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

针对 HIV 上 CD4 结合位点的抑制剂的设计 - 1gp120

• 批准号: 10882232
• 负责人: Asim K Debnath
• 金额: $ 77.74万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10882232
• 关键词: 3-Dimensional; ADME Study; Agonist; Animals; Anti-HIV Agents; Area; Area Under Curve; Binding; Binding Sites; Biological Assay; Biological Availability; Calorimetry; Canis familiaris; Cells; Characteristics; Clinical Trials; Collaborations; Combined Modality Therapy; Complex; Cryoelectron Microscopy; Data; Development; Drug Combinations; Drug Targeting; Drug resistance; FDA approved; Fingerprint; Formulation; Generations; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV-1; Healthcare; In Vitro; Knowledge; Measures; Mediating; Modification; Oral; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Predisposition; Process; Proteins; RNA-Directed DNA Polymerase; Rattus; Reporting; Residual state; Resistance; Resistance profile; Resort; Reverse Transcriptase Inhibitors; Roentgen Rays; Route; SCID-hu Mice; Sprague-Dawley Rats; Structure; Surface Plasmon Resonance; Techniques; Thermodynamics; Time; Toxic effect; Viral; Virus; antagonist; clinical candidate; clinical subtypes; clinically relevant; design; drug action; drug development; effective therapy; experience; in vivo; inhibitor; lead optimization; male; meetings; molecular modeling; monomer; mouse model; mutant; next generation; non-nucleoside reverse transcriptase inhibitors; novel; novel therapeutics; pre-clinical; prevent; scaffold; small molecule; small molecule inhibitor; transmission process; vaccine development

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.

项目总结/摘要 HIV-1包膜糖蛋白（Env）gp 120在介导病毒进入宿主细胞中是关键的，并且是HIV-1包膜糖蛋白（Env）gp 120的启动子。 小分子药物和疫苗开发的目标。最近FDA批准了Env gp 120靶向 fostemsavir（Rukobia，ViiV Healthcare）验证了该蛋白质作为药物开发的靶点。然而，一个48- 一周的2b期临床试验报告了几种耐药突变体，降低了对fostemsavir的敏感性。 因此，迫切需要继续开发针对该靶标的新型药物，以有效地治疗癌症。 治疗我们的团队通过开发一个新的类，在满足这一迫切需求方面取得了重大进展。 靶向HIV-1 Env gp 120的Phe 43空腔的HIV-1进入抑制剂，与fostemsavir结合不同 绝佳的价钱此外，我们发现一些最有活性的gp 120拮抗剂对HIV-1也有活性 逆转录酶（RT）。然而，由于Phe 43腔非常窄并且不能容纳任何 对于更大的支架，我们假设增加RT抑制活性的修饰将导致RT抑制活性的丧失。 gp 120靶向进入抑制活性，反之亦然。基于这些考虑，我们决定将重点放在 优化本发明中的GP 120拮抗活性。我们获得了3D的广泛知识 通过解析GP 120-拮抗剂复合物的晶体结构来分析结构特征。我们还确定 抑制剂中的关键二维结构指纹，使其成为强gp 120拮抗剂，具有弱RT 抑制活性我们假设，这些新的发现，从结构分析将有助于剖析 这些抑制剂的机制，并铺平了道路，设计和优化先导化合物，以一类新的， 特异性靶向gp 120的Phe 43腔的进入抑制剂。我们的目标是开发2-3种HIV-1进入抑制剂， 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非常有效的， 临床相关的口服药物作为HIV-1进入抑制剂，有效对抗耐药突变体。在 此外，这些新的进入抑制剂有望丰富预防病毒进入的药物的可用性， 靶向gp 120，并作为联合治疗的新武器，特别是在治疗经验丰富的 患者，有助于制定长效药物。