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TitleThe trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants.
Journal, issue, pagesNat Biotechnol, Vol. 40, Issue 12, Page 1845-1854, Year 2022
Publish dateJul 21, 2022
AuthorsSylvia Rothenberger / Daniel L Hurdiss / Marcel Walser / Francesca Malvezzi / Jennifer Mayor / Sarah Ryter / Hector Moreno / Nicole Liechti / Andreas Bosshart / Chloé Iss / Valérie Calabro / Andreas Cornelius / Tanja Hospodarsch / Alexandra Neculcea / Thamar Looser / Anja Schlegel / Simon Fontaine / Denis Villemagne / Maria Paladino / Dieter Schiegg / Susanne Mangold / Christian Reichen / Filip Radom / Yvonne Kaufmann / Doris Schaible / Iris Schlegel / Christof Zitt / Gabriel Sigrist / Marcel Straumann / Julia Wolter / Marco Comby / Feyza Sacarcelik / Ieva Drulyte / Heyrhyoung Lyoo / Chunyan Wang / Wentao Li / Wenjuan Du / H Kaspar Binz / Rachel Herrup / Sabrina Lusvarghi / Sabari Nath Neerukonda / Russell Vassell / Wei Wang / Julia M Adler / Kathrin Eschke / Mariana Nascimento / Azza Abdelgawad / Achim D Gruber / Judith Bushe / Olivia Kershaw / Charles G Knutson / Kamal K Balavenkatraman / Krishnan Ramanathan / Emanuel Wyler / Luiz Gustavo Teixeira Alves / Seth Lewis / Randall Watson / Micha A Haeuptle / Alexander Zürcher / Keith M Dawson / Daniel Steiner / Carol D Weiss / Patrick Amstutz / Frank J M van Kuppeveld / Michael T Stumpp / Berend-Jan Bosch / Olivier Engler / Jakob Trimpert /
PubMed AbstractThe 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 ...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).
External linksNat Biotechnol / PubMed:35864170 / PubMed Central
MethodsEM (single particle)
Resolution4.2 - 9.6 Å
Structure data

EMDB-11953: SARS-CoV-2 S 2P trimer in complex with monovalent DARPin R2 (State 1) - Composite Map
Method: EM (single particle) / Resolution: 4.2 Å

EMDB-11954: SARS-CoV-2 S 2P trimer in complex with monovalent DARPin R2 (State 2)
Method: EM (single particle) / Resolution: 9.6 Å

EMDB-14810: SARS-CoV-2 S 2P trimer in complex with monovalent DARPin R2 (State 1) - Consensus Map
Method: EM (single particle) / Resolution: 4.2 Å

EMDB-14811: SARS-CoV-2 S 2P trimer in complex with monovalent DARPin R2 (State 1) - Focused Refinement
Method: EM (single particle) / Resolution: 6.1 Å

Source
  • Severe acute respiratory syndrome-related coronavirus
  • synthetic construct (others)
  • Severe acute respiratory syndrome coronavirus 2

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