Tác động của protease HIV-1 lên các chức năng tế bào và ứng dụng tiềm năng của nó trong liệu pháp kháng retrovirus

Springer Science and Business Media LLC - Tập 2 - Trang 1-8 - 2012
Hailiu Yang1, Joseph Nkeze2, Richard Y Zhao2,3,4
1University of Maryland School of Medicine, Baltimore, USA
2Department of Pathology, University of Maryland, School of Medicine, Baltimore, USA.
3Department of Microbiology-Immunology, University of Maryland School of Medicine, Baltimore, USA
4Institute of Human Virology, University of Maryland School of Medicine, Baltimore, USA

Tóm tắt

Inhibitor protease của virus HIV-1 (HIV-1 PIs) là nhóm thuốc mạnh nhất trong các liệu pháp kháng retrovirus. Tuy nhiên, sự kháng thuốc của virus đối với các PI có thể xuất hiện nhanh chóng, dẫn đến giảm hiệu quả của những thuốc này. Đáng chú ý, tất cả các PI đã được FDA phê duyệt hiện tại đều là các chất ức chế cạnh tranh, tức là các chất ức chế cạnh tranh với các chất nền cho vị trí enzym hoạt động. Phương pháp ức chế chung này làm tăng khả năng phát triển các chủng HIV-1 kháng thuốc mà kháng lại nhiều hoặc tất cả các PI hiện có. Do đó, cần phải tìm kiếm các PI mới mà không dựa trên mục tiêu hiện tại của vị trí enzym hoạt động. Cụ thể, cần tìm kiếm các chất ức chế allosteric, là những chất ức chế ngăn cản hoạt động enzym của PR thông qua việc gắn kết không cạnh tranh với PR. Một đặc điểm chung khác của các PI hiện tại là tất cả chúng đều được phát triển dựa trên thiết kế dựa trên cấu trúc. Những thuốc được phát triển từ chiến lược dựa trên cấu trúc có thể tạo ra các chất ức chế cụ thể và mạnh mẽ. Tuy nhiên, loại thiết kế thuốc này chỉ có thể nhắm mục tiêu vào một vị trí tại một thời điểm và những thuốc được phát hiện bằng phương pháp này thường liên quan đến các tác dụng phụ mạnh mẽ, chẳng hạn như độc tính tế bào, hạn chế số lượng lựa chọn mục tiêu, hiệu quả và tính ứng dụng. Ngược lại, một hệ thống dựa trên tế bào có thể cung cấp một chiến lược thay thế hữu ích để vượt qua nhiều khuyết điểm thừa kế liên quan đến thiết kế thuốc dựa trên cấu trúc. Ví dụ, có thể tìm kiếm các PI allosteric bằng cách sử dụng hệ thống dựa trên tế bào mà không cần xem xét vị trí hoặc cơ chế ức chế. Ngoài ra, một hệ thống dựa trên tế bào có thể loại bỏ những PI có tác dụng độc tế bào mạnh. Quan trọng nhất, một hệ thống tế bào eukaryotic đơn giản, tiết kiệm và dễ duy trì như nấm men sẽ cho phép chúng tôi tìm kiếm các PI tiềm năng trong một hệ thống sàng lọc cao thông lượng quy mô lớn (HTS), do đó tăng cơ hội thành công. Dựa trên nhiều năm kinh nghiệm của chúng tôi trong việc sử dụng nấm men phân cắt như một hệ thống mô hình để nghiên cứu HIV-1 Vpr, chúng tôi đề xuất việc sử dụng nấm men phân cắt như một hệ thống thay thế khả thi để nghiên cứu tác động của protease HIV-1 lên các chức năng tế bào và khám phá khả năng ứng dụng của nó như một hệ thống HTS để tìm kiếm các PI mới nhằm chiến đấu với các chủng HIV-1 kháng thuốc.

Từ khóa


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