Structural delineation and computational design of SARS-CoV-2-neutralizing antibodies against Omicron subvariants

• Published in: Nature communications Vol. 14; no. 1; pp. 4198 - 17
• Main Authors: Moriyama, Saya, Anraku, Yuki, Taminishi, Shunta, Adachi, Yu, Kuroda, Daisuke, Kita, Shunsuke, Higuchi, Yusuke, Kirita, Yuhei, Kotaki, Ryutaro, Tonouchi, Keisuke, Yumoto, Kohei, Suzuki, Tateki, Someya, Taiyou, Fukuhara, Hideo, Kuroda, Yudai, Yamamoto, Tsukasa, Onodera, Taishi, Fukushi, Shuetsu, Maeda, Ken, Nakamura-Uchiyama, Fukumi, Hashiguchi, Takao, Hoshino, Atsushi, Maenaka, Katsumi, Takahashi, Yoshimasa
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.07.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/31; 38; 38/39; 38/47; 38/77; 38/88; 49; 59; 631/250/2152/2153/1291; 631/250/255/2514; 631/61/24; 64; Amino acids; Antibodies; Antibodies, Neutralizing; Antibodies, Viral; Binding Sites; Broadly Neutralizing Antibodies; COVID-19; Footprints; Humanities and Social Sciences; Humans; Hydrophobicity; Monoclonal antibodies; multidisciplinary; Mutation; Neutralizing; Receptors; Resilience; SARS-CoV-2 - genetics; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - genetics; Tyrosine; Viral diseases; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-39890-8

SARS-CoV-2 Omicron subvariants have evolved to evade receptor-binding site (RBS) antibodies that exist in diverse individuals as public antibody clones. We rationally selected RBS antibodies resilient to mutations in emerging Omicron subvariants. Y489 was identified as a site of virus vulnerability and a common footprint of broadly neutralizing antibodies against the subvariants. Multiple Y489-binding antibodies were encoded by public clonotypes and additionally recognized F486, potentially accounting for the emergence of Omicron subvariants harboring the F486V mutation. However, a subclass of antibodies broadly neutralized BA.4/BA.5 variants via hydrophobic binding sites of rare clonotypes along with high mutation-resilience under escape mutation screening. A computationally designed antibody based on one of the Y489-binding antibodies, NIV-10/FD03, was able to bind XBB with any 486 mutation and neutralized XBB.1.5. The structural basis for the mutation-resilience of this Y489-binding antibody group may provide important insights into the design of therapeutics resistant to viral escape. In this study, the authors isolated SARS-CoV-2 receptor binding site monoclonal antibodies resistant to Omicron mutations. An amino acid in the receptor binding domain, tyrosine-489, is a virus-vulnerable site and a common footprint of broadly neutralizing antibodies.