Optimization of a Piperidine CD4-Mimetic Scaffold Sensitizing HIV-1 Infected Cells to Antibody-Dependent Cellular Cytotoxicity.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-10-28 eCollection Date: 2024-11-14 DOI:10.1021/acsmedchemlett.4c00403

Daniel Lee, Ling Niu, Shilei Ding, Huile Zhu, William D Tolbert, Halima Medjahed, Guillaume Beaudoin-Bussières, Cameron Abrams, Andrés Finzi, Marzena Pazgier, Amos B Smith

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Abstract

The ability of the HIV-1 accessory proteins Nef and Vpu to decrease CD4 protects infected cells from antibody-dependent cellular cytotoxicity (ADCC) by limiting the exposure of vulnerable epitopes to envelope glycoprotein (Env). Small-molecule CD4 mimetics (CD4mcs) based on piperidine scaffolds represent a new family of agents capable of sensitizing HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes on Env that are recognized by non-neutralizing antibodies which are abundant in plasma of people living with HIV. Here, we employed the combined methods of parallel synthesis, structure-based design, and optimization to generate a new line of piperidine-based CD4mcs, which sensitize HIV-1 infected cells to ADCC activity. The X-ray crystallographic study of the CD4mcs within the gp120 residues suggests that the positioning of the CD4mc inside the Phe43 cavity and synergistic contact of the CD4mc with the β_20-21 loop and the α₁-helix lead to improved antiviral activity.

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优化哌啶CD4模拟支架，使HIV-1感染细胞对抗体依赖性细胞毒性敏感

HIV-1 辅助蛋白 Nef 和 Vpu 能够减少 CD4，通过限制易受感染表位暴露于包膜糖蛋白（Env），保护感染细胞免受抗体依赖性细胞毒性（ADCC）的侵害。基于哌啶支架的小分子 CD4 拟效物（CD4mcs）代表了一个新的制剂家族，它们通过暴露 Env 上 CD4 诱导的（CD4i）表位，使 HIV-1 感染细胞对 ADCC 敏感，而这些表位会被 HIV 感染者血浆中大量的非中和抗体识别。在这里，我们采用了平行合成、基于结构的设计和优化等综合方法，生成了一系列新的基于哌啶的 CD4mcs，它们能使受 HIV-1 感染的细胞具有 ADCC 活性。对gp120残基内CD4mcs的X射线晶体学研究表明，CD4mc在Phe43空腔内的定位以及CD4mc与β20-21环和α1-螺旋的协同接触提高了抗病毒活性。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.

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