ジャーナル: Commun Biol / 年: 2025 タイトル: Development of an ultrahigh affinity, trimeric ACE2 biologic as a universal SARS-CoV-2 antagonist. 著者: Juliet Gonzales / Tynan Young / Hyeran Choi / Miso Park / Yead Jewel / Chengcheng Fan / Rahul Purohit / Pamela J Bjorkman / John C Williams / 要旨: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19 pandemic, utilizes membrane-bound, angiotensin-converting enzyme II (ACE2) for internalization and infection. ...Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19 pandemic, utilizes membrane-bound, angiotensin-converting enzyme II (ACE2) for internalization and infection. We describe the development of a biologic that takes advantage of the proximity of the N-terminus of bound ACE2 to the three-fold symmetry axis of the spike protein to create an ultrapotent, trivalent ACE2 entry antagonist. Distinct disulfide bonds were added to enhance serum stability and a single point mutation was introduced to eliminate enzymatic activity. Through surface plasmon resonance, pseudovirus neutralization assays, and single-particle cryo-electron microscopy, we show this antagonist binds to and inhibits SARS-CoV-2 variants. We further show the antagonist binds to and inhibits a 2003 SARS-CoV-1 strain. Collectively, structural insight has allowed us to design a universal trivalent antagonist against all variants of SARS-CoV-2 tested, suggesting it will be active against the emergence of future mutants.
名称: Collagen alpha-1(XVIII) chain,Processed angiotensin-converting enzyme 2 タイプ: protein_or_peptide / ID: 1 詳細: residues 1442-1496 (Uniprot numbering) of collagen chain, followed by a linker and then residues 19-614 of ACE2 コピー数: 3 / 光学異性体: LEVO
ソフトウェア - 名称: cryoSPARC 詳細: Patch motion correction and Patch CTF applied after Import Movies and before Blob Picker タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION
source_name: PDB, initial_model_type: experimental model
詳細
Initial fitting done by superposition of three components of 6M0J (complex of ACE2 and RBD of SARS-CoV-2 spike protein) onto each of the three RBDs of 6VXX (full SARS-CoV-2 spike hexapro protein trimer)
精密化
空間: REAL / プロトコル: RIGID BODY FIT
得られたモデル
PDB-9bne: SARS-CoV-2 spike HexaPro protein in complex with T3A trimeric antagonist