Inhibition of HIV Entry by Targeting the Envelope Transmembrane Subunit gp41.
Inhibition of HIV Entry by Targeting the Envelope Transmembrane Subunit gp41.
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DOI：
10.2174/1570162x14999160224103908
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发表时间：
2016
影响因子：
1
通讯作者：
Jacobs A
中科院分区：
文献类型：
--
作者：
Yi HA;Fochtman BC;Rizzo RC;Jacobs A
HIV包膜蛋白的跨膜亚基gp41是抑制HIV进入的脆弱靶标。有一种融合抑制剂T20（商品名：Fuzeon，通用名：恩夫韦肽）可通过处方获得。然而，它有几个缺点，如耐药性的发展水平高，体内半衰期短，肾清除快，口服生物利用度低，它只被用作挽救治疗。因此，研究人员一直在研究各种不同的模式，试图克服这些局限性。对HIV gp41、抑制机制和抑制剂进行了全面的文献检索。收集了最新的结构信息，并综述了针对gp41的多种抑制策略。许多抑制剂的最新进展是基于肽的。还进行了几种创造性的修饰策略以提高肽的抑制功效并克服T20治疗的缺点。小分子化合物也是一个密集研究的领域。从针对蛋白质特定区域的虚拟筛选到天然产物，开发的种类繁多。最后，广泛中和抗体也是重要的研究领域。抗体的靶区域的不可接近性是一个挑战，然而，正在进行广泛的努力以开发更好的中和抗体。融合蛋白gp41作为抑制病毒和靶细胞之间膜融合的有希望的靶点已被广泛研究。同时，它是一个具有挑战性的目标，因为蛋白质的脆弱构象仅短暂暴露。然而，生物化学、生物物理学、结构学和免疫学研究的进展正在共同推动该领域更接近于对gp41结构和功能的理解，这将导致新药和疫苗的开发。
The transmembrane subunit of the HIV envelope protein, gp41 is a vulnerable target to inhibit HIV entry. There is one fusion inhibitor T20 (brand name: Fuzeon, generic name: enfuvirtide) available by prescription. However, it has several drawbacks such as a high level of development of drug resistance, a short-half life in vivo, rapid renal clearance, low oral bioavailability, and it is only used as a salvage therapy. Therefore, investigators have been studying a variety of different modalities to attempt to overcome these limitations. Comprehensive literature searches were performed on HIV gp41, inhibition mechanisms, and inhibitors. The latest structural information was collected, and multiple inhibition strategies targeting gp41 were reviewed. Many of the recent advances in inhibitors were peptide-based. Several creative modification strategies have also been performed to improve inhibitory efficacy of peptides and to overcome the drawbacks of T20 treatment. Small compounds have also been an area of intense research. There is a wide variety in development from those identified by virtual screens targeting specific regions of the protein to natural products. Finally, broadly neutralizing antibodies have also been important area of research. The inaccessible nature of the target regions for antibodies is a challenge, however, extensive efforts to develop better neutralizing antibodies are ongoing. The fusogenic protein, gp41 has been extensively studied as a promising target to inhibit membrane fusion between the virus and target cells. At the same time, it is a challenging target because the vulnerable conformations of the protein are exposed only transiently. However, advances in biochemical, biophysical, structural, and immunological studies are coming together to move the field closer to an understanding of gp41 structure and function that will lead to the development of novel drugs and vaccines.