Tăng cường độ gắn kết của kháng thể tương tác chéo chống lại virus sốt xuất huyết thông qua hỗ trợ bằng máy tính

Cell Biochemistry and Biophysics - Tập 81 - Trang 737-755 - 2023
Nisha Amarnath Jonniya1,2, Sayan Poddar1, Subhasmita Mahapatra1, Parimal Kar1
1Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, India
2Department of Pharmacology, University of California San Diego, La Jolla, USA

Tóm tắt

Virus sốt xuất huyết (DENV), bao gồm bốn loại Flavivirus khác nhau nhưng có liên hệ huyết thanh, gây ra bệnh virus mới nổi quan trọng nhất, với gần 400 triệu ca nhiễm mỗi năm. Hiện tại, chưa có liệu pháp được phê duyệt. Mặc dù nhiễm DENV tạo ra miễn dịch suốt đời chống lại cùng một huyết thanh, nhưng các kháng thể được sinh ra lại góp phần vào bệnh nặng trong các nhiễm trùng khác huyết thanh. Do đó, việc hiểu cơ chế trung hòa DENV bởi các kháng thể là rất quan trọng trong việc thiết kế vắc xin chống lại tất cả các loại huyết thanh. Nghiên cứu này báo cáo một phân tích so sánh cấu trúc và năng lượng của kháng thể đơn dòng (mAb) 4E11 trong phức hợp với miền mục tiêu III của protein vỏ cho tất cả bốn loại huyết thanh DENV. Chúng tôi sử dụng mô phỏng động học phân tử lặp lại mở rộng kết hợp với tính toán năng lượng tự do gắn kết. Hơn nữa, các đột biến điểm đơn và đôi được thiết kế thông qua đột biến định hướng tại chỗ bằng máy tính và quan sát rằng kháng thể được tái thiết kế thể hiện độ gắn kết cao và hoạt động trung hòa rộng đối với các loại huyết thanh. Kết quả của chúng tôi cho thấy độ gắn kết được cải thiện nhờ vào việc tăng thêm nội năng, điều này có thể được quy cho sự ổn định của các tương tác cầu muối và liên kết hydro tại giao diện kháng nguyên-kháng thể. Những phát hiện này cung cấp kết quả quý giá trong việc hiểu động lực cấu trúc và đóng góp năng lượng sẽ hữu ích cho việc thiết kế các kháng thể có độ gắn kết cao chống lại nhiễm virus sốt xuất huyết.

Từ khóa

#Đặc tính virus sốt xuất huyết #kháng thể đơn dòng #miễn dịch #năng lượng tự do gắn kết #mô phỏng động học phân tử

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