2020年12月1日
Structure-based design and discovery of novel anti-tissue factor antibodies with cooperative double-point mutations, using interaction analysis
Scientific Reports
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- 巻
- 10
- 号
- 1
- 開始ページ
- 17590
- 終了ページ
- 17590
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1038/s41598-020-74545-4
- 出版者・発行元
- NATURE RESEARCH
The generation of a wide range of candidate antibodies is important for the successful development of drugs that simultaneously satisfy multiple requirements. To find cooperative mutations and increase the diversity of mutants, an in silico double-point mutation approach, in which 3D models of all possible double-point mutant/antigen complexes are constructed and evaluated using interaction analysis, was developed. Starting from an antibody with very high affinity, four double-point mutants were designed in silico. Two of the double-point mutants exhibited improved affinity or affinity comparable to that of the starting antibody. The successful identification of two active double-point mutants showed that a cooperative mutation could be found by utilizing information regarding the interactions. The individual single-point mutants of the two active double-point mutants showed decreased affinity or no expression. These results suggested that the two active double-point mutants cannot be obtained through the usual approach i.e. a combination of improved single-point mutants. In addition, a triple-point mutant, which combines the distantly located active double-point mutation and an active single-point mutation collaterally obtained in the process of the double-point mutation strategy, was designed. The triple-point mutant showed improved affinity. This finding suggested that the effects of distantly located mutations are independent and additive. The double-point mutation approach using the interaction analysis of 3D structures expands the design repertoire for mutants, and hopefully paves a way for the identification of cooperative multiple-point mutations.
- リンク情報
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- DOI
- https://doi.org/10.1038/s41598-020-74545-4
- PubMed
- https://www.ncbi.nlm.nih.gov/pubmed/33067496
- PubMed Central
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567794
- Web of Science
- https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000585845700034&DestApp=WOS_CPL
- Scopus
- https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85092657268&origin=inward 本文へのリンクあり
- Scopus Citedby
- https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=85092657268&origin=inward
- ID情報
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- DOI : 10.1038/s41598-020-74545-4
- ISSN : 2045-2322
- eISSN : 2045-2322
- PubMed ID : 33067496
- PubMed Central 記事ID : PMC7567794
- SCOPUS ID : 85092657268
- Web of Science ID : WOS:000585845700034