Moreira, F. R. | Search bioRxiv

bioRxiv2025

Human coronavirus HKU1 neutralization by glycan receptor mimicry

Entry of seasonal human coronavirus HKU1 (HCoV-HKU1) into host cells is facilitated by sequential binding to sialoglycans and transmembrane serine protease 2 (TMPRSS2) receptors. However, the neutralizing capacity of antibodies disrupting these receptor interactions have not been examined. Here, we describe the isolation and characterization of a human monoclonal antibody (mAb) HKU1-2 that recognizes the HCoV-HKU1 spike protein and exhibits dose-dependent neutralization of the virus. Epitope mapping and structural analysis revealed that HKU1-2 mAb targets the sialoglycan binding site in the N-terminal domain of the spike protein. A cryo-electron microscopy (cryo-EM) structure of the spike-Fab complex further demonstrated the ability of HKU1-2 to mimic sialic acid binding thereby effectively blocking sialoglycan receptor engagement. HKU1-2 binding is primarily mediated by CDRH3 recognition of NTD residues K80 and W89 that are known to be critical for sialic acid engagement. Overall, our results demonstrate antibody recognition and neutralization of HCoV-HKU1 by receptor mimicry.

immunology↗

bioRxiv2021

Therapeutic efficacy of an oral nucleoside analog of remdesivir against SARS-CoV-2 pathogenesis in mice.

The COVID-19 pandemic remains uncontrolled despite the rapid rollout of safe and effective SARS-CoV-2 vaccines, underscoring the need to develop highly effective antivirals. In the setting of waning immunity from infection and vaccination, breakthrough infections are becoming increasingly common and treatment options remain limited. Additionally, the emergence of SARS-CoV-2 variants of concern with their potential to escape therapeutic monoclonal antibodies emphasizes the need to develop second-generation oral antivirals targeting highly conserved viral proteins that can be rapidly deployed to outpatients. Here, we demonstrate the in vitro antiviral activity and in vivo therapeutic efficacy of GS-621763, an orally bioavailable prodrug of GS-441524, the parental nucleoside of remdesivir, which targets the highly conserved RNA-dependent RNA polymerase. GS-621763 exhibited significant antiviral activity in lung cell lines and two different human primary lung cell culture systems. The dose-proportional pharmacokinetic profile observed after oral administration of GS-621763 translated to dose-dependent antiviral activity in mice infected with SARS-CoV-2. Therapeutic GS-621763 significantly reduced viral load, lung pathology, and improved pulmonary function in COVID-19 mouse model. A direct comparison of GS-621763 with molnupiravir, an oral nucleoside analog antiviral currently in human clinical trial, proved both drugs to be similarly efficacious. These data demonstrate that therapy with oral prodrugs of remdesivir can significantly improve outcomes in SARS-CoV-2 infected mice. Thus, GS-621763 supports the exploration of GS-441524 oral prodrugs for the treatment of COVID-19 in humans.

microbiology↗