Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potent therapeutic antibody

Abstract

The COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in an unprecedented public health crisis. There are no approved vaccines or therapeutics for treating COVID-19. Here we reported a humanized monoclonal antibody, H014, efficiently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 at nM level by engaging the S receptor binding domain (RBD). Importantly, H014 administration reduced SARS-CoV-2 titers in the infected lungs and prevented pulmonary pathology in hACE2 mouse model. Cryo-EM characterization of the SARS-CoV-2 S trimer in complex with the H014 Fab fragment unveiled a novel conformational epitope, which is only accessible when the RBD is in open conformation. Biochemical, cellular, virological and structural studies demonstrated that H014 prevents attachment of SARS-CoV-2 to its host cell receptors. Epitope analysis of available neutralizing antibodies against SARS-CoV and SARS-CoV-2 uncover broad cross-protective epitopes. Our results highlight a key role for antibody-based therapeutic interventions in the treatment of COVID-19.

Structures of Echovirus 30 in complex with its receptors inform a rational prediction for enterovirus receptor usage

“…Generally, the standard verification of a bona fide viral receptor involves a number of assays, such as that expression of this receptor enables normally unsusceptible cell lines to support viral propagation; loss of expression of this receptor or its binding partner (e.g., antibodies) renders cells resistant to viral infection; soluble receptor could directly bind viral particles and neutralizes infection, but these assays are timeconsuming. By contrast, the recent 'resolution revolution' in cryo-EM has accelerated the process for determining high-resolution structures of a wide array of previously intractable biological systems [52][53][54][55][56][57][58] . In this study, we provided models for E30 in complex with its receptors CD55 and FcRn and systematically analyzed available human EVs-receptor interactions, which pinpointed key structure-receptor usage correlates.…”

Serotype specific epitopes identified by neutralizing antibodies underpin immunogenic differences in Enterovirus B

“…The host humoral immune response acts as a major defense against viral infections 9 . Vaccines prime these defenses by eliciting protective neutralizing antibodies (NAbs) 10 .…”

Small-MoleculeIn VitroInhibitors of the Coronavirus Spike – ACE2 Protein-Protein Interaction as Blockers of Viral Attachment and Entry for SARS-CoV-2

“…For both SARS-CoV and SARS-CoV-2, this involves binding to angiotensin converting enzyme 2 (ACE2) followed by proteolytic activation by human proteases (3,5,12,13). Hence, blockade of the RBD-hACE2 protein-protein interaction (PPI) can disrupt infection efficiency, and most vaccines and neutralizing antibodies (nAbs) aim to abrogate this interaction (14,15). CoV nAbs, including those identified so far for SARS-CoV-2, primarily target the trimeric S glycoproteins, and their majority recognizes epitopes within the RBD that binds the ACE2 receptor (15)(16)(17)(18)(19).…”

“…Hence, blockade of the RBD-hACE2 protein-protein interaction (PPI) can disrupt infection efficiency, and most vaccines and neutralizing antibodies (nAbs) aim to abrogate this interaction (14,15). CoV nAbs, including those identified so far for SARS-CoV-2, primarily target the trimeric S glycoproteins, and their majority recognizes epitopes within the RBD that binds the ACE2 receptor (15)(16)(17)(18)(19). It would be important to have broadly cross-reactive nAbs that can neutralize a wide range of viruses that share similar pathogenic outcomes (17).…”