering a broad-spectrum intervention against SARS-CoV-2 variants.

To address the challenges of insufficient small target recognition, difficulty in edge information extraction, and high computational overhead in insulator defect detection, this paper proposes a lightweight detection method based on the YOLO-MLSL model for transmission line insulator defect detection. First, a C2f-LRFCA module is introduced, effectively enhancing feature interaction through a long-range convolutional attention mechanism, thereby improving the perception of fine-grained defects. Second, an MEUM multi-scale feature enhancement module is designed to achieve more efficient contextual information fusion during upsampling, improving the detection performance for multi-scale targets. Third, the ShapeIoU loss function is employed to improve the bounding box regression accuracy in complex backgrounds, and LAMP pruning technology significantly reduces the model’s computational and storage overhead. Experimental results show that the improved algorithm achieves an mAP@0.5 of 85.4%, a 4.1% improvement compared to the original YOLOv8n, while maintaining a low parameter count and computational complexity, demonstrating both high accuracy and efficiency. This research provides a valuable reference for the design and application of lightweight target detection models in the intelligent inspection of power equipment.

The rigid-flexible coupling cable system under large deformation is studied, and the beam element from absolute node coordinate formulation is used to establish flexible cable body of the system. Different numerical integral algorithms are discussed for solving the rigid-flexible cable system and an integration strategy which combines Implicit Euler with Minimum Residual Method (MINRES) is proposed. The influence of the position and number of rigid components and different the lengths of the flexible elements on the system dynamics are analyzed. With constant total mass of the system, higher number of rigid components and their uniform distribution contribute to stabilization of the swing of the flexible cable body. When the total length of the cable is constant, increasing the number of beam elements enhances the nonlinear characteristics of the swing motion and damages the stability. The influence of different factors on the movement of large deformation flexible cable body is obtained through modeling and simulation of the rigid-flexible coupling cable system.

HCoV-HKU1, one of seven human coronaviruses (HCoVs) that have harmful effects on human health, accounts for a substantial portion of common cold cases and can cause severe respiratory diseases in certain populations. Currently, effective antiviral treatments against this virus are limited. Recently, TMPRSS2, a host protease long acknowledged for its role in priming the spike proteins of various CoVs and promoting viral entry, was identified as a functional receptor for HCoV-HKU1, opening an avenue for anti-HCoV-HKU1 therapy development. In this study, we elucidate the detailed molecular mechanism underlying the interaction between the HCoV-HKU1 receptor-binding domain (RBD) and TMPRSS2 via crystallography. Guided by these structural insights, we successfully develop two types of therapeutic antibodies against HCoV-HKU1. The first type neutralizes the RBD, potently disrupting its interaction with TMPRSS2 and preventing viral infection. The second type targets TMPRSS2, inhibiting its enzymatic activity and/or interfering with its binding to the RBD. The latter demonstrates broad-spectrum anti-CoV activity, as the enzymatic activity of TMPRSS2 is crucial for both HCoV-HKU1 infection and other CoV infections. Our findings provide crucial structural insights into the recognition of TMPRSS2 by HCoV-HKU1 and offer promising antibody-based strategies for combating HCoV-HKU1 and other CoV infections. This study investigates the HCoV-HKU1 RBD-TMPRSS2 interaction, identifying two antibody types: one that blocks RBD-TMPRSS2 binding, while the other inhibits TMPRSS2, showing broad anti-coronavirus potential.

Cytoplasmic incompatibility (CI) results when Wolbachia bacteria-infected male insects mate with uninfected females, leading to embryonic lethality. “Rescue” of viability occurs if the female harbors the same Wolbachia strain. CI is caused by linked pairs of Wolbachia genes called CI factors (CifA and CifB). The co-evolution of CifA-CifB pairs may account in part for the incompatibility patterns documented in insects infected with different Wolbachia strains, but the molecular mechanisms remain elusive. Here, we use X-ray crystallography and AlphaFold to analyze the CI factors from Wolbachia strain w Mel called CidA w Mel and CidB w Mel . Substituting CidA w Mel interface residues with those from CidA w Pip (from strain w Pip) enables the mutant protein to bind CidB w Pip and rescue CidB w Pip -induced yeast growth defects, supporting the importance of CifA-CifB interaction in CI rescue. Sequence divergence in CidA w Pip and CidB w Pip proteins affects their pairwise interactions, which may help explain the complex incompatibility patterns of mosquitoes infected with different w Pip strains. Wolbachia induced cytoplasmic incompatibility (CI) is caused by linked pairs of genes named cifA and cifB . Here, authors show that the residues at interfaces of the CidA-CidB complex is crucial for their binding and contribute to the diversity of CI.