tetano
Editor, Senior Moderator
Science
. 2021 Jan 12;eabe6230.
doi: 10.1126/science.abe6230. Online ahead of print.
Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape
Paul-Albert Koenig[SUP] 1 2 [/SUP], Hrishikesh Das[SUP] #[/SUP][SUP] 3 [/SUP], Hejun Liu[SUP] #[/SUP][SUP] 4 [/SUP], Beate M K?mmerer[SUP] 5 6 [/SUP], Florian N Gohr[SUP] #[/SUP][SUP] 2 [/SUP], Lea-Marie Jenster[SUP] #[/SUP][SUP] 2 [/SUP], Lisa D J Schiffelers[SUP] #[/SUP][SUP] 2 [/SUP], Yonas M Tesfamariam[SUP] #[/SUP][SUP] 2 [/SUP], Miki Uchima[SUP] #[/SUP][SUP] 2 [/SUP], Jennifer D Wuerth[SUP] #[/SUP][SUP] 2 [/SUP], Karl Gatterdam[SUP] 7 [/SUP], Natalia Ruetalo[SUP] 8 [/SUP], Maria H Christensen[SUP] 2 [/SUP], Caroline I Fandrey[SUP] 2 [/SUP], Sabine Normann[SUP] 2 [/SUP], Jan M P T?dtmann[SUP] 9 [/SUP], Steffen Pritzl[SUP] 9 [/SUP], Leo Hanke[SUP] 10 [/SUP], Jannik Boos[SUP] 11 [/SUP], Meng Yuan[SUP] 4 [/SUP], Xueyong Zhu[SUP] 4 [/SUP], Jonathan L Schmid-Burgk[SUP] 12 [/SUP], Hiroki Kato[SUP] 13 [/SUP], Michael Schindler[SUP] 8 [/SUP], Ian A Wilson[SUP] 4 14 [/SUP], Matthias Geyer[SUP] 7 [/SUP], Kerstin U Ludwig[SUP] 11 [/SUP], B Martin H?llberg[SUP] 15 16 [/SUP], Nicholas C Wu[SUP] 17 18 19 [/SUP], Florian I Schmidt[SUP] 1 2 [/SUP]
Affiliations
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to spread with devastating consequences. For passive immunization efforts, nanobodies have size and cost advantages over conventional antibodies. Here, we generated four neutralizing nanobodies that target the receptor-binding domain of the SARS-CoV-2 spike protein. We defined two distinct binding epitopes using x-ray crystallography and cryo-electron microscopy. Based on the structures, we engineered multivalent nanobodies with more than 100-fold improved neutralizing activity than monovalent nanobodies. Biparatopic nanobody fusions suppressed the emergence of escape mutants. Several nanobody constructs neutralized through receptor-binding competition, while other monovalent and biparatopic nanobodies triggered aberrant activation of the spike fusion machinery. These premature conformational changes in the spike protein forestalled productive fusion, and rendered the virions non-infectious.
. 2021 Jan 12;eabe6230.
doi: 10.1126/science.abe6230. Online ahead of print.
Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape
Paul-Albert Koenig[SUP] 1 2 [/SUP], Hrishikesh Das[SUP] #[/SUP][SUP] 3 [/SUP], Hejun Liu[SUP] #[/SUP][SUP] 4 [/SUP], Beate M K?mmerer[SUP] 5 6 [/SUP], Florian N Gohr[SUP] #[/SUP][SUP] 2 [/SUP], Lea-Marie Jenster[SUP] #[/SUP][SUP] 2 [/SUP], Lisa D J Schiffelers[SUP] #[/SUP][SUP] 2 [/SUP], Yonas M Tesfamariam[SUP] #[/SUP][SUP] 2 [/SUP], Miki Uchima[SUP] #[/SUP][SUP] 2 [/SUP], Jennifer D Wuerth[SUP] #[/SUP][SUP] 2 [/SUP], Karl Gatterdam[SUP] 7 [/SUP], Natalia Ruetalo[SUP] 8 [/SUP], Maria H Christensen[SUP] 2 [/SUP], Caroline I Fandrey[SUP] 2 [/SUP], Sabine Normann[SUP] 2 [/SUP], Jan M P T?dtmann[SUP] 9 [/SUP], Steffen Pritzl[SUP] 9 [/SUP], Leo Hanke[SUP] 10 [/SUP], Jannik Boos[SUP] 11 [/SUP], Meng Yuan[SUP] 4 [/SUP], Xueyong Zhu[SUP] 4 [/SUP], Jonathan L Schmid-Burgk[SUP] 12 [/SUP], Hiroki Kato[SUP] 13 [/SUP], Michael Schindler[SUP] 8 [/SUP], Ian A Wilson[SUP] 4 14 [/SUP], Matthias Geyer[SUP] 7 [/SUP], Kerstin U Ludwig[SUP] 11 [/SUP], B Martin H?llberg[SUP] 15 16 [/SUP], Nicholas C Wu[SUP] 17 18 19 [/SUP], Florian I Schmidt[SUP] 1 2 [/SUP]
Affiliations
- PMID: 33436526
- DOI: 10.1126/science.abe6230
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to spread with devastating consequences. For passive immunization efforts, nanobodies have size and cost advantages over conventional antibodies. Here, we generated four neutralizing nanobodies that target the receptor-binding domain of the SARS-CoV-2 spike protein. We defined two distinct binding epitopes using x-ray crystallography and cryo-electron microscopy. Based on the structures, we engineered multivalent nanobodies with more than 100-fold improved neutralizing activity than monovalent nanobodies. Biparatopic nanobody fusions suppressed the emergence of escape mutants. Several nanobody constructs neutralized through receptor-binding competition, while other monovalent and biparatopic nanobodies triggered aberrant activation of the spike fusion machinery. These premature conformational changes in the spike protein forestalled productive fusion, and rendered the virions non-infectious.