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发表于 2024-7-18 15:50:40
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目标#23：埃博拉GP1 | Target # 23: Ebola GP1
发表于11 Jul 2024, 9:02:55 UTC
Dear participants,
亲爱的参与者，
as target # 22 is almost finished, we are glad to introduce the next target. Most of you have voted for Ebolavirus glycoprotein (GP) (174 out of 425 votes, wow!)
由于目标 # 22 即将完成，我们很高兴介绍下一个目标。你们中的大多数人都投票给了埃博拉病毒糖蛋白 (GP)（425 票中的 174 票，哇！ ）
The Ebola virus is a highly virulent pathogen responsible for causing Ebola hemorrhagic fever, a severe and often fatal disease. A key factor in the virus's ability to infect host cells and cause disease is its surface glycoprotein (GP), making it an attractive target for antiviral drug development. The Ebola GP is a trimeric protein composed of two subunits per monomer: GP1, responsible for receptor binding, and GP2, which mediates fusion between the viral and host cell membranes. Initially synthesized as a precursor protein, the GP is cleaved by host proteases (furin, cathepsin) into its functional subunits, a process essential for its role in mediating viral entry. The GP facilitates the virus's attachment to the host cell surface, followed by conformational changes that enable membrane fusion, allowing the virus to enter the host cell (to the host endosomal Niemann-Pick C1 (NPC1) receptor or via direct membrane binding; Vaknin et al.; ACS Infect. Dis. 2024, 10, 5, 1590–1601).
埃博拉病毒是一种高度致命的病原体，可引起埃博拉出血热，这是一种严重且往往致命的疾病。病毒能感染宿主细胞并引起疾病的一个关键因素是其表面糖蛋白 (glycoprotein, GP)，使其成为抗病毒药物开发的有吸引力的目标。埃博拉 GP 是一种三聚体蛋白，每个单体由两个亚基组成：GP1，负责受体结合，GP2，介导病毒和宿主细胞膜之间的融合。GP 最初作为前体蛋白合成，被宿主蛋白酶（弗林蛋白酶、组织蛋白酶）切割成其功能性亚基，这一过程对于其介导病毒进入的作用至关重要。 GP 促进病毒附着在宿主细胞表面，随后发生构象变化，实现膜融合，从而使病毒进入宿主细胞（进入宿主内体尼曼-匹克 C1 (NPC1) 受体或通过直接膜结合；Vaknin 等人；ACS Infect. Dis. 2024, 10, 5, 1590–1601）。
Targeting the GP for drug development is advantageous due to its essential role in viral infection, its highly conserved structure among different Ebola virus strains, and the availability of specific binding cavities that can accommodate small-molecule inhibitors. Structural studies using techniques such as X-ray crystallography have identified these binding cavities and elucidated the GP's conformation in both its free and inhibited states. These insights enable the design of drugs that can specifically bind to and inhibit the GP by stabilizing it in its pre-fusion conformation or interfering with its cleavage, thereby preventing the necessary conformational changes for membrane fusion. We will employ high-resolution structures to conduct virtual screening experiments coupled to molecular dynamics simulations to ultimately identify potential GP inhibitors/modulators.
以 GP 为目标进行药物开发具有优势，因为它在病毒感染中起着重要作用，其在不同埃博拉病毒株之间的结构高度保守，并且具有可安置小分子抑制剂的特定结合腔。使用 X 射线晶体学等技术进行的结构研究已经确定了这些结合腔，并阐明了 GP 在游离状态和抑制状态下的构象。这些见解使得我们能设计出可特异性结合并抑制 GP 的药物，经由稳定 GP 的融合前构象或干扰其裂解，从而防止膜融合所需的构象变化。我们将采用高分辨率结构进行虚拟筛选实验，并结合分子动力学模拟，最终确定潜在的 GP 抑制剂/调节剂。
Promising compounds identified through these computational methods will hopefully undergo further validation using biochemical assays, pseudovirus entry assays, and structural analyses to confirm their inhibitory activity. Targeting the GP offers specificity, as it minimizes off-target effects on host cells and reduces the likelihood of resistance development. Moreover, due to the conserved nature of the GP, drugs targeting it could be effective against multiple Ebola virus strains and variants.
通过这些计算方法确定的有前景的化合物有望通过包含生化测定、假病毒进入测定和结构分析的进一步验证，以确认其抑制活性。以 GP 为靶点具有特异性，因为它可以最大限度地减少对宿主细胞的脱靶效应并降低产生抗药性的可能性。此外，由于 GP 的保守性，针对它的药物可能对多种埃博拉病毒株和变种有效。
We hope that our computations will contribute to the fight against Ebola!
我们希望我们的计算能够为抗击埃博拉病毒做出贡献！
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发表于 2024-2-14 14:13:28
