Optimization of Small Molecules That Sensitize HIV-1 Infected Cells to Antibody-Dependent Cellular Cytotoxicity.,ACS Medicinal Chemistry Letters

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Optimization of Small Molecules That Sensitize HIV-1 Infected Cells to Antibody-Dependent Cellular Cytotoxicity.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2019-11-15 , DOI: 10.1021/acsmedchemlett.9b00445
Melissa C Grenier ₁ , Shilei Ding _{2,

3} , Dani Vézina _{2,

3} , Jean-Philippe Chapleau _{2,

3} , William D Tolbert ₄ , Rebekah Sherburn ₄ , Arne Schön ₅ , Sambasivarao Somisetti _{1,

6} , Cameron F Abrams ₆ , Marzena Pazgier ₄ , Andrés Finzi _{2,

3} , Amos B Smith ₁

Affiliation

With approximately 37 million people living with HIV worldwide and an estimated 2 million new infections reported each year, the need to derive novel strategies aimed at eradicating HIV-1 infection remains a critical worldwide challenge. One potential strategy would involve eliminating infected cells via antibody-dependent cellular cytotoxicity (ADCC). HIV-1 has evolved sophisticated mechanisms to conceal epitopes located in its envelope glycoprotein (Env) that are recognized by ADCC-mediating antibodies present in sera from HIV-1 infected individuals. Our aim is to circumvent this evasion via the development of small molecules that expose relevant anti-Env epitopes and sensitize HIV-1 infected cells to ADCC. Rapid elaboration of an initial screening hit using parallel synthesis and structure-based optimization has led to the development of potent small molecules that elicit this humoral response. Efforts to increase the ADCC activity of this class of small molecules with the aim of increasing their therapeutic potential was based on our recent cocrystal structures with gp120 core.

中文翻译：

优化小分子，使 HIV-1 感染细胞对抗体依赖性细胞毒性敏感。

全球约有 3700 万艾滋病毒感染者，每年报告的新感染人数估计为 200 万，因此需要制定旨在根除 HIV-1 感染的新策略仍然是全球面临的一项严峻挑战。一种潜在的策略是通过抗体依赖性细胞毒性（ADCC）消除受感染的细胞。 HIV-1 已进化出复杂的机制来隐藏位于其包膜糖蛋白 (Env) 中的表位，这些表位可被 HIV-1 感染者血清中存在的 ADCC 介导抗体识别。我们的目标是通过开发小分子来规避这种逃避，这些小分子暴露相关的抗 Env 表位并使 HIV-1 感染细胞对 ADCC 敏感。使用平行合成和基于结构的优化快速阐述初步筛选的结果，导致了引发这种体液反应的有效小分子的开发。提高此类小分子的 ADCC 活性以提高其治疗潜力的努力是基于我们最近以 gp120 为核心的共晶结构。

更新日期：2019-11-17

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