RESUMEN
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has become the dominant infective strain. We report the structures of the Omicron spike trimer on its own and in complex with angiotensin-converting enzyme 2 (ACE2) or an anti-Omicron antibody. Most Omicron mutations are located on the surface of the spike protein and change binding epitopes to many current antibodies. In the ACE2-binding site, compensating mutations strengthen receptor binding domain (RBD) binding to ACE2. Both the RBD and the apo form of the Omicron spike trimer are thermodynamically unstable. An unusual RBD-RBD interaction in the ACE2-spike complex supports the open conformation and further reinforces ACE2 binding to the spike trimer. A broad-spectrum therapeutic antibody, JMB2002, which has completed a phase 1 clinical trial, maintains neutralizing activity against Omicron. JMB2002 binds to RBD differently from other characterized antibodies and inhibits ACE2 binding.
Asunto(s)
Enzima Convertidora de Angiotensina 2/química , Anticuerpos Neutralizantes/química , Anticuerpos Antivirales/química , SARS-CoV-2/química , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/química , Enzima Convertidora de Angiotensina 2/metabolismo , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/metabolismo , Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/metabolismo , Sitios de Unión , Microscopía por Crioelectrón , Epítopos , Humanos , Fragmentos Fab de Inmunoglobulinas/química , Fragmentos Fab de Inmunoglobulinas/inmunología , Fragmentos Fab de Inmunoglobulinas/metabolismo , Modelos Moleculares , Mutación , Unión Proteica , Conformación Proteica , Dominios Proteicos , Dominios y Motivos de Interacción de Proteínas , Multimerización de Proteína , Subunidades de Proteína/química , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/metabolismo , TermodinámicaRESUMEN
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease-2019 (COVID-19), interacts with the host cell receptor angiotensin-converting enzyme 2 (hACE2) via its spike 1 protein during infection. After the virus sequence was published, we identified two potent antibodies against the SARS-CoV-2 receptor binding domain (RBD) from antibody libraries using a phage-to-yeast (PtY) display platform in only 10 days. Our lead antibody JMB2002, now in a Phase 1 clinical trial (ChiCTR2100042150), showed broad-spectrum in vitro blocking activity against hACE2 binding to the RBD of multiple SARS-CoV-2 variants, including B.1.351 that was reportedly much more resistant to neutralization by convalescent plasma, vaccine sera and some clinical-stage neutralizing antibodies. Furthermore, JMB2002 has demonstrated complete prophylactic and potent therapeutic efficacy in a rhesus macaque disease model. Prophylactic and therapeutic countermeasure intervention of SARS-CoV-2 using JMB2002 would likely slow down the transmission of currently emerged SARS-CoV-2 variants and result in more efficient control of the COVID-19 pandemic.