Design of inhibitors targeted to the CD4 binding site on HIV - 1gp120

项目摘要/摘要 HIV-1包膜糖蛋白(Env)gp120在介导病毒进入宿主细胞中起关键作用，是一种重要的 小分子药物和疫苗开发的目标。FDA最近批准了Env gp120靶向 福斯特萨韦(Rukobia，ViiV Healthcare)验证了这种蛋白质作为药物开发目标的有效性。然而，48- 周2b期临床试验报告了几个耐药突变株，它们降低了对福司他韦的敏感性。 因此，迫切需要继续开发符合这一有效目标的新药 治疗。我们的团队在满足这一迫切需求方面取得了重大进展，开发了一个新的班级 靶向HIV-1 env gp120的Phe43空腔的HIV-1进入抑制剂，与foystsavir结合不同 地点。此外，我们发现一些最活跃的gp120拮抗剂也对hiv-1有活性。 逆转录酶(RT)。然而，由于Phe43腔非常窄，无法容纳任何 较大的支架，我们假设增加RT抑制活性的修改将导致 Gp120-靶向进入抑制活性，反之亦然。基于这些考虑，我们决定把重点放在 优化本方案中的gp120拮抗活性。我们获得了广泛的3D知识 从解析gp120-拮抗剂配合物的晶体结构看其结构特征。我们还确认了 抑制物中的关键2D结构指纹使其成为RT较弱的强gp120拮抗剂 抑制活性。我们假设，这些来自结构分析的新发现将有助于剖析 这些抑制剂的作用机理，并为设计和优化一类新型的先导化合物铺平了道路 靶向gp120的Phe43空洞的进入抑制剂。我们的目标是开发2-3种HIV-1进入抑制剂，如 潜在的临床前和临床候选人。这一协调良好的提案预计将产生高度有效的、 临床相关的口服药物，作为HIV-1进入的抑制剂，对耐药突变株有效。在……里面 此外，这些新型进入抑制剂有望通过以下方式丰富防止病毒进入的药物的可获得性 靶向gp120并作为联合治疗的新武器库，特别是在有治疗经验的患者中 患者，促进了长效药物的形成。

Project Summary/Abstract The HIV-1 envelope glycoprotein (Env) gp120 is critical in mediating viral entry into host cells and is a prime target for small-molecule drug and vaccine development. The recent FDA approval of the Env gp120–targeting fostemsavir (Rukobia, ViiV Healthcare) validates this protein as a target for drug development. However, a 48- week Phase 2b clinical trial reported several resistant mutants that reduced susceptibility to fostemsavir. Therefore, a critical need exists for the continued development of novel drugs against this target for effective therapies. Our group has made significant advances toward meeting this urgent need by developing a new class of HIV-1 entry inhibitors targeting the Phe43 cavity of HIV-1 Env gp120, distinct from the fostemsavir binding site. In addition, we discovered that some of the most active gp120 antagonists are also active against HIV-1 reverse transcriptase (RT). However, because the Phe43 cavity is very narrow and cannot accommodate any larger scaffolds, we hypothesize that modifications to increase the RT-inhibitory activity would result in a loss of gp120-targeted entry inhibitory activity and vice versa. Based on these considerations, we decided to focus on optimizing the gp120-antagonistic activity in the current proposal. We gained extensive knowledge of the 3D structural features from resolving the crystal structures of gp120–antagonist complexes. We also identified critical 2D structural fingerprints in the inhibitors that made them strong gp120 antagonists with weak RT inhibitory activity. We hypothesize that these novel findings from structural analyses will help to dissect the mechanism of these inhibitors and pave the way to design and optimize lead compounds to a novel class of entry inhibitors targeting specifically the Phe43 cavity of gp120. We aim to develop 2–3 HIV-1 entry inhibitors as potential preclinical and clinical candidates. This well-coordinated proposal is expected to generate highly potent, clinically relevant, orally available drugs as HIV-1 entry inhibitors and effective against resistant mutants. In addition, these novel entry inhibitors are expected to enrich the availability of drugs that prevent virus entry by targeting gp120 and serve as a new arsenal for combination therapies, especially in treatment-experienced patients, contributing to the formulation of long-acting drugs.