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Structure paper

タイトル	De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2.
ジャーナル・号・ページ	Science, Vol. 370, Issue 6521, Page 1208-1214, Year 2020
掲載日	2020年12月4日
著者	Thomas W Linsky / Renan Vergara / Nuria Codina / Jorgen W Nelson / Matthew J Walker / Wen Su / Christopher O Barnes / Tien-Ying Hsiang / Katharina Esser-Nobis / Kevin Yu / Z Beau Reneer / Yixuan J Hou / Tanu Priya / Masaya Mitsumoto / Avery Pong / Uland Y Lau / Marsha L Mason / Jerry Chen / Alex Chen / Tania Berrocal / Hong Peng / Nicole S Clairmont / Javier Castellanos / Yu-Ru Lin / Anna Josephson-Day / Ralph S Baric / Deborah H Fuller / Carl D Walkey / Ted M Ross / Ryan Swanson / Pamela J Bjorkman / Michael Gale / Luis M Blancas-Mejia / Hui-Ling Yen / Daniel-Adriano Silva /
PubMed 要旨	We developed a de novo protein design strategy to swiftly engineer decoys for neutralizing pathogens that exploit extracellular host proteins to infect the cell. Our pipeline allowed the design, ...We developed a de novo protein design strategy to swiftly engineer decoys for neutralizing pathogens that exploit extracellular host proteins to infect the cell. Our pipeline allowed the design, validation, and optimization of de novo human angiotensin-converting enzyme 2 (hACE2) decoys to neutralize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The best monovalent decoy, CTC-445.2, bound with low nanomolar affinity and high specificity to the receptor-binding domain (RBD) of the spike protein. Cryo-electron microscopy (cryo-EM) showed that the design is accurate and can simultaneously bind to all three RBDs of a single spike protein. Because the decoy replicates the spike protein target interface in hACE2, it is intrinsically resilient to viral mutational escape. A bivalent decoy, CTC-445.2d, showed ~10-fold improvement in binding. CTC-445.2d potently neutralized SARS-CoV-2 infection of cells in vitro, and a single intranasal prophylactic dose of decoy protected Syrian hamsters from a subsequent lethal SARS-CoV-2 challenge.
リンク	Science / PubMed:33154107 / PubMed Central
手法	EM (単粒子)
解像度	3.9 - 4.2 Å
構造データ	EMDB-22913: Structure of the SARS-CoV-2 S 6P trimer in complex with the ACE2 protein decoy, CTC-445.2 (State 1) 手法: EM (単粒子) / 解像度: 3.9 Å EMDB-22914: Structure of the SARS-CoV-2 S 6P trimer in complex with the ACE2 protein decoy, CTC-445.2 (State 2) 手法: EM (単粒子) / 解像度: 3.9 Å EMDB-22915: Structure of the SARS-CoV-2 S 6P trimer in complex with the ACE2 protein decoy, CTC-445.2 (State 4) 手法: EM (単粒子) / 解像度: 4.2 Å 22916 7kl9 EMDB-22916, PDB-7kl9: Structure of the SARS-CoV-2 S 6P trimer in complex with the ACE2 protein decoy, CTC-445.2 (State 4) 手法: EM (単粒子) / 解像度: 4.1 Å
化合物	ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose / N-アセチル-β-D-グルコサミン / N-アセチルグルコサミン
由来	severe acute respiratory syndrome coronavirus 2 (SARSコロナウイルス2) homo sapiens (ヒト)
キーワード	ANTIVIRAL PROTEIN / SARS-CoV-2 (SARSコロナウイルス2) / ACE2 decoy / mini-protein / inhibitor (酵素阻害剤) / COVID-19 (新型コロナウイルス感染症 (2019年))