EMD-11953
SARS-CoV-2 S 2P trimer in complex with monovalent DARPin R2 (State 1) - Composite Map
EMD-11953
Single-particle4.2 Å
Deposition: 18/11/2020Map released: 04/05/2022
Last modified: 17/08/2022
Sample Organism:
Severe acute respiratory syndrome-related coronavirus,
synthetic construct
Sample: SARS-CoV-2 S 2P trimer in complex with monovalent DARPin R2 (State 1)
Deposition Authors: Hurdiss DL
,
Drulyte I
Sample: SARS-CoV-2 S 2P trimer in complex with monovalent DARPin R2 (State 1)
Deposition Authors: Hurdiss DL
,
Drulyte I
The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants.
Rothenberger S ,
Hurdiss DL ,
Walser M,
Malvezzi F,
Mayor J,
Ryter S ,
Moreno H,
Liechti N ,
Bosshart A,
Iss C ,
Calabro V,
Cornelius A,
Hospodarsch T,
Neculcea A,
Looser T,
Schlegel A,
Fontaine S,
Villemagne D ,
Paladino M,
Schiegg D,
Mangold S,
Reichen C,
Radom F,
Kaufmann Y,
Schaible D,
Schlegel I,
Zitt C,
Sigrist G,
Straumann M,
Wolter J,
Comby M,
Sacarcelik F,
Drulyte I ,
Lyoo H ,
Wang C,
Li W ,
Du W,
Binz HK ,
Herrup R,
Lusvarghi S ,
Neerukonda SN,
Vassell R,
Wang W,
Adler JM ,
Eschke K,
Nascimento M ,
Abdelgawad A,
Gruber AD,
Bushe J ,
Kershaw O,
Knutson CG,
Balavenkatraman KK,
Ramanathan K,
Wyler E ,
Teixeira Alves LG,
Lewis S,
Watson R,
Haeuptle MA,
Zurcher A,
Dawson KM ,
Steiner D,
Weiss CD ,
Amstutz P,
van Kuppeveld FJM,
Stumpp MT ,
Bosch BJ ,
Engler O ,
Trimpert J
(2022) Nat Biotechnol
,
Hurdiss DL ,
Walser M,
Malvezzi F,
Mayor J,
Ryter S ,
Moreno H,
Liechti N ,
Bosshart A,
Iss C ,
Calabro V,
Cornelius A,
Hospodarsch T,
Neculcea A,
Looser T,
Schlegel A,
Fontaine S,
Villemagne D ,
Paladino M,
Schiegg D,
Mangold S,
Reichen C,
Radom F,
Kaufmann Y,
Schaible D,
Schlegel I,
Zitt C,
Sigrist G,
Straumann M,
Wolter J,
Comby M,
Sacarcelik F,
Drulyte I ,
Lyoo H ,
Wang C,
Li W ,
Du W,
Binz HK ,
Herrup R,
Lusvarghi S ,
Neerukonda SN,
Vassell R,
Wang W,
Adler JM ,
Eschke K,
Nascimento M ,
Abdelgawad A,
Gruber AD,
Bushe J ,
Kershaw O,
Knutson CG,
Balavenkatraman KK,
Ramanathan K,
Wyler E ,
Teixeira Alves LG,
Lewis S,
Watson R,
Haeuptle MA,
Zurcher A,
Dawson KM ,
Steiner D,
Weiss CD ,
Amstutz P,
van Kuppeveld FJM,
Stumpp MT ,
Bosch BJ ,
Engler O ,
Trimpert J
(2022) Nat Biotechnol
Abstract:
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with potential resistance to existing drugs emphasizes the need for new therapeutic modalities with broad variant activity. Here we show that ensovibep, a trispecific DARPin (designed ankyrin repeat protein) clinical candidate, can engage the three units of the spike protein trimer of SARS-CoV-2 and inhibit ACE2 binding with high potency, as revealed by cryo-electron microscopy analysis. The cooperative binding together with the complementarity of the three DARPin modules enable ensovibep to inhibit frequent SARS-CoV-2 variants, including Omicron sublineages BA.1 and BA.2. In Roborovski dwarf hamsters infected with SARS-CoV-2, ensovibep reduced fatality similarly to a standard-of-care monoclonal antibody (mAb) cocktail. When used as a single agent in viral passaging experiments in vitro, ensovibep reduced the emergence of escape mutations in a similar fashion to the same mAb cocktail. These results support further clinical evaluation of ensovibep as a broad variant alternative to existing targeted therapies for Coronavirus Disease 2019 (COVID-19).
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with potential resistance to existing drugs emphasizes the need for new therapeutic modalities with broad variant activity. Here we show that ensovibep, a trispecific DARPin (designed ankyrin repeat protein) clinical candidate, can engage the three units of the spike protein trimer of SARS-CoV-2 and inhibit ACE2 binding with high potency, as revealed by cryo-electron microscopy analysis. The cooperative binding together with the complementarity of the three DARPin modules enable ensovibep to inhibit frequent SARS-CoV-2 variants, including Omicron sublineages BA.1 and BA.2. In Roborovski dwarf hamsters infected with SARS-CoV-2, ensovibep reduced fatality similarly to a standard-of-care monoclonal antibody (mAb) cocktail. When used as a single agent in viral passaging experiments in vitro, ensovibep reduced the emergence of escape mutations in a similar fashion to the same mAb cocktail. These results support further clinical evaluation of ensovibep as a broad variant alternative to existing targeted therapies for Coronavirus Disease 2019 (COVID-19).