Back analysis of long-term stability of a 92 m span ancient quarrying cavern

Long-term stability of large-span caverns is a challenging issue for design and construction of underground rock engineering. The Heidong cavern group consisting of 21 caverns was constructed about 1400 years ago for quarrying in massive Cretaceous tuff. The cavern No. 5 of the Heidong cavern group is characterized by an unsupported span up to 92 m, with the overburden thickness of only 3–25 m. To analyze its long-term stability, a detailed investigation was conducted to obtain its geometry and rock mass characteristics, and to monitor surrounding rock displacements. Based on field survey and laboratory tests, numerical simulations were performed using the finite difference code FLAC3D. The analysis results revealed that for the long-term stability of the cavern No. 5, some major factors should be carefully considered, such as cavern excavation method in hard massive rocks, site investigation using trial pits, tools like short iron chisel and hammer for manual excavation, geometric dome roof, and waste rocks within abutment or on the floor. The highlights of the technologies obtained from this large-scale ancient underground project can provide reference for other similar project excavations in practice

Discovery of SARS-CoV-2 3CLPro Peptidomimetic Inhibitors through the Catalytic Dyad Histidine-Specific Protein–Ligand Interactions

As the etiological agent for the coronavirus disease 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenges the ongoing efforts of vaccine development and drug design. Due to the accumulating cases of breakthrough infections, there are urgent needs for broad-spectrum antiviral medicines. Here, we designed and examined five new tetrapeptidomimetic anti-SARS-CoV-2 inhibitors targeting the 3C-Like protease (3CLPro), which is highly conserved among coronaviruses and essential for viral replications. We significantly improved the efficacy of a ketoamide lead compound based on high-resolution co-crystal structures, all-atom simulations, and binding energy calculations. The inhibitors successfully engaged the catalytic dyad histidine residue (H41) of 3CLPro as designed, and they exhibited nanomolar inhibitory capacity as well as mitigated the viral loads of SARS-CoV-2 in cellular assays. As a widely applicable design principle, our results revealed that the potencies of 3CLPro-specific drug candidates were determined by the interplay between 3CLPro H41 residue and the peptidomimetic inhibitors

Discovery of 2′-α-C-Methyl-2′-β-C-fluorouridine Phosphoramidate Prodrugs as Inhibitors of Hepatitis C Virus

2′-α-C-Methyl-2′-β-C-fluorouridine and its phosphoramidate prodrugs were synthesized and evaluated for their inhibitory activity against HCV. The structure–activity relationship analysis of the phosphoramidate moiety found that <b>17m</b>, <b>17q</b>, and <b>17r</b> exhibit potent activities against HCV, with EC₅₀ values of 1.82 ± 0.19, 0.88 ± 0.12, and 2.24 ± 0.22 μM, respectively. The docking study revealed that the recognition of the 2′-β-F by Arg158, 3′-OH by N291, and the Watson–Crick pairing with the template allowed <b>23</b> to form the in-line conformation necessary for its incorporation into the viral RNA chain

Site-Specific Chemical Modification of Peptide and Protein by Thiazolidinediones

A direct aldol reaction employing 2,4-thiazolidinediones as nucleophilic donors was performed to modify peptides and protein under mild conditions. Various functional groups could be readily introduced into protein without conformation change

Cyanohydrin as an Anchoring Group for Potent and Selective Inhibitors of Enterovirus 71 3C Protease

Cyanohydrin derivatives as enterovirus 71 (EV71) 3C protease (3C^pro) inhibitors have been synthesized and assayed for their biochemical and antiviral activities. Compared with the reported inhibitors, cyanohydrins (<b>1</b><i><b>S</b></i>,<b>2</b><i><b>S</b></i>,<b>2</b>′<i><b>S</b></i>,<b>5</b><i><b>S</b></i>)-<b>16</b> and (<b>1</b><i><b>R</b></i>,<b>2</b><i><b>S</b></i>,<b>2</b>′<i><b>S</b></i>,<b>5</b><i><b>S</b></i>)-<b>16</b> exhibited significantly improved activity and attractive selectivity profiles against other proteases, which were a result of the specific interactions between the cyanohydrin moiety and the catalytic site of 3C^pro. Cyanohydrin as an anchoring group with high selectivity and excellent inhibitory activity represents a useful choice for cysteine protease inhibitors