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：

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小分子的优化，使HIV-1感染的细胞对抗体依赖性细胞的细胞毒性敏感。

全世界大约有3700万人感染艾滋病毒，每年据报告有200万新感染，因此，有必要制定出旨在消除HIV-1感染的新策略，这仍然是世界范围内的一项严峻挑战。一种潜在的策略涉及通过抗体依赖性细胞毒性（ADCC）消除感染的细胞。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避免这种逃避，这些小分子可以暴露相关的抗Env表位并使HIV-1感染的细胞对ADCC敏感。使用平行合成和基于结构的优化对初始筛选命中物的快速阐述导致了引发这种体液反应的强效小分子的发展。为了提高这类小分子的ADCC活性，以提高其治疗潜力为目标，这是基于我们最近与gp120核心形成的共晶结构。