Association between time of onset and Omicron BA.2 RNA clearance time in children: a retrospective cohort study.

Background: The association between the time of onset [time from the date of detection of a positive real-time reverse-transcription polymerase chain reaction (RT-PCR) to the date of detection of a positive RT-PCR in the first child] and viral RNA clearance time (time from first positive RT-PCR to two consecutive negative RT-PCR) remains unclear. Our study aimed to evaluate their association. That can provide a reference for the number of nucleic acid tests. Methods: We conducted a retrospective analysis of children diagnosed with Omicron BA.2 infection at Fujian Medical University Affiliated First Quanzhou Hospital between March 14, 2022 (date the first child in the outbreak was found positive for RT-PCR) and April 9, 2022 (date the last child was found positive for RT-PCR). We used the electronic medical record to extract demographic data, symptoms, radiology and laboratory findings, treatments, and viral RNA clearance time. The 282 children were divided equally into 3 groups according to the time of onset. We calculated the factors affecting viral RNA clearance time by univariate and multivariate analysis. We used the generalized additive model to investigate the relationship between the time of onset and viral RNA clearance time. Results: 46.45% of children were female. Fever (62.06%) and cough (15.60%) were the dominant onset symptoms. We found no serious cases and all children were cured. The median time to viral RNA clearance was 14 days (IQR 12-17 days), with a range of 5 to 35 days. After adjustment for potential confounders, the viral RNA clearance time was reduced by 2.45 (95% CI: 0.85, 4.04) days in the 7-10 days group and by 4.62 (95% CI: 2.38, 6.14) days in > 10 days group compared to the ≤6 days group. There was a non-linear association between the time of onset and viral RNA clearance time. Conclusions: Time of onset was non-linearly associated with Omicron BA.2 RNA clearance time. During the first 10 days of the outbreak, viral RNA clearance time decreased with increasing onset date. After 10 days of the outbreak, viral RNA clearance time did not decrease with increasing onset date.

In Silico Discovery of Small Molecule Modulators Targeting the Achilles' Heel of SARS-CoV-2 Spike Protein.

The spike protein of SARS-CoV-2 has been a promising target for developing vaccines and therapeutics due to its crucial role in the viral entry process. Previously reported cryogenic electron microscopy (cryo-EM) structures have revealed that free fatty acids (FFA) bind with SARS-CoV-2 spike protein, stabilizing its closed conformation and reducing its interaction with the host cell target in vitro. Inspired by these, we utilized a structure-based virtual screening approach against the conserved FFA-binding pocket to identify small molecule modulators of SARS-CoV-2 spike protein, which helped us identify six hits with micromolar binding affinities. Further evaluation of their commercially available and synthesized analogs enabled us to discover a series of compounds with better binding affinities and solubilities. Notably, our identified compounds exhibited similar binding affinities against the spike proteins of the prototypic SARS-CoV-2 and a currently circulating Omicron BA.4 variant. Furthermore, the cryo-EM structure of the compound SPC-14 bound spike revealed that SPC-14 could shift the conformational equilibrium of the spike protein toward the closed conformation, which is human ACE2 (hACE2) inaccessible. Our identified small molecule modulators targeting the conserved FFA-binding pocket could serve as the starting point for the future development of broad-spectrum COVID-19 intervention treatments.

In Silico Discovery of Small Molecule Modulators Targeting the Achilles' Heel of SARS-CoV-2 Spike Protein

The spike protein of SARS-CoV-2 has been a promising target for developing vaccines and therapeutics due to its crucial role in the viral entry process. Previously reported cryogenic electron microscopy (cryo-EM) structures have revealed that free fatty acids (FFA) bind with SARS-CoV-2 spike protein, stabilizing its closed conformation and reducing its interaction with the host cell target in vitro. Inspired by these, we utilized a structure-based virtual screening approach against the conserved FFA-binding pocket to identify small molecule modulators of SARS-CoV-2 spike protein, which helped us identify six hits with micromolar binding affinities. Further evaluation of their commercially available and synthesized analogs enabled us to discover a series of compounds with better binding affinities and solubilities. Notably, our identified compounds exhibited similar binding affinities against the spike proteins of the prototypic SARS-CoV-2 and a currently circulating Omicron BA.4 variant. Furthermore, the cryo-EM structure of the compound SPC-14 bound spike revealed that SPC-14 could shift the conformational equilibrium of the spike protein toward the closed conformation, which is human ACE2 (hACE2) inaccessible. Our identified small molecule modulators targeting the conserved FFA-binding pocket could serve as the starting point for the future development of broad-spectrum COVID-19 intervention treatments. Computationally identified compound SPC-14 stabilizes the ACE2-inaccessible closed conformation of the SARS-CoV-2 spike protein by targeting a less mutation-prone free fatty acids-binding pocket.