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Thiết kế peptide điều trị dựa trên defensin để giảm nhẹ bệnh đa dây thần kinh amyloid gia đình do TTR V30M gây ra
Tóm tắt
Trong nghiên cứu này, chúng tôi nhằm mục tiêu hình thành một ứng viên điều trị hiệu quả chống lại protein transthyretin (TTR) đột biến V30M để ngăn chặn việc gập gềnh bệnh lý của nó. Peptide kháng khuẩn Nicotiana alata Defensin 1 (NaD1) đã được chọn do xu hướng kết tập của nó, điều này có thể cạnh tranh với các vùng hấp dẫn kết tập của protein TTR bệnh lý. Dựa trên tiềm năng của NaD1 trong việc liên kết với TTR V30M, chúng tôi đề xuất các peptide tetras do NaD1 tạo ra: CKTE và SKIL như những ứng viên điều trị ban đầu. Dựa trên sự liên kết của chúng với protein TTR đột biến, peptide tetras CKTE cho thấy sự tương tác đáng kể và tiềm năng chữa trị so với peptide tetras SKIL. Các phân tích tiếp theo từ mô phỏng động học phân tử riêng biệt khẳng định hiệu quả của peptide tetras CKTE như một 'beta-sheet breaker' chống lại TTR V30M. Nhiều phân tích quỹ đạo sau mô phỏng gợi ý rằng peptide tetras CKTE thay đổi động lực cấu trúc của protein TTR V30M bệnh lý, do đó có khả năng làm suy yếu các beta-sheet của nó và ngăn chặn sự kết tập của nó. Mô phỏng phân tích chế độ bình thường khẳng định rằng hình dạng của TTR V30M được thay đổi khi tương tác với peptide CKTE. Hơn nữa, các phát hiện về nhiệt độ giả lập cho thấy rằng phức hợp CKTE-TTR V30M dễ bị biến tính giả lập hơn so với TTR V30M bệnh lý, củng cố tiềm năng của peptide CKTE trong việc làm thay đổi hình dạng bệnh lý của TTR V30M. Hơn nữa, phân tích sự thất bại vùng còn lại đã tăng cường xu hướng của peptide tetras CKTE trong việc định hướng lại cấu trúc của TTR V30M. Do đó, chúng tôi dự đoán rằng peptide tetras CKTE có thể là một ứng viên điều trị hứa hẹn trong việc giảm nhẹ các tác động có hại do amyloid của TTR V30M đối với chứng đa dây thần kinh amyloid gia đình (FAP).
Từ khóa
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