Making the HIV-1 gp41 pocket amenable to small-molecule drug discovery

这里提出的研究的长期目标是为发现一种 新型口服生物可利用的小分子药物，靶向HIV-1 gp 41口袋。因为 形成gp 41口袋的残基是非常高度保守的，预计这类药物 具有广谱活性，并且对“逃逸”突变的发展具有相对抗性。 这类新药可能特别适用于病毒已经发展的患者， 对一种或多种抗艾滋病毒药物产生耐药性。 早些时候，HIV-1的环状D肽抑制剂被分离出来，与gp 41口袋结合。然而，在这方面， 尽管在过去的15年里，学术界和工业界都做了大量的努力， 在临床开发中靶向gp 41口袋的小分子HIV-1抑制剂。 事实上，gp 41口袋已经被称为“不可药”的目标。 与不同蛋白质和肽配体结合的gp 41口袋的结构分析 表明GP 41袋是高度可延展的。我们假设， 鉴定与靶标相比具有延展性的靶标的良好小分子药物先导物 这是僵化的。我们还假设，建立有用的结构活性关系（SAR） 对于药物先导化合物的化学类似物，与具有延展性的靶相比， 刚性目标 我们提出了几种方法来“硬化”的gp 41口袋。当我们创造了一个僵化的 gp 41口袋，我们将测试基于上述两个假设的预测。首先，我们预测， 具有刚性gp 41口袋的高通量筛选（HTPS）将产生比 有延展性的口袋其次，我们预测，我们将能够更容易地建立有用的SAR 刚性的GP 41口袋比韧性的口袋好。 以这种方式鉴定的配体预期对天然的（即， 延展性）GP 41囊袋，与硬化囊袋相比。本质上，结合亲和力将 通过将天然GP 41口袋锁定成固定构象所需的能量而减少。的 然而，关键的一点是，通过提高HTPS工作的成功率和获得有用的SAR， (with刚性gp 41口袋），将有可能优化 小分子药物的作用，因此锁定天然gp 41的能量成本 口袋变成一个固定的构象可以很容易地支付。

The long-term objective of the research proposed here is to set the stage for the discovery of a new class of orally bioavailable, small-molecule drugs that target the HIV-1 gp41 pocket. Because the residues that form the gp41 pocket are extremely highly conserved, such drugs are predicted to have broad-spectrum activity and be relatively resistant to the development of “escape” mutations. This new class of drugs could be particularly useful in patients with viruses that have developed resistance to one or more classes of anti-HIV drugs. Earlier, cyclic D-peptides inhibitors of HIV-1 were isolated that bind to the gp41 pocket. However, in spite of numerous efforts in academia and industry over the past ~15 years, there are no small-molecule HIV-1 inhibitors targeting the gp41 pocket in clinical development. Indeed, the gp41 pocket has been referred to as an “undruggable” target. Analysis of the structures of the gp41 pocket bound to different protein and peptide ligands indicate that the gp41 pocket is highly malleable. We hypothesize that it is more difficult to identify good small-molecule drug leads for a target that is malleable, as compared to a target that is rigid. We also hypothesize that establishing useful structure-activity relationships (SARs) for chemical analogs of drug leads will be more difficult with a malleable target, as compared to a rigid target. We propose several approaches to “rigidify” the gp41 pocket. After we have created a rigidified gp41 pocket(s), we will test predictions based on the two hypotheses above. First, we predict that a high-throughput screen (HTPS) with a rigid gp41 pocket will yield better hit rates than the malleable pocket. Second, we predict that we will be able to more readily establish useful SARs with a rigid gp41 pocket than with a malleable one. Ligands identified in this manner are expected to have weaker affinity for the natural (i.e., malleable) gp41 pocket, as compared to the rigidified pocket. In essence, the binding affinity will be decreased by the energy necessary to lock the natural gp41 pocket into a fixed conformation. The key point, however, is that by increasing the success of HTPS efforts and obtaining useful SARs (with the rigid gp41 pocket), it will be possible to optimize binding affinity of the small-molecule hits by medicinal chemistry, so that the energetic cost of locking the natural gp41 pocket into a fixed conformation can be readily paid.